Am J Physiol Heart Circ Physiol 293: H2667–H2679, 2007.
First published August 10, 2007; doi:10.1152/ajpheart.00704.2007.
History Article
The history of the capillary wall: doctors, discoveries, and debates
Charlotte Hwa and William C. Aird
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
Submitted 17 June 2007; accepted in final form 9 August 2007
endothelium; microvessels
ANCIENT GREEK PHYSICIANS,
having limited knowledge of the
vasculature, believed that arteries and veins were separated by
a fluid called “parenchyma” that effused from the blood (Fig.
1A). After William Harvey (1578 –1657) published his discovery of the circulation of the blood in 1628, scientists further
investigated the mechanisms by which blood traversed from
arteries to veins. Harvey himself did not know of the existence
of the capillaries. While some texts state that he “surmised” or
“postulated” the existence of these minute vessels, Harvey
preferred the notion that blood simply “percolated through the
tissues somewhat as water permeated the earth” (quoted in Ref.
30) (Fig. 1B). Indeed, many of his contemporaries refused to
believe that the arteries and veins were directly connected; like
Harvey, they thought that blood leaked out of one vessel and
filtered through the organ tissue to the other vessel. Still others
argued that a direct vascular connection from arteries to veins
had to exist but acknowledged that this connection remained
unproven.
At first glance, Marcello Malpighi’s (1628 –1694) discovery
of the capillaries in 1661 should have settled the question.
Indeed, most modern accounts of the history of the capillary
begin with a passing reference to Malpighi’s observations and
then jump in time to the work of the great physiologists of the
late nineteenth century and early twentieth century, including
Ernest Starling, August Krogh, and Eugene Landis. In fact,
Malpighi’s discovery was followed by 200 years of uncertainty
as to the true nature of capillary structure (Fig. 2 shows time
line). In the present review, we explore the basis for this
uncertainty.
Address for reprint requests and other correspondence: W. C. Aird, Molecular Medicine, Beth Israel Deaconess Medical Center, RW-663, 330 Brookline
Ave., Boston, MA 02215 (e-mail: [email protected]).
http://www.ajpheart.org
Why revisit the events that led to the discovery of what
today seems so obvious, that capillaries possess a wall? There
are, of course, many advances in the history of the microcirculation that might seem to bear greater immediate relevance
(and perhaps interest) to the modern-day biomedical practitioner, including the seminal contributions of the aforementioned
late nineteenth-/early twentieth-century physiologists, the use
of electron microscopy in the 1950s and 1960s to gain insights
into the ultrastructure of the endothelium, the first successful
culture of primary endothelial cells in the early 1970s, and the
discovery of nitric oxide. There are two reasons for turning our
attention to the capillary wall. First, in contrast to the more
familiar milestones of the late nineteenth century and early to
mid-twentieth century, little has been written about the history
of the capillaries in the preceding era. More importantly, a
consideration of the process by which investigators arrived at
the consensus that capillaries have walls yields insights into
how science progresses.
Proving the Existence of Capillaries
In 1640, William Harvey had boiled organs, including the
liver, spleen, lungs, and kidney, and then dissected the tissue
until he could see “capillamenta,” or capillary threads. The
minute vessels he saw were actually small arteries or veins, as
opposed to true capillaries, which are invisible to the naked
eye. Harvey posited that
. . .in the members and in the extremities the blood passes
from the arteries into the veins either directly by means of an
anastomosis or indirectly through the porosities of the flesh, or
by both these means. (Ref. 16, p. 88)
In their paper on “Harvey and the problem of the ‘capillaries,’” Elkana and Goodfield (14) explain the rationale for
Harvey’s hypothesis that “blood might pour into the flesh as
into a sponge”:
A hypothesis of this form is a very rational one, both for
reasons of structure and for reasons of function. For, if one
postulated a system of blood circulating through a series of
completely closed vessels—which is what a capillary connection entails—then one must face the question: how do the heat
and the nutritive substances carried in the blood reach the flesh
where they are required? Harvey believed that blood had both
these functions. (Though during Harvey’s time heat was treated
as an incorporeal substance, which might perhaps be expected
to go through the walls of the blood vessels easily, food
substances certainly were not regarded as incorporeal.) (Ref.
14, p. 67)
Just four years after Harvey’s death, Malpighi, a professor of
medicine at the University of Bologna, discovered the capillaries while studying the lungs of frogs with a compound
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Hwa C, Aird WC. The history of the capillary wall: doctors, discoveries, and debates. Am J Physiol Heart Circ Physiol 293: H2667–H2679,
2007. First published August 10, 2007; doi:10.1152/ajpheart.00704.2007.—
In 1628, William Harvey provided definitive evidence that blood
circulates. The notion that blood travels around the body in a circle
raised the important question of how nutrients pass between blood and
underlying tissue. Perhaps, Harvey posited, arterial blood pours into
the flesh as into a sponge, only then to find its way into the veins. Far
from solving this problem, Marcello Malpighi’s discovery of the
capillaries in 1661 only added to the dilemma: surely, some argued,
these entities are little more than channels drilled into tissues around
them. As we discuss in this review, it would take over 200 years to
arrive at a consensus on the basic structure and function of the
capillary wall. A consideration of the history of this period provides
interesting insights into not only the central importance of the capillary as a focus of investigation, but also the enormous challenges
associated with studying these elusive structures.
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HISTORY OF THE CAPILLARY WALL
double-convex lens microscope (Fig. 3A). In 1661, Malpighi
detailed his observations in a letter written to his advisor,
Giovanni Borelli, a mathematics professor at the University of
Pisa:
From this I could clearly see that the blood is divided and
flows through tortuous vessels and that it is not poured out into
spaces, but is always driven through tubules and distributed by
the manifold bendings of the vessels [Malpighi commented on
the presence of particles in the blood, but did not appreciate the
existence of red blood corpuscles, which had been described by
Jan Swammerdam in 1658]. (Ref. 1, vol. 1, p. 194)1
Malpighi had a contemporary in the Netherlands, Antoni van
Leeuwenhoek (1632–1723), who devoted his time and skill to
microscopy. Leeuwenhoek’s microscopes were simple single
lenses that he ground himself—they were composed only of a
piece of metal that held the magnifying glass and screws that
adjusted the position and focus of the object. He used his
microscopes to study the vasculature of tadpoles, fish, rooster
combs, rabbit ears, and bat wings (Fig. 3B shows the tail of an
eel). Leeuwenhoek did not see capillaries as structurally distinct structures, but rather as functional entities defined by the
direction of blood flow, relative to the heart:
Hereby it plainly appeared to me, that the blood-vessels I
now saw in this animal, and which bear the names of arteries
and veins, are, in fact, one and the same, that is to say, that they
1
According to L. J. Rather, Malpighi: “. . .did not see the circulation as a
whole in action, as one might stand back and see, for example, the pumpdriven circulation of a coloured fluid in a system of pipes all accessible to
simultaneous observation. What he saw was as follows: 1) movement of blood
in one direction in progressively more finely branching arteries (in the
mesentery of living animals), 2) movement in the opposite direction of
presumably the same stream in the veins; 3) a gap between, in which he was
unable to make out what was taking place, and finally 4) in the dried lungs of
frogs the newly discovered minute blood-vessels. He then inferred that the
same vessels were present throughout the bodies of animals” (Ref. 30, p. 56).
