Force-Induced Polarized Mitosis of Endothelial and Smooth
Muscle Cells in Arterial Remodeling
Dorota Dajnowiec, Peter J.B. Sabatini, Thea C. Van Rossum, Jacky T.K. Lam, Ming Zhang,
Andras Kapus, B. Lowell Langille
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Abstract—Arteries display highly directional growth and remodeling that are specific to increases in the mechanical loads
imposed on them by blood pressure, blood flow, and lengthwise tensile forces that are transmitted from the tissues to
which they are attached. This study examined the effect of mechanical forces on the direction in which mitosis delivers
daughter cells, as a mechanism for directional growth. Lateral forces were imposed on surface integrins of cultured
endothelial cells by seeding the cells with arginine-glycine-aspartate peptide–coated magnetic microspheres and
applying a magnetic field. Video images revealed that the mitotic axis of dividing cells became highly biased in the
direction of applied force. Distribution of cortactin, which participates in polarized mitoses driven by other stimuli, was
highly sensitive to mechanical loading and interfering with cortactin function arrested cell growth. Smooth muscle cell
mitoses also proved to be sensitive to mechanical force: when lengthwise force imposed on rabbit carotid arteries was
altered by excision of a vessel segment and reanastomosis of the cut ends, direction of mitosis was dramatically altered.
These findings indicate that influences of mechanical force can modulate the manner in which mitosis of vascular cells
contributes to reorganization of arterial wall tissue. (Hypertension. 2007;50:255-260.)
Key Words: blood vessels 䡲 blood pressure 䡲 hyperplasia 䡲 integrins 䡲 tensile stress 䡲 remodeling
䡲 vascular diseases
B
which the microtubule system becomes highly directionalized.6,7 In particular, the polarized positioning of the endothelial
microtubule organizing center and associated centrosome may
play a pivotal role in aligning the spindle axis during mitosis. In
addition, endothelial cells elongate in the shear direction, and
cell shape alone can influence direction of mitosis.8 Accordingly, we found that endothelial cells exposed to shear stress
underwent mitosis that was consistently aligned with shear stress
both in vivo and in vitro; furthermore, alignment of cells was lost
when blood flow was obstructed in vivo.7
In the current study, we tested whether imposing lateral force
on cell surface–associated integrins, which are thought to be
important in force transduction, is sufficient to polarize mitosis
and/or whether cell elongation in the shear direction is required.
We also asked whether the observations that we made with
endothelium apply to mechanically loaded smooth muscle cells.
lood vessels are constantly subjected to mechanical
forces that greatly influence their development, function,
and pathology. For example, chronic increases in shear stress
selectively gives rise to growth of arterial diameter,1,2
whereas increased pressure and lengthwise stretch cause wall
thickening3 and axial growth,4 respectively. Smooth muscle
cells, the only cells resident in the media, must achieve much
of this remodeling, but it is unclear how these cells selectively
deliver extracellular matrix or daughter cells after mitosis in
different directions in response to different mechanical
forces. The endothelial monolayer also remodels in response
to hemodynamic forces, with shear stress inducing elongation, cytoskeletal alignment, and planar cell polarity of these
cells. Again, growth and remodeling are affected, because
regrowth after endothelial denudation proceeds much more
rapidly along the shear axis then perpendicular to it.5
We hypothesized that mitosis of vascular cells induced by
mechanical forces is polarized so that delivery of daughter
cells occurs in a direction that is specific for the force that is
applied to the tissue. We initially focused on endothelial cells
because of profound morphological responses to shear stress
that they display. Most notably, shear stress induces planar
cell polarity of endothelium, a cell-polarizing response in
Methods
Imposition of Mechanical Load on Endothelial
Cells via Magnetic Microspheres
To explore the role of local, ligand-specific loading of cell surface
structures on mitosis, ferromagnetic microspheres coated with integrin ligand were seeded onto cell surfaces, allowed to stabilize for 1
Received February 23, 2007; first decision March 16, 2007; revision accepted April 13, 2007.
