Cardiovascular Research 46 (2000) 403–411
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Review
Endogenous factors involved in regulation of tone of arterial vasa
vasorum: implications for conduit vessel physiology
Ramona S. Scotland*, Patrick J.T. Vallance, Amrita Ahluwalia
Centre for Clinical Pharmacology, University College London, The Rayne Institute, 5 University St., London WC1 E 6 JJ, UK
Received 14 September 1999; accepted 13 January 2000
Abstract
The walls of conduit blood vessels are nourished by diffusion of oxygen from luminal blood and from the vasa vasorum. The vasa
vasorum, or ‘vessels of a vessel’, form a network of microvessels that lie in the adventitia and penetrate the outer media of the host vessel
wall. Although the importance of the vasa vasorum in providing nutritional support is not well defined, obstruction of blood flow through
these vessels has been implicated in the pathogenesis of certain cardiovascular diseases including atherosclerosis. This review focuses on
the mechanisms that regulate tone in the vasa vasorum of large arteries and the functional implications of changes in reactivity of vasa
vasorum.  2000 Published by Elsevier Science B.V. All rights reserved.
Keywords: Arteries; Atherosclerosis; Blood flow; Capillaries; Restenosis
1. Morphology
The morphology of the vasa vasorum is critical in
understanding the mechanisms by which these vessels
regulate their tone. This is supported by the fact that the
distribution of vasa changes in certain vascular diseases
and varies between vascular beds as well as within any
single blood vessel, as with the aorta. This striking
plasticity may relate directly to a flexibility in their
function according to environmental conditions.
The vasa vasorum surrounds and penetrates the adventitia and outer media of large arteries and veins including
aorta, vena cava, coronary, femoral, carotid and some
intracerebral arteries [1]. The vasa vasorum itself consists
of a network of small arteries typically flanked by two
small veins, providing an entire microvascular bed within
the wall of the host blood vessel [2]. Capillary vessels have
also been noted in the vasa vasorum although in some
cases they are short enough to constitute arteriovenous
shunts [2]. Vasa can originate from several different sites.
For example, vasa in the ascending aorta arise from
*Corresponding author. Tel.: 144-171-209-6606; fax: 144-171-2096212.
E-mail address: [email protected] (R.S. Scotland)
coronary and brachiocephalic arteries; vasa in the descending thoracic aorta originate from the intercostal arteries;
and vasa in the abdominal aorta may arise from the lumbar
and mesenteric arteries and from the lumen of the aorta
itself. Large veins are also supplied by vasa, the vasa
venarum, which lie in the adventitia and penetrate the
media. In some veins, the vasa venarum extends to the
intima [3] indicating that these microvessels have a more
important role in nutrition of the walls of veins than
arteries. The source of the vasa venarum is also arterial and
arises from branchpoints of adjacent arteries. Similar to the
vasa vasorum, the vasa venarum consists of a network of
small arteries and veins. It has been suggested that the
venules of the vasa venarum emerge from the adventitia
and empty into adjacent veins rather than into the lumen of
the parent vessel [4].
There are two anatomically distinct patterns of vasa; first
order vasa run longitudinally to the lumen of the host
vessel; while second order vasa are arranged circumferentially around the host vessel [5]. Arterial vasa are readily
distinguishable from venous vasa since they have a straight
course whereas the course of venous vasa is more tortuous
[2]. In addition, arterial vasa are less numerous with fewer
Time for primary review 24 days.
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PII: S0008-6363( 00 )00023-7
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R.S. Scotland et al. / Cardiovascular Research 46 (2000) 403 – 411
branches and have a smaller lumen than the small veins.
Fig. 1 shows an arterial vasa at the adventitial–medial
border of a porcine thoracic aorta. It is clear that these
microvessels consist of layers of smooth muscle oriented
radially around a single layer of endothelium [6], indicating that these vessels have the capacity to regulate tone.
