Regulation of proteolysis in vascular remodeling

Abstract

The extracellular matrix (ECM) is the scaffolding on which cells adhere and is comprised of fibrous proteins (such as collagens and elastin), proteoglycans, and water. Matrix-cell adhesion provides essential cell survival cues and the matrix sequesters various growth factors that can regulate the behavior of adjacent cells. However, the matrix, and in particular, the basement membrane, presents a confining barrier that limits vascular cell movement. Thus, reorganization of the ECM is an essential step in vascular remodeling processes. ECM proteolysis allows for sprouting angiogenesis and arteriogenesis in response to physiological stimuli, such as increased blood flow or increased metabolic activity. However, unregulated extracellular matrix degradation is associated with vascular diseases such as diabetic retinopathy, tumor angiogenesis, and thrombosis. In this review, we describe the structure and function of the major matrix protease families secreted by endothelial cells: The matrix metalloproteinases (MMPs) and plasminogen activator (PA)/plasmin system. We also discuss the function and regulation of the endogenous protease inhibitors, the tissue inhibitor of metalloproteinases (TIMPs), and the plasminogen activator inhibitors (PAIs). The equilibrium between proteases and inhibitors plays an integral role in establishing the maintenance and structural remodeling of the vasculature. We review the regulation of these proteases and their inhibitors in vascular cells, particularly in response to altered shear stress. The specific involvement of members of the MMP/TIMP system and the PA/plasmin/PAI system proteases in vascular remodeling of capillaries (angiogenesis) and arteries (arteriogenesis) are discussed.