From the Department of Laboratory Medicine and Pathobiology (D.D., P.J.B.S., T.C.V.R., J.T.K.L., M.Z., B.L.L.), University of Toronto, Toronto,
Ontario, Canada; Toronto General Research Institute (D.D., P.J.B.S., T.C.V.R., J.T.K.L., M.Z., B.L.L.), University Health Network, Toronto, Ontario,
Canada; and the Department of Surgery (A.K.), University of Toronto and St Michael’s Hospital Research Institute, Toronto, Ontario, Canada.
Correspondence to B. Lowell Langille, MaRS Centre, Toronto Medical Discovery Tower, 3rd Floor, Room 3–308, 101 College St, Toronto, Ontario,
M5G 1L7, Canada. E-mail [email protected]
© 2007 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/HYPERTENSIONAHA.107.089730
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hour, and exposed to magnetic fields.9 Endothelial cells at 90% to
100% confluence were cultured in sterile tissue culture dishes
(Falcon, VWR) in Medium199 plus 10% FBS (Invitrogen), 1%
amphotericin B (Fungizone), and 1% penicillin/streptomycin. The
cells were seeded with 2 to 5 ␮m iron (II and III) oxide microspheres
(Sigma) that were coated with cyclic arginine-glycine-aspartate
(RGD) peptides (Peptides International), which bind to endothelial
␣5␤1 and ␣v␤3 integrins,10 at a seeding density of 2 to 4 microspheres
per cell. Microspheres coated with RGD peptides mimic ligation to
vitronectin or fibronectin but not collagen. Four 3⫻12⫻12-mm
neodymium magnets (Jobmaster Magnets Canada Inc) were stacked
and placed within 1.5 to 2.0 cm of the field to be observed so that
they exerted a mean lateral force of 1.13⫻10⫺2 pN per bead on the
microspheres (see below). In control experiments, the magnets were
omitted. Twenty-four– hour phase contrast videos of the cultures
were made using a Nikon TE300 inverted optical microscope using
a ⫻10 objective, with images captured at 5-minute intervals. For all
of the conditions, 3 independent experiments were performed, with
an average of 25 to 55 mitoses per experiment undergoing analysis.
Analysis consisted of measuring the angle between force direction
and nuclear centroids (geometric centers) of daughter cells at the end
of cytokinesis using Simple PCI software.
Mean force per bead (F) was determined by capturing video
images of beads suspended in culture medium at 37°C as they were
drawn toward permanent magnets positioned as for experiments.
Bead radius (R) and velocity (v) were measured and combined with
viscosity of the culture medium (␮⫽0.0069 P at 37°C) to determine
force on the beads using Stokes Law (F⫽6 ␲␮Rv).
Analysis of Endothelial Cell Alignment With Force
Cell shape can influence direction of mitosis,8 and endothelial cells
coalign with shear stress7; therefore, we tested whether the cells also
aligned with the direction of force imposed on magnetic microspheres bound to cell surface integrins, as described previously.7
Briefly, a rectangular grid, with lines parallel and perpendicular to
axis of the magnetic force, was placed over the final frame (24-hour
time point) of each movie, and the number of cells per millimeter
that were encountered by lines parallel to the magnetic force axis was
determined. The inverse of this number (millimeters per cell)
provided the mean cell length parallel to the direction of applied
force (L//). Mean cell length in the direction perpendicular to the applied
force (L⬜) was determined in a similar manner. The ratio of these
dimensions (L///L⬜) provided a measure of elongation in the direction of
force. This simple method for assessing directional elongation of cells in
monolayers avoids limitations of “shape factors” that are based on cell
area/perimeter relations, limitations that are related to the indeterminacy
of cell perimeter because of its fractal nature.