Like other small resistance arteries, arterial vasa are
neuronally innervated. Fig. 2a shows an isolated porcine
vasa labelled with antibody to general neural marker
protein product 9.5 (PGP 9.5). These nerves appear to be
sympathetic fibres since they stain heavily anti-neuropeptide Y (NPY) (Fig. 2b). Similarly, the vasa vasorum of
the human saphenous vein is densely innervated by
unmyelinated sympathetic nerve fibres [7] and NPY,
vasoactive intestinal peptide (VIP) and dopamine b-hydroxylase-immunoreactive nerves have also been demonstrated to supply the vasa vasorum of deep dorsal penile
vein [8]. Although the neural innervation of vasa is mainly
sympathetic, other nerve types are also present in some
vasa vasorum. For example, calcitonin gene-related peptide
(CGRP) and substance P (SP)-containing nerves have been
demonstrated around the vasa vasorum of human saphenous vein [7] and rat carotid arteries [9].
The presence of the vasa vasorum in blood vessels is
likely to be related to nutritional needs. Comparison of
different species revealed that vasa are present in the
media of the aorta of those animals in which the aortic
wall thickness exceeds 0.5 mm [10], or as redefined by
Wolinsky and Glagov [11], when aortic thickness exceeds
29 lamellae. Indeed if one considers the aorta, in those
species where the aorta has less than 29 lamellae the vasa
vasorum is absent from the media, whereas in the aorta of
large animals the inner 29 lamellae are avascular and the
outer lamellae are supplied by the vasa vasorum. Consistent with this definition, the media of human abdominal
aorta has 28 lamellae and is avascular. Interestingly, the
avascular regions of the abdominal aorta also show the
greatest propensity for atherosclerosis [11], implying that
the blood supply provided by the vasa vasorum may be
protective in this respect. Therefore, one could speculate
that if the vasa vasorum are important in providing
protection of the host vessel, decreases in blood flow
through these microvessels may contribute to atherosclerosis. Coronary arteries are an exception to the above
definitions since the critical wall thickness is less in
coronary arteries (0.35 mm) than in the aorta [10]. This
anomaly suggests that the above definition may not hold
true for all vessels and that as well as wall thickness, an
important determinant for the presence of vasa vasorum
may be luminal oxygen tension. In support of this are the
findings that large veins, which have thin walls but low
luminal oxygen tension, are supplied by a dense network
of vasa and that vasa vasorum of the canine aorta dilate in
response to acute systemic hypoxia [12]. This latter
response may represent an important mechanism whereby
the supply of oxygen to a blood vessel wall is increased
when diffusion of oxygen from the lumen is limited.
Similar to veins, the pulmonary artery, which also has low
Fig. 1. Haematoxylin and eosin staining of porcine thoracic aorta demonstrating an arterial vasa at the adventitial (ADV)–medial (MED) border.
R.S. Scotland et al. / Cardiovascular Research 46 (2000) 403 – 411
405
Fig. 2. Whole mount indirect immunofluorescence (yellow) of isolated porcine thoracic aortic vasa vasorum (red) incubated with (A) anti-protein gene
product 9.5 (PGP 9.5) and (B) anti-neuropeptide Y (NPY).
luminal oxygen tension, has a more extensive supply of
vasa vasorum in the adventitia and outer media than
systemic arteries [13]. Indeed measurement of blood flow
to canine pulmonary artery is equal to that to the aorta
despite a difference in wall thickness and lamellar units
(29 compared to 49) [12]. Therefore, both oxygen tension
and wall thickness appear to be important determinants of
the presence of vasa. This may have important implications for the host vessel in diseases that result in increases
in wall thickness or hypoxia (see later) since the dis-
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R.S. Scotland et al. / Cardiovascular Research 46 (2000) 403 – 411
tribution of the vasa is not fixed. It is clear that in certain
cardiovascular diseases (see later), including atherosclerosis, the number and density of vasa changes and it seems
that this relates closely to changes in blood supply to the
conduit vessel wall.