AJP-Heart Circ Physiol • VOL
are properly termed arteries as long as they convey the blood to
the farthest extremities of its vessels, and veins when they bring
it back towards the heart. (Ref. 19, p. 92)2
Anatomic injections were used extensively in the seventeenth century to demonstrate the internal structure of the body
and particularly the vasculature, including the capillaries (35).
For example, Malpighi injected vessels with ink, urine colored
with ink, and black-colored liquid mixed with wine. He demonstrated that such medium injected into the renal artery (but
not the renal vein) reaches the smallest branches of the artery
and the internal glands (Malpighi bodies, or glomeruli) so as to
produce the appearance of “a beautiful tree loaded with apples”
(Fig. 4A). Employing wax injections, the Dutch investigator
Frederik Ruysch (1638 –1731) demonstrated the presence of
blood vessels in virtually all tissues and organs of the body,
including the vasa vasorum and the bronchial capillaries. In
1696, Ruysch suggested that “tissues were only vascular networks variously arranged” (quoted in Ref. 35, p. 305). According to this view of “vascular autocracy,” in which “the whole
body is almost nothing more than a prodigious assemblage of
lymphatic and blood vessels” (quoted in Ref. 35, p. 321),
differences in function between tissues were attributed to
variations in the arrangement of the vascular networks.
Despite the growing body of evidence that capillaries existed, remarkably little attention was devoted to these minute
2
In a letter from Delft, Leeuwenhoek extrapolated his observations of
capillaries in tadpoles to the circulation of humans: “If we now plainly
perceive, that the passage of the blood from the arteries into the veins of the
tadpole, is not performed in any other than those vessels, which are so minute
as only to admit the passage of a single globule at a time, we may conclude that
the same is performed in like manner in our own bodies, and in those of other
animals” (Leeuwenhoek A von. The Select Works of Antony van Leeuwenhoek:
Containing His Microscopical Discoveries in Many of the Works of Nature.
New York: Arno, 1977).
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Fig. 1. Historical models of circulation.
A: Galen viewed the arteries and veins as
distinct conduit systems, delivering air and
blood, respectively, to the organs (small
amounts of blood passed from the right to the
left side of the heart through invisible pores
or holes in the interventricular septum).
B: Harvey demonstrated that blood circulates
(note the change in direction of arrows).
Without a microscope, Harvey could not see
the connections between the arteries and
veins. C: Malpighi used a microscope with a
double-convex lens to observe the capillaries. His findings, which predated the discovery of cells, did not distinguish between wallless channels and walled tubes. D: Schwann,
the founder of the cell theory, noted that the
capillaries possessed an inner cell lining, a
finding that was ultimately confirmed by silver
nitrate staining.
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HISTORY OF THE CAPILLARY WALL
vessels in the 1700s. Eighteenth-century investigators viewed
the microscope as unreliable and untrustworthy. The early
lenses were flawed, creating artifacts and optical illusions.
Moreover, a perceptual consensus was lacking: each observer
saw what he wanted through the microscope. It was not until
compound achromatic lenses were introduced in the 1830s that
microscopy became widely adopted as a research tool (Ref. 10,
p. 58).
Defining the Capillary
By the nineteenth century, it was generally agreed that the
arteries and veins were connected by capillaries. However,
there was no immediate consensus as to what defined a capillary. In Robley Dunglison’s 1856 publication Human Physiology (11) the capillaries were synonymous with the term “intermediate vessels,” described as vessels of “extreme minuteness. . . by some considered to be formed by the terminations
of arteries and the commencement of veins; by others to be a
distinct set of vessels” (Ref. 11, p. 343).
Marshall Hall (1790 –1857) from London was among those
who believed that capillaries were independent entities (Fig. 5A).
He was one of the first to distinguish between the minutest
arteries/veins and the true capillaries on anatomic grounds. In
1831, he wrote:
The last branches of the arterial system and the first roots of
the venous, may be denominated minute; but the term capillary
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must be reserved and appropriated to designate vessels of a
distinct character and order, and of an intermediate station,
carrying red globules, and perfectly visible by means of the
microscope. (Ref. 15, p. 18)
Hall was also among the first to emphasize the functional
significance of capillaries:
At this point there is an obvious and remarkable change in
the appearance of the circulation: the course of the blood
becomes of only half its former velocity, and the globules,
consequently, instead of moving too rapidly to be seen, become
distinctly visible. If the vessel be traced, it is next observed, not
to subdivide, but to unite with other branches, and to pass into
that distinct system and net-work of vessels to which I would
restrict and appropriate the term capillary. The object of this
peculiar distinction and character of the capillary vessels is
very obvious: a more diffused and slower circulation is required for administering to the nutrient vessels or functions,
than that of the arteries. . . the capillaries. . . anastomose continually, so as to form a complete net-work of vessels of
uniform character and dimensions. [Emphasis added] (Ref. 15,
p. 29 and 31)
In 1835, Allen Thomson [writing in Todd’s Cyclopaedia of
Anatomy and Physiology (38)] countered that it was best to
include all the minute vessels as capillaries, because
. . .the communicating vessels are not every where of the
same kind and that from the use already made of the term by
physiological writers its meaning will thus be more easily
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Fig. 2. Major milestones in the discovery of
the circulation and the capillaries. Note that
while Bichat worked during the microscopy
era, he did not utilize this instrument. Portraits courtesy of the National Library of
Medicine.
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HISTORY OF THE CAPILLARY WALL
understood. The vessels which lead from arteries to veins are of
very various sizes, some admitting only one globule at once,
others being so large as to allow the passage of three, four, or
even a greater number of red globules together. (Ref. 38, p.
669)
The following description by Thomson of the capillaries was
reminiscent of Leeuwenhoek’s functional definition:
The small arteries pass into veins quite in a gradual manner,
the ramifications of each class of vessel becoming more and
more minute until they meet, the two kinds of vessel presenting
no difference of character other than the change of direction
assumed by the moving blood, which enables us to say with
certainty where the artery terminates, and at what point the vein
begins, and affording thus no reason to consider the continuous
tube by which they join as different in structure from either the
minute artery or vein. (Ref. 38, p. 669)3
. . .the mode of ramification in the small intestines resembles
a tree which is not in leaf, in the placenta a tuft, in the spleen
an asperge or sprinkling brush, in the muscles a branch of
twigs, and in the choroid plexus of the brain a lock of hair, in
the Schneiderian membrane a trellis-work. These meshes are
smallest in the lung, liver and kidneys; largest and most sparse
in ligaments and tendons. (Ref. 24, p. 219)4
In his book Elements of Physiology (24), Johannes Müller
(1801–1858), a renowned professor of anatomy and physiology at the University of Berlin, defined capillaries as “a
network of microscopic vessels, in the meshes of which the
proper substance of tissue lies. . . the reticulated vessels connecting the arteries and veins” (Ref. 24, p. 217–218). Although
Müller could not precisely define “the point at which arteries
terminate and the minute veins commence,” he noted that
3
Previous investigators had argued that in addition to capillaries, arterioles
also gave rise to open-ended vessels “of a particular order, whose office it is
to pour out, by their free extremity, the materials of nutrition” (Ref. 11, p. 349).