Role of Cortactin in Polarized Mitosis of
Endothelial Cells
Cortactin can participate in orientation of mitotic spindles; therefore,
endothelial cells were transfected by electroporation (Amaxa) with
10 ␮g of wild-type cortactin (control) and 10 ␮g of nonphosphorylatable mutant cortactin11,12 at 10⫻105 cell density. RGD-coated
microspheres were again used to impose force and were subjected to
24 hours of magnetic force (as described above).
Immunofluorescence Detection of Proteins
Endothelial cells were fixed with 4% paraformaldehyde in 0.1 mol/L
of PBS (2 mmol/L of NaH2PO4, 8 mmol/L of Na2HPO4, 150 mmol/L
of NaCl, 0.1 mmol/L of CaCl2, and 0.1 mmol/L of MgCl2 [pH 7.4])
for 20 minutes at room temperature, washed, and then permeabilized
with 0.2% Triton X-100. Cells were then incubated with primary
antibodies to cortactin (Chemicon; 1:100) and ␣-tubulin (Sigma;
1:50) for 1 hour, washed with PBS, and incubated with fluorescently
conjugated secondary antibodies for 30 minutes. Secondary antibodies included Alexa 568 goat anti-rabbit (Molecular Probes/Invitrogen; 1:100) and fluorescein isothiocyanate– conjugated donkey antimouse (Jackson ImmunoResearch Laboratories Inc; 1:100).
Confocal images of samples were examined using a Olympus
FluoView 1000 (IX 81) inverted microscope (⫻60 oil immersion
objective, numerical aperture⫽1.4; Olympus America Inc).
Elevation of Axial Strain In Vivo
Animal experimental protocols were approved by the animal care
committee of the University Health Network and were conducted in
accordance with the Guidelines of the Canadian Council on Animal
Care. We also examined the influence of tensile forces on polarized
mitosis of vascular smooth muscle in vivo. Adult male New Zealand
White rabbits (body weight, 3.0 kg ⫾0.5 kg) and 3-week-old
weanling rabbits (body weight, 1.1 kg ⫾0.2 kg) were anesthetized by
IM injection of 0.8 mL/kg of xylazine (20 mg/mL) and 1.8 mL of
ketamine hydrochloride (90 mg/mL), and anesthesia was maintained
with a continuous intravenous infusion of the 1:9 xylazine/ketamine
mixture (0.03 mL/min). A cervical midline incision was made, a
segment of the left carotid artery was excised, and the cut ends of the
vessel were reanastomosed using an 8 – 0 polypropylene suture
(Ethicon). The length of the excised artery was adjusted such that
lengthwise stretch of the artery was increased from resting levels of
60% to 100%.4 The incision was closed, and the animals were given
0.5 mL of Longisil (150 000 IU/mL of benzathine penicillin G,
150 000 IU/mL of procaine penicillin G, 0.9 mg of methyl paraben,
and 0.1 mL of propyl paraben) IM and 0.2 mL of the analgesic
Buprenex (0.3 mg/mL of buprenorphine HCl) SC. Arteries from
unmanipulated animals served as controls.
At surgery or 3 days later, the rabbits were given IM injections of
the thymidine analog bromodeoxyuridine (BrdU; 30 mg/kg), which
incorporates into DNA in the S phase of the cell cycle. BrdU is
cleared from the circulation within 60 minutes13; however, tissues
were fixed ⱖ24 hours after injections, after BrdU-labeled cells had
completed mitosis, so that the relative positions of doublets of
daughter cell nuclei, detected by BrdU immunohistochemistry, could
be used to assess the direction of mitosis.7 Six treatment groups were
studied: groups 1 to 3, nonsurgical controls fixed 1, 3, or 7 days after
BrdU injection, respectively; group 4, BrdU injection at surgery, fixed
after 1 day; and groups 5 and 6, BrdU injection at 3 days after surgery,
euthanized 1 or 4 days later, respectively. Later time points allow for
assessment of relative migration of daughter cells after mitosis.