2. Regulation of blood flow
The presence of several layers of smooth muscle implies
that the vessels of the vasa vasorum actively regulate their
own tone rather than serving as a passive channel for blood
flow. The first studies supporting this hypothesis investigated vasa vasorum reactivity to vasoactive agents in dogs
in vivo [14]. This study exploited the microsphere technique in which microspheres labelled with gamma-emitting
isotopes were injected into the left atria, distributed
throughout the circulation and, since they are too large to
pass through capillaries, extracted following a single
passage through the vasa vasorum. The results of this study
suggested that the diameter of the vasa vasorum of canine
thoracic aorta increased in response to intravenous infusion
of adenosine [14]. In contrast another study using the same
technique showed no change in blood flow through the
vasa vasorum of carotid arteries of monkeys during
infusion of either the vasoconstrictor phenylephrine (PE)
or 5-hydroxytryptamine (5-HT) [15]. Ohhira and Ohhashi
[16] removed sections of the vasa vasorum attached to the
canine thoracic aorta and examined the reactivity of the
vasa vasorum in vitro by measurement of perfusion
pressure. In this study the vasa vasorum appeared sensitive
to a range of constrictor agents: 5-HT4noradrenaline
(NA)5adrenaline4dopamine. Indeed, in vitro receptor
autoradiography has demonstrated dense binding of [ 3 H]5-HT in the vasa vasorum of human saphenous vein [17].
Whilst these studies appear to support the hypothesis that
the vasa vasorum regulates its own tone, in both systems
vasa reactivity was not studied in isolation. The possibility
that the responses seen were secondary to effects on the
host vessel and not direct effects of the agonists on the
vascular smooth muscle of the vasa vasorum cannot be
excluded in these studies. More recently, however, clear
evidence of vasa vasorum reactivity has been provided by
studies of these vessels in isolation using the tension
myography technique [6]. This study showed that isolated
porcine vasa contract to a range of constrictors. Interestingly, the profile of vasoconstrictor reactivity of the isolated
vasa is quite different from other small arteries, in that,
whilst endothelin-1 (ET-1) produced potent concentrationdependent contractions (see Fig. 3) the vasa appear to be
relatively insensitive to NA, thromboxane A 2 (TXA 2 )
mimetics and angiotensin II (AngII). A similar profile of
reactivity was also seen in vasa isolated from bovine aortic
arch and therefore is likely to represent a general pattern of
reactivity of isolated arterial vasa of the aorta. These data
show clearly that the vasa vasorum can respond to
Fig. 3. Typical contractile response of isolated porcine thoracic aortic
vasa (normalised diameter |150 mm) to endothelin-1 (ET-1, 0.1–500
nM) mounted in a tension myograph.
vasoconstrictors and support the hypothesis that these
vessels regulate their own tone independently of the host
vessel. Although the functional significance of this unusual
reactivity is not known, we hypothesize that this may
represent a mechanism whereby the vasa vasorum is
protected from the constrictor effects of TXA 2 released
from activated platelets or NA released from sustained
sympathetic activity. Such a resistance to these constrictors
would maintain vasa patency despite the presence of
substances that constrict the host vessel.
ET-1 produces concentration-related contraction of isolated vasa with a similar potency to that reported in other
porcine [18] and human small arteries [19]. Circulating
levels of ET-1 are typically low. However, studies on
forearm blood flow in humans using ET receptor antagonists indicate that ET-1 has a role in local regulation of
basal tone [20], suggesting that basal levels of ET-1 may
be sufficient to directly affect tone in vasa vasorum.
Characterisation of the contractile responses to ET-1 in
vasa vasorum has identified the presence of both ETA and
ET B receptor subtypes [21]. ET-1, at low concentrations,
also sensitizes arterial vasa to the constrictor effects of
NA; such that in the presence of ET-1 the maximum
contraction to NA increases 4-fold, an effect that is
abolished by inhibition of L-type calcium channels [21].