These were commonly termed “exhalants,” “exhalant vessels,” or “nutrient
vessels.” Thomson argued that “arteries terminate always by direct continuity
of tube in the veins, and that no other visible passages are connected with the
minute vessels. . . we must suppose that the various interchanges of materials
occurring between the blood and the organized textures. . . as in nutrition,
secretion, respiration, transpiration etc. must take place by some process of
organic transduction through invisible apertures of the minute vessels” (Ref.
38, p. 671).
AJP-Heart Circ Physiol • VOL
within a given vascular bed, the capillaries had a uniform
diameter (“the small vessels which compose [the intermediate
network] maintain the same diameter throughout”; Ref. 24, p.
218). According to Müller, capillaries differed only in “size of
the meshes” (i.e., density) and their configuration (see Fig. 4).
He employed colorful metaphors to describe organ-specific
configurations of the capillary networks:
The lack of uniformity in the definition of a capillary
persisted past the mid-nineteenth century and was brought to
attention by H. N. Eastman of Geneva Medical College in a
paper published in New York in 1867 (13). He criticized
physiologists for “confound[ing] the terms ‘capillaries,’ ‘capillary arteries,’ ‘capillary veins,’ and ‘minute vessels’”. Eastman suggested using terms such as “terminal or distal arteries,
or arterioles, and radical veins, venules or veinlets” in place of
“capillaries”: “Not only the student is confused, and fails to
acquire any precise idea of the author’s meaning, but the more
advanced scholar is led to doubt whether the writer really
recognizes any distinctive difference in the terms he employs”
4
Like Thomson, Müller denied the existence of minute arteries with open
mouths: “Microscopic observations and minute injections have shown that the
capillary vessels are merely fine tubes which form the medium of transition
from arteries to veins, and that no other kind of vessel arises from them; that
the minute arteries have no other mode of termination than the communication
with the veins by means of the capillaries; in a word, that there are no vessels
terminating by open extremities” (Ref. 24, p. 221).
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Fig. 3. Capillaries as viewed by Malpighi
and Leeuwenhoek in the 1600s. A, top: frog
lungs with attached trachea. Bottom: enlarged view of an alveolus from the lung of
a frog, as observed by intravital microscopy.
B: Leeuwenhoek’s description of blood vessels in the tail of an eel in 1686 [redrawn by
Adams in Adams G. Micrographia Illustrata
(1st ed.). London: printed for the author,
1747 (Pre-1801 Imprint Collection. Library
of Congress)].
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HISTORY OF THE CAPILLARY WALL
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(Ref. 13, p. 75). He theorized along the lines of Hall and
Müller: the capillaries are distinct in structure and function
from both arteries and veins.
From Tissue Theory to Cell Theory
Prior to the 1800s human physiology and pathology was
solidly rooted in Hippocratic principles. Disease arose from an
imbalance of the four humors, and therapy (e.g., bloodletting,
laxatives, and emetics) was directed toward reestablishing
equilibrium. In the early 1800s, physicians began to see patients not as sick individuals but as diseases. Advances in
anatomic pathology (particularly in France) served to localize
disease to discrete regions of the body. Marie Francois Xavier
Bichat (1771–1802), who is considered the “father of descriptive anatomy,” emphasized the importance of tissues. In his
book, Treatise on Membranes, Bichat wrote that organs “are
themselves composed of several tissues of very different nature, which truly form the elements of these organs” (quoted in
Ref. 34, p. 59).5
5
Bichat, who relied on gross observation, described the macroscopic appearance of the inner layer of the blood vessels: “The inside of the internal
membrane of the vascular system is incessantly moistened with a mucous fluid,
the sources of which are still unknown, and which guards it from the
impression of the blood, with which it is in contact. . . what is the nature of it?
We have no datum respecting it; less extensible than any one of the membranes
already described, it breaks by the least effort, as we see in aneurysm and in
ligatures on the arteries, strongly tied. Its mode of sensibility is hitherto little
known” (Bichat X. A Treatise on the Membranes in General, and on Different
Membranes in Particular. Boston, MA: Cummings and Hilliard, 1813, p. 141).
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The focus on gross pathology in early to mid-eighteenthcentury France contrasted with the growing use of light microscopy in Germany and Britain. The microscope provided
investigators with the means to resolve organs and tissues into
finer units of structure. Until that time, tissues were believed to
consist of fibers. Early microscopy did little to change that
view. As Everard Home reported in 1820, the tissue fibers
appeared to be composed of a string of beads, or “minute
globules connected together by a gelatinous substance” (Ref.
18, p. 25). During the second quarter of the nineteenth century,
improvements in the light microscope led to the gradual recognition of the cell as the primary structural unit of tissue,
culminating in Theodor Schwann’s (1810 –1882) founding of
the cell theory in 1839.6 He wrote that all organic tissues have
. . .one common principle of development as their basis, viz.
the formation of cells; that is to say, nature never unites
molecules immediately into a fibre, a tube, and so forth, but she
always in the first instance forms a round cell, or changes, when
it is requisite, cells into the various primary tissues. (quoted in
Ref. 40, p. 222)
According to early iterations of the cell theory, an amorphous substance (termed the blastema or cytoblastema) gave
rise to cells in the tissues. In 1855, Rudolph Virchow (1821–
1902), a student of Müller’s, published a paper entitled Cellu6
Robert Hooke (1635–1703), who is often credited with first coining the
word “cell” in biology, used the term “cell” to describe the honeycomb cavities
in thin sections of cork. In other words, his notion of a cell was a pore or an
opening. Hooke subscribed to the belief that tissues were formed from fibers.
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Fig. 4. Organ-specific configuration of capillary networks as depicted in the 1800s. Early injection studies of the capillaries revealed remarkable heterogeneity
in architecture. A: capillaries of the Malpighi bodies (glomeruli). B: capillaries of muscle, forming long meshes. C: capillaries of smooth mucous membrane,
forming large polygonal meshes. D: capillaries of the papillae of the skin of the tip of the finger, forming single loops. E: capillaries of the villi of the mucous
membrane of the small intestine, forming small meshes. F: capillaries of the terminal extremity of a duct of the parotid gland, forming very close meshes.
G: capillaries of injected muscle of cat. A: from Bowman W. On the structure and use of the Malpighian bodies of the kidney, with observations on the circulation
through that gland. Philos Trans R Soc 132: 57– 80, 1842. B–F: from Marshall J. Outlines of Physiology, Human and Comparative. Philadelphia, PA: Henry C.
Lea, 1868. G: from Ref. 37.
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lar Pathology in which he refuted the blastema theory (to
which he had originally subscribed) and instead famously
advocated cytogenesis (“all cells are derived from other cells”).
Although this essay represented a synthesis of old ideas espoused by some of Virchow’s colleagues, he proposed the
novel and important hypothesis that cells were autonomous or
“sovereign.” Moreover, the body consisted of “anatomical
units” containing cells, blood vessels, and nerves. Finally,
Virchow introduced the paradigm of cellular pathology:
All diseases are in the last analysis reducible to disturbances,
either active or passive, of large or small groups of living units
whose functional capacity is altered in accordance with the
state of their molecular composition and is thus dependent on
physical and chemical changes of their contents. . . . All pathological formations are either degenerations, transformations, or
repetitions of typical physiological structures. (Quoted in Ref.
30, p. 132)
As we discuss below, these changing perceptions of tissue
organization in health and disease were integral to the recognition of the capillary wall.