Tissue Fixation and Immunohistochemistry
Rabbits were euthanized with IV injection of barbiturate (pentobarbital sodium, 100 mg/kg, Bimeda-MTC Animal Health Inc) overdose. A rapid bilateral thoracotomy was followed by retrograde
cannulation of the descending thoracic aorta and perfusion–fixation
of the carotid arteries with 3% paraformaldehyde in PBS for 20
minutes at a perfusion pressure of 100 mm Hg. Whole-mount
preparations of the vessel segments were prepared for en face immunohistochemistry. Alternatively, histological en face sections were
stained with anti-BrdU antibody (Abcam), and images captured with a
Nikon TE300 inverted optical microscope were analyzed using Simple
PCI software to determine the axis of replication of daughter cells. The
distance between centroids (geometric centers) of daughter cell nuclei
was also determined to test for migration of daughter cells over time.
Statistics
Sample sizes for in vivo experiments are presented in the Results
sections and figure legends. All of the in vitro data represent a
minimum of 3 independent replicates of each experiment. ANOVA
followed by Bonferroni-corrected t tests were used to determine
whether force application caused preferential orientation of mitosis
or significant migration after mitosis. Student’s t test was used to
determine whether force caused significant elongation of endothelial
cells. P⬍0.05 was taken to indicate statistical significance.
Results
Lateral Loading of Integrins Induces Orientation
of Endothelial Cell Mitosis
Seeding RGD-coated microspheres, with and without application of force, did not affect mitosis rates or cell viability
Dajnowiec et al
Polarized Mitosis in Arterial Remodeling
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Figure 1. Direction of endothelial cell mitosis is regulated by
lateral loading of integrins. Analysis of direction of endothelial
cell mitosis seeded with RGD-coated microspheres without
(䡺) and with (f) application of lateral force for 24 hours. The
abscissa represents the absolute angle (degree) of mitotic doublets from the axis of force, binned in intervals of 30°. The ordinate represents the percentage of cells found to orient within 0°
to 30° of the force vector, 30° to 60° of the force vector, and
60° to 90° of the force vector.
and, as expected, cells displayed random orientation of
mitoses when no force was applied (Figure 1). During
application of lateral force to RGD-coated beads over 24
hours, the orientation of cell division became strongly biased
along the force vector. Accordingly, ⬎50% of mitoses were
oriented within 30° of the force vector, and ⬇85% of mitoses
were within 60° of the force vector.
Cell shape can influence orientation of mitosis,8 and
endothelial cells elongate under shear stress; therefore, we
tested whether loading integrins with microspheres induces
similar elongation. Cells displayed significant elongation in
the force direction length:width ratios after 24 hours, albeit to
a much lesser extent than with application of physiological
shear stress for the same duration. L///L⬜ became slightly
⬍1.5 (Figure 2), whereas shear stress caused cells to become
⬎2.5-fold longer in the shear direction than perpendicular to
shear.7 However, no elongation was detectable at 16 hours
after application of force (L///L⬜⫽1.04), a time by which 78%
of the mitoses analyzed in Figure 1 were completed. These
findings indicate that force, without coincident shape change,
is probably an adequate stimulus for directional mitosis.
Role of Cortactin Is Control of Mitosis
Immunofluorescence imaging revealed that phosphorylated
cortactin is ubiquitously expressed in confluent endothelial
cells, including in the nucleus, diffusively through the cytoplasm and in a punctate distribution at the cell periphery
(Figure 3, top). Imposition of lateral force effected redistribution of cortactin. Nuclear localization was lost, as was
diffuse staining in the cell body and punctate staining at the
cell periphery. Instead, the antibody decorated a subset of
microtubules (Figure 3, bottom).
