The Role of the ECM in Regulating Vascular Integrin Functions

The angiogenic switch model [10] posits that a delicate balance exists between pro- and antiangiogenic factors. Changes in the levels of such factors regulate whether a blood vessel remains in a quiescent state, or becomes activated and angiogenic. Many ECM proteins within the vascular basement membrane, acting via integrins, are major regulators of the angiogenic switch. An emerging theme is that the exact function of a given ECM protein, as well as the integrin receptor(s) it binds, can be greatly affected by proteolytic events [11]. Several examples of how such endogenous "cryptic" fragments affect microvascular function are described next.

Type IV collagen, a major component of the vascular basement membrane, is normally a ligand for the integrins a1P1 and a2P1. MMP9 cleavage of collagen IV yields the potent angiogenesis inhibitor tumstatin. In vitro tumstatin induces apoptosis of endothelial cells by inhibiting the protein translation machinery. Likewise in vivo, tumstatin is a potent inhibitor of tumor neovascularization. Tumstatin's antiangiogenic effects are mediated by binding to the avP3 integrin.

Proteolysis of the C-terminal NC1 domain of collagens XV or XVIII generates the antiangiogenic factor endostatin. Murine endostatin inhibits VEGF- or bFGF-induced endothelial cell proliferation and migration in vitro, and also represses pathological angiogenesis in some transplantable tumor models. Endostatin is reportedly a ligand for both a5P1 and avP3. Intact collagen XV and XVIII do not bind to these integrins. Importantly, while the exact molecular mechanisms by which endostatin exerts its antiangiogenic effects remain unknown, it is clear that they are different from those regulated by tumstatin and do not require avP3.

Proteolysis of many other ECM proteins also generates antiangiogenic fragments, although the mechanistic details of how they exert these effects remain unclear. For example, when proteolytically cleaved, thrombospondin-1 "cryptic fragments" bind to the scavenger receptor CD36 and serve as potent repressors of angiogenesis [12]. Similarly, degra-

Angiostatin Collagen A XV/XVIII

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Essentials of Human Physiology

Essentials of Human Physiology

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