The Capillary Wall
Progress in delineating the true nature of the capillary wall
in the 1800s proceeded along two distinct, though overlapping
lines of investigation: anatomy/histology and physiology/
pathophysiology.
The anatomists and histologists. It was typical for authors of
medical texts to first acknowledge Malpighi and Leeuwenhoek
for discovering the capillaries and to then voice their own
opinions on whether or not capillaries actually had walls.
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A sampling of major publications in the first half of the
nineteenth century suggests that many investigators believed
that capillaries were wall-less canals or channels in the tissues,
paths carved out by dying cells. In describing these structures,
authors often appealed to metaphors. For example, in 1835,
J. W. Earle (12) described capillaries as membraneless channels, “like brooks in the moist earth,” and referred to the
observations of a Dr. Wedemeyer from Hanover:
At length [arteries] gradually terminate altogether in membraneless canals formed in the substance of the tissues. The
blood in the finest capillaries no longer flows within actual
vessels whose parietes are formed by a membranous substance,
distinguished from the adjoining cellular tissue by its texture
and compactness, but in simple furrows, or canals, whose walls
are formed by the surrounding cellular tissue. (Ref. 12, p. 8)
In a publication covering his work from 1818 to 1820, Ignaz
Döllinger (1770 –1841) stated that the blood was walled in by
mucus, the fundamental substance of tissues, “just as a stream
receives a bed of earth and does not have to be enclosed in a
tube” (quoted in Ref. 30, p. 60). In 1831, Hall wrote that
capillaries were “mere canals” as opposed to “real tubes” (Ref.
15, p. 47). He did not elaborate on his “many reasons” for his
thinking, but did point out that more research was needed in
this area. In 1833, Müller claimed in the first edition of
Elements of Physiology that “one must think of the capillary
vascular walls as mere thickened margins of the substance,
not however as very self-sufficient membranes” (quoted in Ref.
30, p. 63).
The claim that capillaries lacked walls was not idle theory,
but rather was based on inductive reasoning. Earle pointed to
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Fig. 5. Hall and Waller’s observations of frog capillaries in the 1830s and 1840s. A: the microcirculation in the web of the frog as depicted by Marshall Hall
(15). The large image “represents the course of the minute arteries and veins in the web of the frog.” The rectangular image “represents the minuter [sic] branches
and subdivisions of the arteries of the web; their final divisions into capillaries in which the globules become distinct, and the union of these so as to form the
roots of veins.” The circular image shows “two layers of capillaries.” Note that Hall believed that these capillaries were “mere canals.” Arrow added for effect.
B: after unsuccessful attempts to observe the circulation in the prepuce of a human subject, Waller settled on the frog tongue as a window for observing the
capillaries (41). C: leukocyte adhesion and transmigration as observed by Waller in the frog tongue. The legend reads as follows (referring first to the left, then
the right image): “Blood-discs and corpuscles with a capillary; some of the latter near the sides were inspected for a long time, and remained fixed in the same
situation, while a rapid current was traversing the vessel. . . . Extra fibrination of a vessel. The smaller globules are probably globular particles of fibrine, the
others are extravasated corpuscles” (Waller A. Microscopic observations on the perforation of the capillaries by the corpuscles of the blood, and on the origin
of mucus and pus-globules. Lond Edinb Dublin Philos Mag 397– 405, p. 405, 1846).
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The parietes of capillary vessels can scarcely be distinguished from the substance of other organs, and we know not,
therefore, any thing certain respecting their texture: we can
only suppose that they are formed by the continuation of the
internal membrane of the arteries and veins. (Ref. 2, p. 42)
In 1835, Allen Thomson noted that injected capillary vessels
in the ears of birds and reptiles could be separated from the
neighboring tissue and argued that the “active properties of the
capillary vessels [might] belong to parietes as in the larger
vessels” (quoted in Ref. 38, p. 670).
In 1839, Theodor Schwann was the first to describe what
would later be named the endothelium:
The capillary vessels, in the tail both of the fully developed
and young tadpoles, are seen to be surrounded by a thin, but
distinctly perceptible membrane, which does not exhibit any
fibrous arrangement. The variety in the thickness of this membrane in different instances sufficiently explains why we cannot
distinguish it in all capillary vessels, just as we cannot detect
the cell-membrane even in the blood-corpuscles, although there
can be no doubt of its existence. (Ref. 33, p. 154)
Schwann further details this thin membrane by stating that
“very distinct cell-nuclei occur at different spots upon the walls
of the capillaries. . . they are either the nuclei of the primary
cells of the capillaries, or nuclei of epithelial cells, which invest
the capillary vessels. . . these nuclei frequently seemed to lie
free upon the internal wall of the vessel. . . that these are the
nuclei of the primary cells of the capillaries is, therefore, most
probable” (Ref. 33, p. 155) (Figs. 1D and 6).
Müller, who in the first edition of Elements of Physiology
had expressed doubts about the existence of the capillary wall,
was evidently convinced by Schwann’s findings. In a later
edition of his book (translated from German in 1843), he
commented:
[Theodor] Schwann has recently ascertained [1839], by
means of the microscope, that the capillaries have not merely
membranous parietes, but a coat in which circular fibres arranged as in the arteries can be distinguished. . . even where no
transverse fibres are visible, the capillaries seem to have delicate membranous parietes, in the substance of which oval
bodies resembling nuclei of epithelium scales appear at intervals. (Ref. 24, p. 225)
Müller now cites additional evidence for the existence of a
true wall: 1) fluids injected into arteries passed into veins
AJP-Heart Circ Physiol • VOL
without extravasation; 2) blood currents were able to cross
above and below each other without uniting; and 3) the solid
matter in between the currents was not involved in the bloodstream, despite the high number of currents and the smallness
of the sections of solid matter between them (Ref. 24, p. 224).
In 1842, the British surgeon and pathologist James Paget
(1814 –1899) likewise stated that capillaries were not “mere
channels drilled into tissues around them” but rather had
distinct walls (Ref. 27, p. 287). The capillaries were “composed of a completely structureless membrane, in which no
fibres or striae are ever discernible, but which bears minute
oval corpuscles, the persistent nuclei of the cells from which
the capillaries are formed. . . this may be named the primary
vascular membrane” (Ref. 27, p. 287). A year later, William
Carpenter at the Bristol Medical School added in his book
Principles of Human Physiology that “there can be no doubt
that [capillaries] are produced. . . by the formation of communications among certain cells, whose cavities become connected with each other, so as to constitute a plexus of tubes, of
which the original cell-walls become the parietes” (Ref. 5, p.
349). Finally, in the fourth (1844) edition of his book, Müller
definitively stated that “capillary vessels are not mere channels
in the substance, they also possess membranous walls” composed of cells (quoted in Ref. 30, p. 63).