Localized distribution of cortactin and its phosphorylation
by the nonreceptor tyrosine kinase Src8 have been implicated
in directional mitosis; therefore, we expressed nonphosphorylatable cortactin in endothelial cells to test whether polar-
Figure 2. Imposition of mechanical load in vitro stimulates elongation of endothelial cells. Bar graph represents length/width
ratio of endothelial cells exposed (f) or not exposed (䡺) to lateral force for 24 hours. Application of force via RGD peptide
induced significant elongation of endothelial cells (P⬍0.05).
ization of mitosis was affected. Surprisingly, growth arrest
resulted (data not shown), possibly because of loss of target
sites for the capture of astral microtubules.8,14,15
Imposition of Mechanical Load In Vivo Induces
Orientation of Smooth Muscle Cell Mitosis
En face sections of carotid arteries from control animals showed
consistent circumferential orientation of all of the daughter cell
doublets, which indicated that mitoses were highly polarized in
these unmanipulated vessels (Figure 4A through 4C). This
distribution was not altered when tissue was examined 3 or 7
days after BrdU infusion; however, a slight but significant
increase in separation of the daughter cells at later times
indicates some postmitotic migration of the cells (Figure 5).
After longitudinal strain was increased from 60% to 100%,
⬍50% of doublets labeled with BrdU at surgery exhibited
circumferential orientation of mitosis 24 hours later (Figure
4D). When cells were labeled at 3 days and examined an
additional 24 hours or 96 hours later, no preferential relative
orientation of daughter cells was observed (Figure 4E and
4F). The data indicate that normalization of tensile stretch in
arteries involved increased delivery of daughter smooth
muscle cells in the axial direction.
Discussion
During development, arterial adaptations to mechanical
forces tune growth and reorganization of the vascular system
to the changing blood supply demands of developing periph-
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Figure 3. Lateral force imposed on integrins regulates cortactin distribution in endothelial cells. Micrographs display immunofluorescence staining of phosphorylated cortactin (red) and ␣-tubulin (green) without (top) and with (bottom) application of lateral force to integrins. Phosphorylated cortactin is normally expressed diffusely in the cell body and in a punctate pattern at the cell periphery. On imposition of force, cortactin localizes to a subdomain of microtubules.
eral tissues, to the changing blood pressures that are required
to drive these flows, and to the changing lengthwise tensions
that are imposed on arteries by growth of contiguous tissues.16 Remodeling induced by mechanical forces also adapts
the adult circulation to chronic changes in cardiovascular
function, including those associated with exercise training,
reproductive cycles, and pregnancy, and it affects the pro-
gression of vascular pathologies, including hypertension,
atherosclerosis, and restenosis.3,17
Perhaps the most striking feature of these remodeling
responses is that they consistently tend to normalize the
mechanical loads imposed on the tissue, but it has remained
unclear how vascular cells appropriately deliver new tissue in
the circumferential, radial, or axial direction to selectively
Figure 4. Smooth muscle cells divide in
circumferential direction in vivo, but
mechanical load changes orientation of
smooth muscle cells of mitosis. Analysis
of en face sections of nonsurgical rabbit
common carotids revealed that most cells
divide preferentially in the circumferential
direction. The x axis is the angle from the
circumferential direction, and the y axis is
percentage of cells in the particular angle.
(A) Group 1, nonsurgical, euthanized 1 day
after BrdU injection. (B) Group 2, nonsurgical, euthanized 3 days after BrdU injection. (C) Group 3, nonsurgical, euthanized
7 days after BrdU injection. The circumferential orientation of smooth muscle cells in
nonsurgical common carotids is lost on
imposition of axial strain, because smooth
muscle daughter cells randomize their orientation. (D) Group 4, surgical, BrdU
injected at surgery, euthanized 1 day later.
(E) Group 5, surgical, BrdU injected 3 days
after surgery, euthanized 1 day later. (F)
Group 6, surgical, BrdU injected 3 days
after surgery, euthanized 4 days later.
Dajnowiec et al
Figure 5. Smooth muscle cells migrate after mitosis in arterial
tissue. Graph displays distance between postmitotic daughter
cell nuclei in carotid arteries at 1 day (group 1), 3 days (group 2),
and 7 days (group 3) after labeling S-phase cells with BrdU.