This sensitisation by ET-1 is not a phenomenon exclusive
R.S. Scotland et al. / Cardiovascular Research 46 (2000) 403 – 411
to the vasa vasorum but has been reported to occur in other
resistance arteries from several species including isolated
human [22,23], rat [24,25] and canine [26] resistance
arteries. Partial depolarization of vasa smooth muscle with
K 1 (10–20 mM) also significantly potentiates the responses to NA and TXA 2 -mimetic. The functional significance of these effects is unclear but the findings suggest
that an increase in ET-1 levels, a feature of certain
cardiovascular diseases, would render vasa vasorum reactive to NA and that slight depolarization of smooth muscle
would enhance responses to both NA and TXA 2 . Consistent with these observations, in a study using monkeys
fed an atherogenic diet, a model associated with elevated
ET-1 levels [27], the diameter of vasa vasorum of coronary
arteries decreased in response to PE or 5-HT whilst these
constrictors had no effect in healthy animals [15]. The
reactivity of vasa vasorum to ET-1 and the considerable
[ 125 I]ET-1 binding to the vasa vasorum of both human
saphenous vein and porcine femoral arteries suggest that
ET-1 may have an important role in regulating nutrient
blood flow through the vasa vasorum, particularly in
situations such as atherosclerosis where ET-1 levels may
be elevated. In such situations vasoconstriction of vasa
vasorum by ET-1, via a direct effect and also by potentiating the contractile effects of other agonists, would theoretically promote such conditions since the nutrient supply to
the host vessel wall would be impaired.
The vasa vasorum is also sensitive to several vasodilators. In vivo studies, again using microspheres, show that
acetylcholine, histamine, isoprenaline, adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine or
sodium nitroprusside all depress perfusion pressure
through the vasa vasorum [16]. Additionally, precontracted
isolated vasa relax to the vasodilators bradykinin (BK), SP
and CGRP [6]. As in many other blood vessels relaxation
to both SP and BK is endothelium-dependent. Endothelium-derived nitric oxide (NO) appears to mediate the
responses to SP whilst the responses to BK may be more
dependent on endothelium-dependent hyperpolarisation
[6]. The high potency of these vasodilators in isolated vasa
indicates that they may have an important role in controlling tone in the vasa vasorum. An increased sensitivity to
vasodilators compared to vasoconstrictors would allow
vasa to maintain a dilated state and thereby maintain blood
flow to the vessel wall. Moreover, the finding that the
endothelium is critical in mediating these responses may
have significant implications in certain disease states or
physical manoeuvers that result in damage to the endothelium.
Whilst it is clear that flow through the vasa vasorum
may be regulated by vasoactive substances, the contribution of neurotransmitters on regulation of tone in vasa
vasorum is not known. It is clear from immunohistochemical studies of isolated vessels that the vasa are innervated.
Additionally, Heistad et al. demonstrated that blood flow
through the vasa vasorum may be sensitive to neural
407
stimulation since stimulation of the stellate ganglion of
dogs decreased blood flow to the outer media of the
thoracic aorta and stimulation of carotid sinus baroreceptors increased blood flow [28]. Therefore, in addition to
certain humoral factors, the tone of vasa vasorum may also
be regulated by neural influences. However there are no
studies that have demonstrated neural responses in isolated
vasa.
3. Role of vasa vasorum in cardiovascular diseases
The presence of the vasa vasorum in blood vessel walls
is considered to be required for the maintenance of conduit
vessel physiology. Evidence to support this hypothesis has
been provided by experimental disruption of blood flow
through the vasa vasorum of healthy blood vessels. Furthermore there is considerable evidence that the vasa
vasorum may be involved in certain cardiovascular diseases, including atherosclerosis. The following section
describes the potential significance of changes in vasa
vasorum morphology and blood flow in specific cardiovascular diseases.
3.1. Atherosclerosis
Atherosclerosis is a progressive inflammatory disease of
large arteries. The response to injury hypothesis proposes
that endothelial dysfunction is the first step in development
of atherosclerosis. However, it has recently been suggested
that the vasa vasorum in the adventitia of large arteries
have a crucial role in the pathogenesis of this disease. In
1966, Nakata and Shionoya [29] demonstrated that occlusion of blood flow through the vasa vasorum of canine
abdominal aorta, with a thrombin and gelatin mix, results
in an initial intimal thickening and smooth muscle proliferation with subsequent lipid deposition and hypertrophy of
the neointima. In addition, studies on normal and atherosclerotic coronary arteries demonstrated an increase in
microvessel density in atherosclerotic arteries that were
derived from adventitial vasa vasorum, and lead to the
hypothesis that neovascularisation of plaques has a role in
the pathogenesis of atherosclerosis [30]. More recently,
Martin et al. [31] described a model of atherosclerosis in
rabbits, in which placement of an inert silastic collar
around the outside of the carotid artery results in the
formation of an atheroma-like intimal lesion. The authors
argue that occlusion of the adventitial vasa vasorum by the
collar leads to hypoxia of the vessel wall and that this
initiates smooth muscle cell proliferation and migration.