It would seem as though the debate over the presence of
capillary walls was settled. However, the controversy continued. In 1849, Bennett Dowler from New Orleans wrote with
incredulity:
Professor Carpenter’s anatomical history of the capillaries
does not seem embarrassed with any doubts whatever, though
it bears on its face very little that can be called absolute
certainty. He says that “the capillary circulation is carried on
through tubes which have distinct membraneous parieties;—
originating in cells”!—in another place, he says that “the
capillaries arise from a minutely anastomosing network, into
which the blood is brought by the ramifications of the arteries
on one side and from which it is returned by the radicles of the
veins on the other.” Cells! network! ramifications! radicles! one
side! and the other side! (Ref. 8, p. 455)
In 1856, the question still remained open in the eighth
edition of Robley Dunglison’s Human Physiology. Some investigators, Dunglison explained, believed that the bloodstream “is seen to work out for itself, easily and rapidly, a new
passage in the tissues, and it is esteemed certain, that in the
figura venosa of the egg, the blood is not surrounded by
vascular parietes” (Ref. 11, p. 347). On the other hand, for
histologists, capillaries did seem to be provided with walls,
“and it has even been announced, that they are composed of a
fibrous structure, analogous to the muscular” (Ref. 11, p. 348).
H. N. Eastman of Geneva Medical College (who, as mentioned
above, had suggested the need to clarify the definition of the
word “capillary”) opined in 1867 that capillaries were channels, “mere repositories of the blood” with walls formed from
the “tissues themselves” and a “tenuous structureless membrane”
(Ref. 13, p. 77).
In the later 1800s, it was not unusual for authors to take an
intermediate position regarding the presence of walls. For
example, in the 1875 publication A Manual of Physiology;
Being a Course of Lectures, Professor Küss at the Medical
School of Strasbourg stated that
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the inability to detect a membrane with light microscopy; the
facility with which globules (cells) passed between blood and
tissues; the “rapidity with which the blood is seen to work out
for itself a new passage, or canal, in the tissues”; the impossibility of detecting any “pores” or “openings” in the sides of
vessels; and the “impossibility of the processes of nutrition and
absorption being carried on through the coats of vessels” (Ref.
12, p. 8). Thompson cited the rapidity with which new capillaries formed (seen by some to be incompatible with capillaries
having fully formed walls) and the ease with which the blood
appeared to pass out of the larger vessels and take an “irregular
and indeterminate course through the non-vascular parenchyma of the organ” (quoted in Ref. 38, p. 670).
Although visual proof was lacking, some investigators correctly inferred the presence of the capillary wall. For example,
in their 1829 text A Manual of General Anatomy, A. L. Bayle,
H. Hollard, and H. Storer stated that:
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HISTORY OF THE CAPILLARY WALL
The capillaries are generally formed of coats of very simple
structure: their tissue is apparently amorphous, but traces of
cellular structure are found in them, in the shape of laminated
flattened plates, the remains of ancient cells, which have lost
the principal physiological properties of the globular element
when losing its form. The capillaries have not, however, perhaps, always distinct walls: this is probably the case with the
capillaries of the liver, which are, apparently, only lacunae
hollowed out in the substance of this organ (interstices between
groups of hepatic cells). (Ref. 22, p. 159)
The physiologists and pathologists. Capillary structure was
by no means restricted to discussions among anatomists. In
fact, notions of capillary structure were directly related to how
physiologists viewed the process of tissue growth and nutrition, and how pathologists thought blood cells traversed the
capillary wall during inflammation.
It has long been recognized that substances utilized and/or
secreted by the cells of the body must pass between blood and
tissue. By the 1800s, this process of “nutrition” was appropriately ascribed to the capillaries. In 1835 Allen Thomson stated
that “all those alterations of composition which accompany
nutrition, growth, secretion, and other organic processes connected with the systemic vessels, occur in the smallest ramifiAJP-Heart Circ Physiol • VOL
cations of the pulmonic and systemic circulation” (quoted in
Ref. 38, p. 669).
In the first half of the nineteenth century, two schools of
thought regarding nutrition and inflammation bore particular
relevance to capillary structure.7 One school of thought was
that blastema, which included albumin and fibrin, left the
bloodstream to feed and form tissue cells (in normal states) or
pus cells (in states of inflammation). The second school of
thought, the corpuscular theory, held that circulating cells
(some believed them to be red blood cells, others white blood
cells) constantly trafficked between blood and extravascular
space, giving rise to tissue cells and pus cells in normal and
pathological conditions, respectively.
As a proponent of the blastema theory, John Hughes Bennett
(1812–1875), an English physiologist, physician, and pathologist, argued in 1841 that the vascular changes that had for so
long occupied center stage in inflammation were a prelude to
7
Before the era of microscopy and the recognition of capillaries, inflammation was widely viewed as resulting from changes in the blood (e.g.,
aggregation of corpuscles acting as plugs) or from alterations in vasomotor
tone of the blood vessels (particularly the small arteries).
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Fig. 6. Scales of investigation. Shown are
examples of the circulation as it appeared to
observers during history. A: Galen’s view of
the splanchnic circulation (drawn by Vesalius) shows limited detail derived from gross
dissection (Vesalius A. Tabulae Sex. Venice,
1538). B: vascular injections [shown is a
sample drawing of splenic vasculature by
Ruysch (Ruysch F. Epistola anatomica,
problematica quarta. Amstelodami, 1737)]
provided further detail of the microvessels.
However, the capillaries remained invisible
to the naked eye. Instead, the microvessels
appear blind-ended (magnified in inset).
C: cross section of a lobule of the liver,
showing the capillary network between the
portal and hepatic veins (Walker J. Anatomy,
Physiology, and Hygiene. New York: A.
Lovell & Co, 1884). With light microscopy,
the capillaries are apparent (white mesh,
inset). D: capillary as viewed by Theodor
Schwann (Ref. 33, p. 155). E: silver nitrate
staining revealed a continuous lining of cells
in capillary (left) and precapillary (right)
from rabbit mesentery (Böhm AA. A Textbook of Histology. Philadelphia, PA: Saunders, 1901). F: example of silver nitrate
staining of capillary from the mesentery of a
guinea pig shows the presence of nuclei
(Cornil and Ranvier, A Manual of Pathological Histology, Philadelphia, PA: H. C. Lea,
1880).
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HISTORY OF THE CAPILLARY WALL
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the exudation of plasma. Bennett described the capillary wall
as “composed of a simple, transparent, yet very firm membrane, without the smallest openings, studded at irregular
intervals with nuclei of various shapes. . . fine filters. . . retaining the solid corpuscles and allowing only the fluid to transudate” (quoted in Ref. 30, p. 85– 86). Bennett believed that the
exudate represented a blastema, transforming into tissue or pus
cells.
Among the foremost advocates of the corpuscular theory
was William Addison (1802–1881), a medical practitioner
from England. Addison denied the existence of a membranous
coat or wall in the capillaries: “Capillary vessels are channels
running in a determinate manner around and among little fixed
islets of living tissue. . . take away the islets and no vessels
remain” (quoted in Ref. 30, p. 89). He argued that the “walls”
consisted of parallel fibrinous fibers (derived from the white
blood cells) that blended in with those of the tissues. During
normal nutrition, the colorless corpuscles adhered to the fibrillar margins of the vascular channels, where they met one of
three fates: 1) disintegration (giving rise to fibrils), 2) incorporation into the vascular wall, or 3) transformation into fixed
structural and/or secretory tissue cells after leaving the bloodstream. Inflammation was associated with an even greater
accumulation of white blood cells on the capillary margins,
ultimately resulting in pus formation (Fig. 7). Addison only
hypothesized that white blood cells passed from the blood into
tissues— he never actually witnessed this movement. In any
event, his hypothesis that cells continually escaped from the
AJP-Heart Circ Physiol • VOL
vasculature argued—in his view—against the presence of a
membranous wall.8 (Conversely, those investigators who accepted the existence of a capillary wall categorically dismissed
the notion that leukocytes could pass between blood and tissue
without rupture of the blood vessel).
