ECM Remodeling in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 181

ECM Remodeling in Angiogenesis

Stephanie J. Grainger and Andrew J. Putnam

Abstract Remodeling of the extracellular matrix (ECM) is an essential component
of the complex vascular biology that drives each step within the angiogenic cascade.
The process of angiogenesis involves a series of events that depend heavily on
proteinases and their ability to remodel the ECM, originating with degradation of
the basement membrane to allow for endothelial cell (EC) breakthrough, migration,
and proliferation. This is followed by organization into nascent blood vessel sprouts,
vessel maturation and stabilization, deposition of basement membrane around the
new vessels, and finally pruning or remodeling of the new vasculature for physio-
logical needs. There is evidence that ECs cooperate with supporting stromal cells to
orchestrate these remodeling events and ultimately to create pericyte-stabilized
functional networks of vessels. During angiogenesis, proteinases not only directly
breakdown the ECM to create a physical path for new EC sprouts, they also
indirectly expose cryptic sites hidden within the ECM to alter the adhesive
microenvironment for pericytes and endothelial cells during sprouting. Physiolog-
ical control of angiogenesis is achieved in part by the angiogenic switch, in which a
balance of pro- and anti-angiogenic factors serves to maintain vessel homeostasis
under normal conditions. Proteinases, and certain matrix metalloproteinases
(MMPs) in particular, function on both sides of the angiogenic switch. They degrade
the basement membrane and nearby ECM surrounding established blood vessels at
the onset of angiogenesis, and release pro-angiogenic growth factors that would
remain otherwise bound to the ECM. However, they also negatively control
angiogenesis, as some proteolytic fragments of the ECM possess anti-angiogenic
properties. In addition to the chemical specificity of proteinases, emerging evidence
suggests that their ability to proteolytically remodel the ECM during angiogenesis

S. J. Grainger A. J. Putnam ( )

Department of Biomedical Engineering, University of Michigan,
1101 Beal Ave, Ann Arbor, MI 48109, USA
e-mail: [e-mail]

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