However, the mechanisms of collar-induced lesions are
controversial. Intimal thickening was also observed in the
rabbit thyroid artery, a small branch of the carotid artery,
despite the absence of vasa vasorum in these arteries [32].
Nevertheless, Barker et al. [33] demonstrated that removal
of the adventitia containing the vasa vasorum of carotid
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R.S. Scotland et al. / Cardiovascular Research 46 (2000) 403 – 411
arteries from rabbits, induces an intimal lesion supporting
the hypothesis that disruption of vasa vasorum blood flow
initiates vascular lesions. Furthermore ligation of the side
branches of femoral arteries, and hence disruption of vasa
vasorum blood flow, in the Yucatan miniature pig produces
significant intimal hyperplasia [34]. Similarly, removal of
the periaortic fat containing the vasa vasorum of canine
ascending aorta results in extensive medial necrosis and an
acute decrease in aortic distensibility [35]. Collectively
these studies suggest that impairment of nutrient blood
flow through the vasa vasorum may contribute to vessel
wall hypoxia and that they might allow predisposition to
atherosclerosis or other degenerative conditions of the host
vessel. All of these studies, however, used artificial means
to reduce flow through vasa vasorum. The fact that vasa
vasorum regulate their own tone identifies a possible
mechanism whereby flow through the vasa may be disrupted. Atherosclerosis is associated with elevation of
ET-1 levels [36] and it is conceivable that arterial vasa
might constrict in response to this ET-1 thus reducing
nutrient blood flow to the vessel wall.
The number of vasa vasorum supplying large arteries
remains constant throughout life. However, vasa can
proliferate in response to acute arterial injury. In particular,
studies on the vasa vasorum of coronary arteries from
hypercholesterolemic pigs suggest that the three-dimensional pattern of second order vasa increases and becomes
disorganised [5]. As mentioned above, the vasa vasorum
are sensitive to oxygen tension and therefore the proliferation of vasa vasorum in arteries occluded by atheromatous
plaques may be due to decreased oxygen tension in the
vessel wall. The severity of atherosclerosis is directly
related to the density of adventitial vasa [15] but the role
of newly formed microvessels in the chronic processes of
atherogenesis is unknown. There are currently two postulates [37]; firstly, microvessels that grow into the media
and intima may nourish and stabilise the growing plaque
by delivering growth factors and hormones. Support for
this hypothesis is provided by immunohistochemical and
confocal microscopy studies on microvessels in human
coronary arteries [38]. These studies demonstrated the
presence of microvessels in thickened intimas and atherosclerotic plaques that was directly related to the size of the
plaque and inversely related to lumen diameter. This rich
neovascularisation could be traced from adventitial vasa
vasorum through the media and occurred predominantly at
the base of the plaque at the border with the normal intima.
Albumin and fibrinogen leakage was associated with these
microvessels and immunoglobulin containing cells were
observed surrounding microvessels indicating that intimal
vascularisation contributes to nourishment of atheromatous
plaques and inflammation in conduit blood vessel walls.
Unlike the resident vasa, it has been suggested that these
newly developed vasa are typically fragile endothelial
channels without smooth muscle layers [39] and therefore
do not have the capacity to regulate tone. In contrast, a
study by Williams et al. in monkeys demonstrates vasa in
the intima-media of coronary arteries with a single layer of
smooth muscle, suggesting that these vessels may have
some capacity to regulate tone [15]. This study also
suggests that the smooth muscle of vasa vasorum of
atherosclerotic arteries is more sensitive to vasoconstrictors, possibly due to the enhancing actions of local
endothelins. A decrease in blood flow to the vessel wall
would contribute to further vessel wall hypoxia and
presumably thereby aid the progression of atheroma formation.