Augustus Waller (1814 –1870), a contemporary of Addison’s from London, developed a technique for studying the
microcirculation in the tongue of the living frog, in which
inflammation was induced by long exposure to air (Fig. 5, B
and C). In 1846, Waller stated: “Let us now examine the
admirable manner in which nature has solved the apparent
paradox, of eliminating, from a fluid circulating in closed
8
Over time Addison would modify his views. Faced with growing evidence
that capillaries had walls, Addison backed off from his contention that
leukocytes continually pass from the bloodstream to tissue. Instead, he suggested that in states of inflammation the capillary walls undergo cellular
transformation (termed retrograde metamorphosis) in which white blood cells
replace the fibrous walls of capillaries, thus opening a passageway to the
underlying tissues. Even then, Addison’s view that pus cells are derived from
circulating white blood cells was met with skepticism. An anonymous review
of his work in 1844 stated that “we cannot agree with him [Addison] in
considering the pus-corpuscles as metamorphosed white corpuscles (because
we cannot think it probable that bodies so large as these can pass out of the
capillaries, without an absolute rupture of their wall).” (Anonymous. Principles
of medicine. . . . Br Foreign Med Rev 18: 91–115, 1844, p. 112). In another
review: “Not only have the capillaries a permanent tubular coat, but it performs
most important functions. It is impossible that corpuscles of the blood can pass
through it without rupture” [Anonymous. Reviews. Lancet 43: 586 –588, 1844,
p. 588].
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Fig. 7. Capillary structure as proposed by Addison in 1844. Addison’s capillary “walls” consisted of parallel fibrinous fibres (derived from the white blood cells)
which blended in with those of the tissues. The legends read as follows: Plate II, Fig. 1: “Represents, theoretically, the normal process of nutrition. The colourless
blood corpuscles first adhere to the walls of the capillaries; they then contribute to form the walls, and pass through the altering tissue, being evolved upon the
nearest free surface in the form of a secretion, epithelial scales, or mucous epithelium.” Plate II, Fig. 2: “Represents, theoretically, an abnormal process of
nutrition. The colourless blood corpuscles are in much greater numbers, passing through the altering tissue, and thrown off in the form of pus globules or
imperfect epithelial cells.” From Addison W. The actual process of nutrition in the living structure demonstrated by the microscope. Trans Prov Med Surg Assoc
12: 235–306, 1844.
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HISTORY OF THE CAPILLARY WALL
9
Concerning emigration, Metchnikoff stated: “I need not insist at length
on the fact that the migration of leucocytes through the vascular wall is due to
their own active movements. In spite of all Cohnheim’s endeavours, in spite of
the general desire to refer all vital phenomena to mechanical causes, the view
that the migration is effected by the amoeboid power of the leucocytes has now
found almost unanimous acceptance” (quoted in Movat HZ. The role of
endothelium in leukocytes emigration: the views of Cohnheim, Metchnikoff
and their contemporaries. Pathol Immunopathol Res 8: 35– 41, 1989).
10
In 1935, Clark and Clark described five phases of inflammation (mild
sticking of leukocytes to endothelium, prolonged leukocyte sticking, emigration of leukocytes, localized bulging and hemorrhages, and disintegration of
endothelium), and concluded: “Metchnikoff (1893) claimed that the whole
process [of diapedesis] was attributable solely to the activity of leukocytes in
response to chemoattraction from without. . . . [Our observations in living
tadpoles and rabbit ears] demonstrated that a change in the endothelium is an
essential preliminary to the sticking of leukocytes” (Ref. 6, p. 428).
11
Lister, who is best known for his discovery of antiseptic treatment of
wounds, wrote a seminal paper entitled “On Early Stages of Inflammation” in
1859 (23), in which he described many of the changes associated with
inflammation of the vascular wall.
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In 1884, G. Hare Philipson, from the University of Durham,
wrote:
By means of the blood the constituent elements of the body
are supplied with the nutrient substances and the oxygen which
they require. By the blood and the lymph are conveyed away
the waste and surplus matters which have ceased to be useful
to the tissues. (Ref. 29, p. 310)
In describing the pathogenesis of edema, Philipson stated
that
The quantity and nature of the liquid which escapes from the
capillaries and veins depend not only on the intravascular
pressure and the resistance of the flow, but also to a great extent
on the character and condition of the vessel wall, and especially
in their endothelial lining. . . . Cohnheim has shown that the
vessel wall is not to be regarded as a dead membrane, but as a
living organ. (Ref. 29, p. 310)
In the late 1800s and early 1900s, the problem of how
substances cross the capillary wall was a central question in
human physiology and pathology. August Krogh, a professor
of zoophysiology at the University of Copenhagen who focused his investigation on the regulation of capillary density
and oxygen delivery (for which he was awarded a Nobel Prize
in physiology or medicine in 1920), was the first to present a
comprehensive theory of capillary function in his 1922 book,
The Anatomy and Physiology of Capillaries (20). In discussing
the exchange of substances through the capillary wall, Krogh
stated:
. . .the chief function of the capillaries [is] the exchange of
substances between the blood and the tissues, or tissue fluids,
taking place through the capillary wall. Apparently, at least,
this function of exchange is a very complex one: gases, water,
inorganic salts, organic crystalloids of the most varied description, and, in certain tissues, even colloids are constantly passing
through the capillary endothelium, and not infrequently the
direction of the passage changes. . . . In the capillary blood
vessels we have, just as in the osmometer, a membrane which
is permeable to crystalloids and impermeable to colloids. An
absorption of isotonic salt solution, can, therefore, take place,
and, indeed, must take place, when the hydrostatic pressure in
the vessels—the capillary blood pressure—is lower than the
osmotic pressure of the proteins. (Ref. 20, p. 266 and 282)
Together with Frank Starling’s observations in 1894 (36),
Krogh’s work would open the door to all of microvascular
physiology concerning capillary function, including that of
Eugene Landis, John Pappenheimer, Robert Chambers, Benjamin Zweifach, Eugene Renkin, Silvio Baez, Ephraim Shorr,
and others.
The essence of this work was captured by Pappenheimer in
his description of vectorial transport as an “ultramicroscopic
circulation”:
. . .visible flow of blood through the capillaries is, in fact,
very small in comparison with the invisible flow of water
and dissolved materials back and forth through the capillary
walls. . . . This invisible component of the circulation takes
place at a rate which is many times greater than that of the
entire cardiac output. Indeed, it is by means of this “ultramicroscopic circulation” through the capillary wall that the
circulatory system as a whole fulfills its ultimate function
in the transport of materials to and from the cells of the
body. (28)
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tubes, certain particles floating in it, without causing any
rupture or perforation in the tubes. . .” (Ref. 41, p. 398). Waller
made the novel observation (where others before him had only
theorized) that at sites of inflammation some leukocytes were
at times “protruding half out of the vessel” and concluded that
corpuscles passed through the capillary wall. In a follow-up
paper, Waller supported Addison’s claim that circulating white
blood corpuscles were identical to the corpuscles of pus and
hypothesized that the corpuscles might release a substance that
dissolved the substance of the capillary walls.
