TYPE IV COLLAGEN IS A MAJOR basement membrane component of blood vessels and plays a key role in the regulation of endothelial cell adhesion, migration, and angiogenesis. Assembly of the type IV collagen network dictates the organization of the vascular basement membrane, which is required for endothelial cell adhesion to the extracellular matrix via interactions with cell surface α1β1-and αvβ3-integrins (10). Collagen IV peptides generated by proteolytic cleavage can be either proangiogenic (HepI, HepIII)(10) or antiangiogenic (tumstatin). Thus collagen cleavage is tightly regulated during angiogenesis to promote endothelial sprouting and lumen formation during the early stages and vessel maturation in the later stages (see Ref. 6 for a recent review).

Given the critical role of collagen IV in angiogenesis, surprisingly little is known about the molecular mechanisms regulating its synthesis. Low-density lipoproteins increase pathologic collagen IV expression by human aortic endothelial cells by a transforming growth factor-β (TGF-β) and MAP kinase-dependent mechanism (15). High shear stress also upregulates type IV collagen synthesis in cultured human umbilical vein endothelial cells (HUVECs; 18), and cAMP-protein kinase A (PKA) promotes collagen IV deposition by cultured rat adrenal medullary endothelial cells (11). In this issue, Wang and Su (17) demonstrate a novel regulation of collagen IV synthesis and secretion by nitric oxide (NO) in porcine pulmonary artery endothelial cells and aortic endothelial cells. Interestingly, NO concomitantly increased the expression of αvβ3, a major collagen IV receptor. This coordinated response results in increased focal adhesion kinase (FAK) phosphorylation and alterations in cell adhesion, migration, and proliferation. Further evidence to link the coordinated regulation of integrin and collagen IV expression comes from the finding that NO stimulated endothelial monolayer wound repair, proliferation, and tube formation that was inhibited by collagen IV small interfering RNA (siRNA) or a neutralizing antibody against αvβ3-integrin (17). NO regulation of collagen IV expression was mediated by the cGMP-protein kinase G (PKG) pathway since both the PKG inhibitor KT5823 and PKG siRNA decreased NO-induced changes in collagen IV protein and mRNA expression as well as endothelial angiogenesis.