It has also been suggested that these vasa may limit the
progression of the lesion by maintaining nutrient blood
flow to the thickened vessel wall. Indeed studies using the
microsphere technique in coronary arteries of monkeys
demonstrated a substantial increase in blood flow through
the vasa vasorum of arteries of atherosclerotic animals
[15]. Furthermore, Barker et al [33] demonstrated that
intimal lesions in rabbit carotid arteries can regress on the
formation of a ‘neoadventitia’, suggesting that maintenance of blood flow through the vasa vasorum might limit
neointimal formation.
Therefore, there is a paradox regarding the benefit of
proliferation of vasa vasorum in atherosclerosis. Whilst
these vessels provide a significant increase in nutrient
blood flow to the thickened artery wall, several studies
suggest that these vessels are ‘leaky’ and prone to rupture.
These vessels may thereby contribute to intraplaque
haemorrhage, plaque rupture and formation of thrombi. In
addition if, in some cases, these vessels do contain smooth
muscle, they appear to be more sensitive to constrictors
and therefore blood flow through these particular vessels
may be compromised.
3.2. Restenosis
Transluminal angioplasty is now a common method of
restoring blood flow in vessels that are occluded with
atheromatous plaques. However, within 6 months, vessel
size often returns to preangioplasty dimensions (restenosis). Recently, a three-dimensional study of the
anatomy of normal and balloon-injured porcine coronary
arteries has demonstrated that there is a decrease in the
ratio of first order to second order vasa 28 days after
balloon injury. Furthermore, the density of vasa was
directly related to the severity of stenosis [40]. However, it
is not yet clear whether these changes in the vasa vasorum
are a consequence or a cause of changes in the vessel wall.
Balloon angioplasty is associated with stretching and
splitting of the intima / media as well as the adventitia of
the vessel [41]. Additionally, several studies clearly show
endothelial damage of the large vessel following this
procedure. Of interest is the possibility that these procedures may also damage the endothelium of the vasa
vasorum resulting in impaired endothelium-dependent
control of blood flow to the vessel wall and subsequent
R.S. Scotland et al. / Cardiovascular Research 46 (2000) 403 – 411
vessel wall hypoxia. Hypoxia itself is a stimulus for the
induction of several growth factors and cytokines and in
this way may contribute to the mechanisms of luminal
narrowing. Several authors have investigated the effect of
angioplasty on the morphology and blood flow through the
vasa vasorum but the findings are inconclusive. In 1982,
Train et al. observed a fine vascular network around the
femoral arteries of three patients immediately following
angioplasty that may have represented hypertrophied vasa
[42]. Yet Cragg et al. did not observe any acute (up to 7
days postangioplasty) morphological changes in the vasa
vasorum of dilated canine carotid arteries [43]. In contrast,
studies on the long-term effects of angioplasty in dogs
showed considerable stretching and rupture of the vasa
vasorum that was followed by extensive proliferation of
vasa [44]. However, this increased vascularisation following angioplasty completely regresses by 18 months [45].
The functional effects of these morphological changes in
the vasa vasorum are not known; measurements of vasa
vasorum blood flow, using the microsphere technique in
dogs, showed that blood flow may be increased [43] or
decreased [46] immediately after angioplasty. Furthermore,
in a balloon-injury model in the rat carotid artery it has
been shown that there is an initial decrease in neuronal
CGRP and SP-immunoreactivity around the vasa vasorum
of the injured vessel and a compensatory increase in the
control contralateral vessel [9]. It is clear that CGRP and
SP may normally vasodilate vasa vasorum [6] and therefore a decrease in the supply of these peptides would
presumably decrease vasa vasorum blood flow to the host
vessel wall.
