Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 657

10.6.16 Mechanical Signals

In addition to sprouting, intussusception and possibly vasculogenesis from nearby
differentiating progenitor cells, vascularization during wound healing mainly results
from translocation of intact vessels by mechanical forces mediated by myofibrob-
lasts, i.e., non-angiogenic expansion of pre-existing vessels [ 1331 ]. Myofibroblasts
and activated fibroblasts participate in the rapid revascularization of the wound
by contraction of the granulation tissue that pulls nearby intact blood vessels.
Resulting vascular loops can then expand (vessel enlargement and elongation). This
process that relies on a mechanical stress field is initially independent of endothelial
sprouting and proliferation. Secondarily, the neovascular network can be remodeled
by splitting, sprouting, and regression of vessels.
In addition, tissue deformation modulates angiogenic signals. Mechanical signals
regulate angiogenesis via both endothelial and smooth muscle cells. Cyclic tensile
strain [ 1332 ]: (1) upregulates the secretion of angiopoietin-2 and PDGFbb dimer
and (2) enhances endothelial migration and sprout formation. Applied strain permits
a directed migration of smooth myocyte toward migrating endothelial cells. A
mechanical stimulus such as a cyclic tensile strain can trigger a cascade of auto-
and paracrine signaling between endothelial and smooth muscle cells. 78
Hemodynamic forces cooperate with chemical messengers and coregulate angio-
genesis. According to the nature of its local gradient (negative or positive), VEGF
causes either vessel dilation or sprouting [ 1333 ]. Endoluminal flow attenuates
VEGF-induced endothelial sprouting via NO, whereas interstitial flow encourages
endothelial sprouting, irrespective of flow direction or VEGF gradient [ 1333 ].
Transverse flow can act on mechanosensors at intercellular adhesion sites. Intra-
luminal flow operates via wall shear stress and induced intramural tension, i.e.,
on both endothelial and smooth muscle cells. Endothelial tip cells preferentially
protrude according to the direction of interstitial flow, toward vessels with higher
internal pressure, in the direction of an increasing VEGF gradient.
Regions of high deformations are associated with a long-range VEGFa gradient
generated by interstitial cells, a local overexpression of VEGFR2 receptor, and local
differences in endothelial cell proliferation [ 1334 ]. In addition to the upregulation
of VEGFR2 expression, cytoskeletal tension regulates the cell proliferation, via
activity of CDK inhibitors such as CKI1b and activators such as cyclin-D.
In cultured tissues with engineered vascular networks, effects of matrix defor-
mation on neovascular network formation and remodeling can depend on loading
application time, as early and delayed mechanical loadings with respect to culture

78 Factor VEGF during the early stage of angiogenesis activates cell migration and sprout-
ing. Angiopoietin-1 mediates the interactions between endothelial and smooth muscle cells.
Angiopoietin-2 disrupts these interactions to promote independent migration. Both Ang1 and Ang2
are produced by vascular cells, bind to receptor TIE2, and act synergistically with VEGF to regulate
angiogenesis. Homodimer PDGFbb released by endothelial cells at a late stage of angiogenesis
recruits smooth muscle cells to stabilize the nascent sprouts.