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normalize shear stress, circumferential tension, or lengthwise
tension, respectively. We have shown that an interesting
remodeling of elastic lamellae contributes to this directionspecific tissue reorganization,18 and we now report that the
delivery of daughter cells during mitosis is sensitive to directional forces and that integrins or integrin-associated molecules
are capable of sensing force and initiating polarized mitosis.
The polarization of endothelial cell mitoses that followed
the application of lateral forces to ␣5␤1 and ␣v␤3 integrins
mimicked the effects of shear stress that we reported
recently.7 Likewise, the capacity of this force application to
recapitulate shear-induced endothelial cell elongation, albeit
to a lesser extent than that seen with physiological levels of
shear, suggests that integrin loading is an adequate stimulus
for a significant repertoire of endothelial cell responses to
shear. Other sites of shear sensing/transduction have been
implicated, with intriguing recent findings particularly implicating the endothelial cell– cell adhesion molecule platelet-endothelial cell adhesion molecule 1 (PECAM-1), and it could be argued
that simple transmission of tension via cytoskeletal structures to
PECAM-1 at cell junctions was eliciting cell elongation and
polarized mitoses. However, additional studies, to be published
elsewhere, have shown that magnetic microsphere loading of
integrins versus PECAM-1 (using microspheres coated with
anti–PECAM-1 antibody) produced very different profiles of
intracellular signaling, for example, for mitogen-activated protein kinases, phosphatidylinositol 3⬘-kinase, and glycogen synthase kinase-3␤. Indeed, 24 hours of PECAM-1 loading consistently led to apoptosis of most cells. These findings argue that
the integrin loading that we studied here was producing a
ligand-specific effect.
An important issue was whether polarized mitosis was a
direct effect of mechanical loading or whether it was secondary to force-induced change in cell shape. We found, however, that change in cell shape was a late event, with no
elongation being detectable after 16 hours. Similarly, shearinduced shape change requires 12 to 24 hours for postconfluent endothelium. Because the great majority (⬇80%) of
mitoses that occur in 24 hours of loading are completed by 16
hours, it is very likely that the highly polarized mitoses of
these cells can be initiated as a primary response to force.
Polarized Mitosis in Arterial Remodeling
259
The signaling pathways through which force regulates orientation of mitoses are unknown. The microtubule system of
cultured endothelial cells that have been exposed to shear stress
displays planar cell polarity, an integrin-dependent behavior in
which the microtubule organizing center moves downstream of
the cell nuclei.19,20 This bias in microtubule positioning before
the onset of mitotic spindle formation may underlie directional
mitosis; therefore, critical signals downstream from integrins
during initiation of planar cell polarity (eg, Cdc42, atypical
protein kinase C␨, and glycogen synthase kinase-3␤) merit
investigation in the regulation of polarized mitoses.19,20
Alternatively, directional cell division has been well studied for some cases where mitoses segregate differentiated
from undifferentiated (stem) daughter cells after parent stem
cell division.21,22 Although caution is needed when extrapolating from these studies of asymmetrical cell division in
which daughter cells differ in the cellular constituents and
often in size23,24 to mitoses that simply deliver similar
daughter cells in defined directions, it is likely that the
regulation of the 2 modes of polarized mitosis overlap.
