Abstract-The extracellular matrix (ECM) is critical for all aspects of vascular biology. In concert with supporting cells, endothelial cells (ECs) assemble a laminin-rich basement membrane matrix that provides structural and organizational stability. During the onset of angiogenesis, this basement membrane matrix is degraded by proteinases, among which membrane-type matrix metalloproteinases (MT-MMPs) are particularly significant. As angiogenesis proceeds, ECM serves essential functions in supporting key signaling events involved in regulating EC migration, invasion, proliferation, and survival. Moreover, the provisional ECM serves as a pliable scaffold wherein mechanical guidance forces are established among distal ECs, thereby providing organizational cues in the absence of cell-cell contact. Finally, through specific integrin-dependent signal transduction pathways, ECM controls the EC cytoskeleton to orchestrate the complex process of vascular morphogenesis by which proliferating ECs organize into multicellular tubes with functional lumens. Thus, the composition of ECM and therefore the regulation of ECM degradation and remodeling serves pivotally in the control of lumen and tube formation and, finally, neovessel stability and maturation. (Circ Res. 2005;97:1093-1107.)Key Words: extracellular matrix Ⅲ endothelial cells Ⅲ angiogenesis Ⅲ vascular morphogenesis Ⅲ vessel stabilization T he extracellular matrix (ECM) provides critical support for vascular endothelium. Primarily through adhesive interactions with integrins on the endothelial cell (EC) surface, ECM provides a scaffold essential for maintaining the organization of vascular ECs into blood vessels. In addition, EC adhesion to ECM is required for EC proliferation, migration, morphogenesis, survival, and ultimately blood vessel stabilization, all of which are critical for neovascularization. The specific mechanisms through which ECM supports EC functions are complex and involve both external structural support and regulation of multiple signaling pathways within the cell, including signaling pathways that control apoptosis, proliferation, the cytoskeleton, and cell shape. Thus, through both mechanical and signaling func- tions, the ECM affects many fundamental aspects of EC biology. Moreover, the diversity of ECM components in the EC microenvironment and the diversity of mechanisms for controlling the synthesis and degradation of ECM have suggested an intricate level of complexity sufficient for ECM to exert significant and precise control over many aspects of neovascularization and blood vessel maturation. The purpose of this review is to provide an overview of the importance of ECM for the biology of vascular ECs, and it is divided into 4 parts: (1) ECM Function in Cellular Morphogenesis and Signaling; (2) ECM Function in EC Lumen Formation and the Switch to Vessel Maturation; (3) Endothelial ECM: Remodeling; and (4) Endothelial ECM Biosynthesis, Assembly, and Structural Functions: Critical Role for EC Basement Membrane Matrix in Vessel Stabilization. ...