ECM Remodeling in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 198

In addition to EC-generated forces regulating angiogenesis, a recent study by
Kilarski et al. reported that external forces generated by myofibroblasts pulling on
the ECM during wound contraction mediated the formation of vascular loops by
pulling on preexisting vascular beds [ 137 ]. This process, known as intussusceptive
microvascular growth [ 138 ], demonstrates that stromal cells influence the process of
angiogenesis in multiple ways. Not only do they secrete pro- and anti-angiogenic
soluble factors, some of which influence the expression and activity of certain
MMPs, and act as pericytes to stabilize the nascent vasculature, they also generate
local forces that dynamically remodel the ECM and preexisting tissue structures.
Understanding the complex interplay between ECs, stromal cells, and the ECM
remains an ongoing challenge for the field.
6 Conclusions
The ECM continuously remodels in response to multiple instructive cues during
the complex process of capillary morphogenesis. From early development of the
capillary plexus in vasculogenesis, to the angiogenic sprouting of new vasculature
in ischemic tissue in adults, many different proteinases work in concert with ECs
and stromal cells to drive matrix breakdown, capillary sprouting, and subsequent
maturation. Various soluble MMPs, membrane-bound MMPs, ADAMs, and
inhibitors of each of these active players, play important roles to maintain the
balance between pro- and anti-angiogenic cues in quiescent vessels, and to tip the
scales to induce capillary morphogenesis and blood vessel development when
needed. An increasing body of literature strongly suggests that pericytes are not
only essential in promoting the stabilization and long-term functionality of
capillary networks, but they can also exert their influence on vessel formation in a
multitude of ways. As discussed here, pericytes also dynamically communicate
with ECs to influence matrix proteolysis, synthesis, integrin expression profiles,
and the mechanical properties of the interstitial matrix, all of which can influence
angiogenesis. Further work is needed to dissect the exact roles of these various
players on matrix remodeling and angiogenesis.
Acknowledgments The authors gratefully acknowledge funding from the National Heart, Lung,
and Blood Institute (R01-HL-085339) and a CAREER award from the National Science Foun-
dation (CBET-0968216). S.J.G. was supported by a predoctoral fellowship from NIH Cellular
Biotechnology Training Grant (T32-GM-008353).
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