3.3. Hypertension
Power-Doppler imaging of blood flow through the vasa
vasorum of normal human carotid arteries demonstrate that
perfusion of vasa vasorum occurs after the main flow
velocity in the lumen of the carotid artery [47]. This
suggests that, similar to the coronary circulation, the vasa
vasorum fill during diastole. It may therefore be expected
that an increase in arterial pressure in the host vessel leads
to a reduction in perfusion of the vasa vasorum. In order to
test this hypothesis Sacks used a model of a section of the
aortic wall, comprising a simulated vasa embedded in a
block of soft material, and measured the patency of the
vasa (flow per unit pressure drop) [48]. In this model,
elevation of radial stress on the vasa resulted in decreased
patency of vasa vasorum. The author suggests that elevation of blood pressure and thus compression of the aortic
wall reduces blood flow through the vasa vasorum. Furthermore, measurements of blood flow in canine thoracic
aortic wall, using the microsphere technique, indicate a
substantial reduction in the vasodilator capacity of vasa
vasorum in animals with chronic hypertension [49]. Therefore it is possible that associated increases in wall tension
in hypertension distort the vasa vasorum thus leading to
409
underperfusion and changes in blood vessel walls. Indeed
previous studies in canine aorta indicate that disruption of
vasa vasorum flow produces acute changes in distensibility
and structural changes of the aortic wall [35]. Studies using
isolated vasa vasorum indicate that under normal conditions these vessels are insensitive to NA and AngII.
However, it is clear that the contractile reactivity of these
vessels may be dramatically altered under certain conditions [21] and therefore this insensitivity to vasoconstrictors is not due to the lack of expression of receptors.
Therefore, in a situation such as hypertension, it is
conceivable that increases in sensitivity to constrictors may
occur. Such decreases in vasa vasorum blood flow would
compound the situation by producing vessel wall hypoxia,
a stimulus for remodelling.
3.4. Deep vein thrombosis and vein bypasses
The vasa venarum is likely to be the most important
source of nutrition for the walls of large veins. O’Neill [4]
demonstrated that experimental disruption of the vasa
venarum of canine jugular vein results in an increase in
permeability of endothelial cells. Subsequent accumulation
of fluid beneath the endothelial layer caused the endothelial cells to lift off. It is apparent that damage to endothelial
cells is the precursor for thrombus formation. Therefore,
disruption of blood flow through microvessels supplying
large veins may have a role in endothelial damage and
subsequent thrombosis.
Similarly, one may speculate that disruption of vasa
venarum blood flow during venous bypasses has implications on the viability of the bypass. Vasa are sensitive to
oxygen tension and therefore exposure of vasa venarum to
arterial oxygen tension may also alter the number and
distribution of these vessels. However, despite acute
changes in distribution of vasa venarum [50], there is little
evidence that indicates that these changes affect the health
of the grafted vein. For example, a study of vein bypasses
in dogs demonstrated that these procedures do not affect
the integrity of the endothelium of the arterialised vein
[51].
4. Conclusion
Despite an increase in attention to the vasa vasorum
relatively little is known about the regulation of blood flow
through these microvessels. Recent studies on isolated vasa
suggest that tone may be regulated by several vasoactive
substances including endothelium and neuronally-derived
agents. However, the profile of reactivity of the vasa
vasorum appears to be different to other resistance arteries
of a similar diameter, a possible reflection of their function. Studies with endothelin suggest that this mediator
may be of particular importance in determining the contractile state and reactivity of the vasa vasorum. Therefore,
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R.S. Scotland et al. / Cardiovascular Research 46 (2000) 403 – 411
endothelin receptor antagonists may be useful in preserving or restoring nutrient blood flow to conduit blood vessel
walls. Disruption of the vasa vasorum of healthy blood
vessels results in vascular lesions and certain vascular
diseases are associated with changes in the vasa vasorum,
which are directly related to the severity of the disease. It
is clear that these vessels are not passive bystanders and a
greater understanding of their biology is likely to give
insight into processes of vascular disease and identify
novel targets for drug action.
[16]
[17]
[18]
[19]
Acknowledgements
We would like to thank Professor J.M. Polak and Dr.
L.D.K Buttery for their technical advice and Dr. R. Corder
for his kind gift of antibody to NPY. AA is the recipient of
an intermediate BHF Fellowship and RS is funded by an
MRC studentship.
[20]
[21]
[22]
[23]
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