Therefore, it will be of interest to assess the roles, in
directional vascular cell mitosis, of key players in the regulation of asymmetrical cell division, including heterotrimeric
G proteins and their regulators (RGS7, RGS14, the guanidine
nucleotide exchange factor, RIC-8, GoLoco, and NuMA).25,26
Asymmetrical cell division may also provide clues concerning how mitotic spindles become oriented in a specific
direction during mitosis. In these mitoses, cell cortical domains, often composed of actin and actin-associated proteins
(cortactin and ezrin), capture astral microtubules and exert
pulling forces that wrench the spindle into a defined location,
possibly through the actions of the microtubule-based motor
protein dynein.20,23–25,27 Accordingly, culturing single isolated cells on micropatterned substrates of different shapes
induces cells to divide along an axis that reflects the geometry
of the substrate, and cortactin distribution is biased in a
manner that reflects the direction of mitosis.8
The tensile forces imposed on integrins that proved capable
of orienting endothelial cell mitosis also caused dramatic
cortactin redistribution but in a manner that was unanticipated. A punctate pattern at the cell periphery, plus a diffuse
distribution throughout the central regions of the cell, including the nucleus, prevailed in unloaded cells. After imposing
tensile stress on integrins for 24 hours, cortactin was excluded
from the nucleus and became largely localized to a subset of
microtubules. This localization may reflect different roles for
cortactin in endothelial and/or force-loaded cells; alternatively,
microtubule-based transport may deliver cortactin to patches that
orient mitoses in the early phases of the cell cycle.
Tyrosine phosphorylation of cortactin by Src was important in polarized mitoses of cells grown on patterned substrates8; therefore, we attempted to assess functions of cortactin by expressing a nonphosphorylatable mutant form of
the protein. Surprisingly, expressing this modified cortactin
induced growth arrest, a finding that underscores the importance of the protein in the control of mitoses but that
neutralized attempts to define how it may participate in
polarization of the process.
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Our observation that mechanical forces influence the direction of mitosis of smooth muscle cells in vivo is potentially of central importance to arterial remodeling. We do not
know whether cell shape or pulsatile arterial distension
underlies the predominantly circumferential orientation of cell
division in unmanipulated arteries, but the effects of perturbations in lengthwise mechanical load were striking and could
clearly contribute to the marked axial growth that follows
increases in these forces, whether these increases are experimental4 or because of growth of tissues to which arteries are tethered.
Undoubtedly, this mode of remodeling may also participate in
developmental and adaptive reorganization of many mechanically loaded nonvascular tissues. In some instances, (forceinduced) mitosis in one direction may drive tissue growth in the
same direction or in an orthogonal direction, for example,
through intercalation of daughter cells between pre-existing
resident cells. Something like the latter may occur during
enlargement of flow-loaded arteries, when increases in vessel
circumference3 accompany axial division of endothelial cells.7
Ultimately, control of mitoses and distribution of daughter
cells are central to the most important vascular pathologies,
including atherosclerosis, restenosis, and transplant arteriosclerosis. The capacity of normal and abnormal blood pressures and flows to influence the delivery of daughter cells
may, therefore, impact significantly on these pathologies and
may provide novel targets for therapeutic interventions.
Perspectives
This study demonstrates that physical forces imposed on
vascular tissue have a dramatic effect on cell division and the
directional delivery of daughter cells during arterial remodeling. This capacity of force transduction to orient mitosis has
the potential to contribute greatly to the preferential wall
thickening that accompanies hypertension, the growth of arterial
diameter that follows elevation of blood flow rate, and the
lengthwise growth of arteries that occurs when adjacent tissues
grow or hypertrophy. As such, this phenomenon is central to the
coordination of arterial growth with developmental changes in
arterial function, the structural adaptation of the mature circulation to long-term alterations in cardiovascular function, and
pathologic remodeling of vascular tissues.
Acknowledgment
We thank Donna Johnston for technical assistance.
Sources of Funding
The study was supported by grant T4910 from the Heart and Stroke
Foundation of Ontario to B.L.L. and a Canadian Institutes for Health
Research operating grant and Premier’s Research Excellence Award
to A.K. D.D. was supported by a studentship from the Canadian
Institutes for Health Research and Canadian Hypertension Society.
P.J.B.S. was supported by a studentship from the Canadian Institutes
for Health Research. T.C.V.R. was supported by the Charles Hollenberg Summer Studentship Program. J.T.K.L. was supported by a
Heart and Stroke Foundation of Ontario summer studentship.
Disclosures
None.
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Hypertension. 2007;50:255-260; originally published online May 7, 2007;
doi: 10.1161/HYPERTENSIONAHA.107.089730
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