Julius Cohnheim (1839 –1884), one of Virchow’s students,
greatly expanded on the findings of his predecessors. Using a
combination of colloidal aniline blue injections and microscopy, Cohnheim proved what Addison hypothesized many 23
years earlier, namely, that white blood cells cross blood vessels
to become pus cells (7). Cohnheim summarized the process as
“an emerging of colourless blood corpuscles from the interior
of a vein to the outside, completely through the intact wall.” He
ultimately hypothesized that leukocyte passage was passive
and secondary to alterations in the blood vessel wall induced
by chemical or mechanical “agencies.” At that time, he seemed
to view inflammation not as an adaptive response, but rather as
a pathological response to small vessel damage. Only later
would Ilya Metchnikov introduce the biological theory of
inflammation, emphasizing the importance of diapedesis as a
defense against microorganisms.9 In the 1900s, Eliot Clark and
Eleanor Clark (a husband and wife team from the University of
Pennsylvania) were the first to prove a critical role of the
endothelium in mediating this process (“[we have] demonstrated that a change in the endothelium itself is an essential
preliminary to the sticking of leukocytes”; Ref. 6, p. 428).10
In addition to diapedesis, increasing attention was being paid
to the mechanisms of transudation and exudation across the
capillary wall. In 1858, Joseph Lister (1827–1912), a surgeon
from England with an interest in inflammation, described the
capillaries as consisting of “a delicate homogeneous membrane
beset with occasional nuclei. . . . The thinness of the walls of
the capillaries, as compared with the small arteries, is doubtless, calculated to favour the mutual interchanges which must
take place between the blood in them and the tissues in their
vicinity” (23).11
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HISTORY OF THE CAPILLARY WALL
Discovery of Endothelial Cells and Rouget Cells
(31).13 Rouget was unable to stain these cells. He observed
them in several vascular beds and concluded that they were
muscle cells.14 Staining of Rouget cells was successfully carried out by Zimmerman in 1886 (with silver nitrate) and Meyer
in 1902 (with methylene blue) (reviewed in Ref. 3). Zimmerman, who ultimately coined the term “pericytes” (43), held that
contraction of these cells controlled capillary permeability
(others such as Krogh would later counter that capillary dilatation, as opposed to contraction, was necessary for regulating
permeability).
Conclusion
In 1865, the Swiss anatomist Wilhelm His (1831–1904)
introduced the term “endothelium” in a programmatic essay
titled “Die Häute und Höhlen des Körpers (The membranes
and cavities of the body)” (17).
In 1873, Rouget described contractile elements on the capillaries of the hyaloid membrane of the frog as oval nuclei
arranged longitudinally with surrounding irregular cell bodies,
the branched processes of which encircled the capillaries
In this review, we have focused on a relatively unknown and
unheralded era in the history of the vascular research, which
culminated in the discovery that capillaries had walls. As we
alluded to in the introduction, the value of considering this
period of history is not so much in the discovery itself as it is
in the lessons that may be drawn from it. In this final section,
we wish to move beyond pure historical narrative and formulate what we believe are the important lessons from this period.
Technology as an engine of progress. Progress in understanding the identity and nature of the capillary wall has
mirrored advances in technology. Imagine the challenge of
piecing together the structure and function of the circulation
with the naked eye. In some cases, investigators relied on sheer
creativity. Harvey, for example, studied cold-blooded animals
in which the circulation was considerably slowed. In other
cases, the development of new techniques afforded incremental
improvements in resolution. For example, the injection of the
vascular system with dyes revealed the existence of yet smaller
vessels (though the capillaries remained invisible). The development of the light microscope represented a major technological breakthrough. Initial studies were limited by the poor
quality of the lenses and the lack of vital stains, and yielded
only vague images of the capillary beds. Later, the use of
special stains, particularly silver nitrate, provided a clearer
view. In the twentieth century, many new tools—including the
electron microscope, the culture of primary endothelial cells,
and molecular biology— contributed to our present-day understanding of the capillary.
Today, perhaps more than ever, technology continues to
drive discovery in the field of microcirculation. One of the
great challenges inherent in studying the capillaries—whether
200 years ago or today—is their invisibility to the human eye.
An additional complexity is the extent to which their component parts, particularly the endothelial cells, undergo phenotypic drift in vitro. New proteomic approaches have revealed
that capillaries and their endothelial lining comprise a mosaic
of phenotypes, which have been variously described as “vas-
12
In his original paper, a mere 8 lines in length, von Recklinghausen did not
describe specifically the endothelium. The following is an English translation
of the paper, entitled “A method to differ between microscopical cavernous
(empty) and solid structures” (39): “If you put fresh or even better dried
animally pieces (tissue) into a light solution of argentum nitricum (so-called
hellstone-solution), put them into a low-concentrated solution of sodium
chloride and expose to the impact of light, you get a dispersed, tight, black
silver precipitation in those areas (of the tissue), that contain essentially watery
solutions, whereas solid areas (of the tissue) (intercellular substances) only
show more scattered grains or diffuse stain or even stay unaltered. Currently I
have to reserve further continuation and more detailed determination for
myself.”
13
In 1873, Rouget stated that these cells: “. . .are arranged in the direction
of the tubes, and surrounded by a zone of protoplasm with branched elongations which embrace the capillaries in a number of places like so many loops”
(quoted in Jones T. The structure and mode of innervation of capillary blood
vessels. Am J Anat 58: 227–250, 1936, p. 229).
14
As recounted by Bensley and Vimtrup in 1928: “In the hyaloid membrane
of the frog these cells were fairly regularly arranged, their protoplasmic
processes running nearly circularly around the capillary. Rouget was not able
to stain these cells; only their nuclei were tinged with carmine. . . . According
to Rouget, these perivascular cells were to be found regularly on capillaries in
various organs of the body, and he presumed that they were real plain muscle
cells and acted as such” (Ref. 3, p. 38).
Without the aid of reagents the structure of the capillaries
appears very simple. A few nuclei with nucleoli are seen
scattered along the walls of an elastic hyaline membrane.
Nitrate of silver dispels this illusion and resolves this homogeneous membrane into a single layer of nucleated cell-plates,
united together by a “cement substance” which is stained a
deep black by the solution. (Ref. 37, p. 113)
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A discussion of the capillary wall would not be complete
without reference to the discovery of its cellular components.
The endothelial cell and the Rouget cell (pericyte) would
become a focal point of capillary research in the twentieth
century. While a comprehensive history of endothelial and
pericyte biology falls outside the scope of the present review,
a brief discussion of their discovery bears relevance to early
concepts of the capillary wall.
Following the widespread use of light microscopy, but
before the development of histological stains, the capillary wall
had the appearance of a bland membrane or syncytium. In the
mid-nineteenth century, the introduction of silver nitrate staining by several German investigators definitively established the
presence of a cellular lining and hence the existence of a
capillary wall (Fig. 6, E and F). After the vessels were injected
with the silver solution and the tissue was exposed to light, a
dark brown precipitate lining the cell boundaries could be
observed (the rest of the cells were left relatively unstained).
