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(Circulation Research. 2001;89:195.)
© 2001 American Heart Association, Inc.

Editorial

Drilling for Oxygen

Angiogenesis Involves Proteolysis of the Extracellular Matrix

Peter Libby, Uwe Schönbeck

From the Leducq Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Peter Libby, MD, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Woman’s Hospital, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail plibby@rics.bwh.harvard.edu

Key Words: extracellular matrix • matrix metalloproteinases • endothelium • inflammation • angiogenesis

All acknowledge the importance of endothelial migration and proliferation in angiogenesis. However, the sprouting of extensions of established vascular channels in most tissues requires much more. The extracellular space does not consist of a vacuum, permitting free spread of endothelial sprouts during angiogenesis. Rather, a complex and often dense extracellular matrix invests the parenchymal cells and microvascular channels of most organs. The endothelial cells must penetrate this extracellular matrix to make a new vessel (Figure 1A). Immediately surrounding the endothelial cells, a basement membrane of type IV collagen, laminin, fibronectin, and many other matrix macromolecules presents the first obstacle to neovascular sprout formation (Figure 1B). That barrier breached, the nascent microvessel must then burrow through collagen fibrils, elastin, microfibrillar proteins, proteoglycans, and other constituents of the surrounding extracellular matrix (Figure 1C). How do the endothelial cells drill their way through these layered impediments to form a new vessel?

View larger version (52K): [in this window] [in a new window]   Figure 1. Formation of neovessels. A, To form new vessels, the endothelial cell layer (typically in a venule) must break down the subjacent basement membrane, composed of a complex mixture of many extracellular matrix components including type IV collagen, laminin, and fibronectin. B, Local action of proteolytic enzymes such as type IV collagenase (MMP-2) activated by MT1-MMP (MMP-14) aids dissolution of a patch of basement membrane. C, Other proteinases, including the MMPs that degrade fibrillar collagen (eg, MMP-1 and MMP-13) or proteoglycan core proteins (eg, MMP-9), assist the subsequent step in which endothelial cells force a . . . [Full Text of this Article]

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