The usefulness of silver nitrate as a histological stain was first
proposed by Friedrich von Recklinghausen (1833–1910) of
Berlin in 1860 (39).12 Two years later, von Recklinghausen
used the reagent to stain the lymphatics and was the first to note
that they were lined with cells (see Ref. 32). In 1863, Oedmanson of Stockholm applied silver nitrate to epithelial surfaces
and theorized that stomata (or openings in the vessel wall) had
to exist (26). Finally, in 1865 and 1866, several German
investigators settled the debate over whether capillary walls
exist when they stained the capillaries with a solution of
silver nitrate mixed with gelatin to keep the capillaries
distended (42).
The resolving power of silver nitrate was captured by Stowell in 1882:
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15
In referring to Harvey’s inference regarding the large quantity of arterial
blood, Hoffman (a Galenist) stated: “A few words, but weighty! But how will
you prove it my dear Harvey? For you would seem to accuse Nature of
stupidity in that she went so far astray in a work of almost prime importance
as is the making and distributing of food. . . . You would seem to impose upon
Nature the character of a most rude and idle artificer who destroys the work she
has done and perfected so that, forsooth, she should not be at a loss for
something to do, for, to make raw again the blood that has been perfected by
all her agents and then again to concoct it, what is it other than this?” (quoted
in Whitteridge G. William Harvey and the circulation of the blood. London:
Macdonald; New York: American Elsevier, 1971, p. 162).
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simply incompatible with their belief that circulating cells
constitutively migrated from blood to tissue. While they would
ultimately acknowledge the indisputable evidence that capillaries had walls, they did so at the expense of abandoning the
important concept of leukocyte transmigration.
A modern-day illustration of the difficulty in accepting new
ideas is provided by Judah Folkman’s hypothesis that tumors
require blood vessels to grow. Folkman faced “‘wall-to-wall
critics’. . . the dogma back then was that tumors do not need a
new blood supply since they grow on existing vessels, and that
redness associated with tumors was inflammation from dying
tumor cells, not vascular tissue” (quoted in Ref. 4).
According to Kuhn, “novelty emerges only with difficulty,
manifested by resistance, against a background provided by
expectation” (Ref. 21, p. 64). Once the novelty is accepted as
fact, we may be less inclined to explore the events around that
discovery. For the unquestioning modern-day practitioner, the
acceptance of the capillary wall as simple fact belies a rich
history of methodological, technical, and conceptual advances.
The study of the capillary wall: dead science or viable pursuit? We have learned from this historical survey that the
capillary (and by extension its wall) was very much at the
forefront of studies in human physiology and pathology. As
the principal site of exchange between blood and tissues, the
capillary underlay fundamental principles of nutrition, metabolism, tissue growth, and repair. Harvey, who applied Bacon’s
scientific method and quantitative physiology to the discovery
of the circulation, was the first to consider the existence of
these tiny connections between arteries and veins. In their
pioneering work with the microscope, Malpighi and Leeuwenhoek focused their lens on the capillary system. Schwann, the
founder of the cell theory, was the first to illustrate cells lining
the capillary. Virchow, who famously introduced the theory of
cytogenesis, struggled for years with the concept of leukocyte
transmigration and pus formation. The focus on capillaries
would continue into the early to mid-twentieth century. It was
not until the recognition of atherosclerosis as a distinct disease
entity in the 1900s that attention shifted from the capillaries to
the large arteries (reviewed in Ref. 9).
These considerations beg the question of whether the capillary wall has lost its appeal as a subject for scientific inquiry.
We believe that the answer is no. While progress in this field
continues unabated, it occurs under different guises. Over the
past 50 years, the field of capillary research has largely splintered along the lines of organ-specific disciplines. Rather than
constituting an integrated system, the capillaries from different
organs fall under the domain of subspecialists whose frame of
reference is not the vasculature per se, but rather the physiology and pathology of the organ in which the capillaries reside.
Progress in understanding the capillary wall has become similarly compartmentalized. For example, neuroscientists are
primarily concerned with improving drug delivery across the
walls of brain capillaries, pulmonary researchers are focused
on reducing transfer of solutes and fluids across the walls of
lung capillaries in acute lung injury, and hepatologists are
interested in preventing the loss of endothelial fenestrations in
liver capillaries in diseases such as cirrhosis. The paucity of
cross-disciplinary interactions notwithstanding, these efforts,
when considered collectively, suggest that the modern-day
study of the capillary wall continues to thrive. More than that,
there is a growing appreciation that site-specific endothelial
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cular addresses” or “zip codes” (25). An exciting prospect for
the future is to identify these addresses and to leverage the
information for delivering drugs to specific vascular beds.
However, the success of site-specific targeting awaits further
advances in technology, including increased resolution of phenotyping tools and improvements in the specificity and safety
of gene/protein delivery systems.
Judging scientific progress in the context of the times. At
first glance, it is surprising that the very existence of the
capillary wall was ever in doubt. However, as we hope to have
conveyed in this review, the controversy was perfectly understandable in the context of eighteenth- and nineteenth-century
science. Other debates that followed seem no less unusual by
today’s standards. For example, is mature endothelium the
source of red blood cells and/or leukocytes? Do capillaries
have the power to elaborate hemoglobin, form lymph, or make
antibodies? Do capillaries constrict by means of endothelial
cell swelling? Each of these questions was posed and debated
by highly capable investigators who, while schooled in the
methods of experimental inquiry, were limited (relative to later
generations) in their knowledge base and technical repertoire.
Referring to the path on which Western medicine has moved
over the past two and a half thousand years, Lelland Rather, a
Stanford pathologist and medical historian, points out that it
culminates not only in our present, but also in an “infinite
number of presents, each one as confident as our own that it
had scaled the heights of time” (Ref. 30, p. 16). Extrapolating
into the future, our present-day concepts of the microvasculature promise to undergo significant, unanticipated changes.
The nonlinearity of progress in the field. A consideration of
the history of the capillary wall reminds us that the impact of
new discoveries is rarely, if ever, immediate. Thomas Kuhn, a
philosopher of science who was responsible for popularizing
the term “paradigm,” argued that mature science develops from
the successive transition from one paradigm to another through
a process of revolution (21). By definition, new paradigms are
at odds with existing notions of health and disease. Consider,
for example, Harvey’s discovery of the circulation in 1628. At
the time, the prevailing view of the vasculature was that veins
delivered blood and arteries delivered air or pneuma to the
various organs of the body. These were open-ended systems in
which blood and air were expelled into and consumed by the
tissues. Harvey’s critics (the “Galenic Brigade”) could not
accept that blood circulated, because Nature would never be so
wasteful as to have the heart make more blood than is consumed by the tissues.15 Once blood was seen to circulate rather
than dissipate, it was necessary to determine how substances
(including solutes and cells) passed between blood and underlying tissue. For those who subscribed to the corpuscular
theory of nutrition, the presence of a true capillary wall was
History Article
HISTORY OF THE CAPILLARY WALL
cell phenotypes in health and disease are significantly influenced by the extracellular environment, particularly at the level
of the capillary. As our focus continues to shift from the culture
dish to the intact vasculature, an understanding of endothelial
behavior in the context of the capillary wall will become
increasingly relevant.
ACKNOWLEDGMENTS
We thank Jack Eckert and Paul Bain from the Department of Rare Books
and Special Collections of the Countway Library, Harvard University for their
help. We also thank Dr. Okan Cinkilic for providing an English translation of
von Recklinghausen’s article. We thank Steve Moskowitz for his art work. We
thank Jane Maienschein for her helpful comments and critical review of the
manuscript.
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REFERENCES
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