Matrix metalloproteinase control of capillary morphogenesis

Matrix metalloproteinases (MMPs) play crucial roles in a variety of normal (e.g., blood vessel formation, bone development) and pathophysiological (e.g., wound healing, cancer) processes. This is not only due to their ability to degrade the surrounding extracellular matrix (ECM), but also because MMPs function to reveal cryptic matrix binding sites, release matrix-bound growth factors inherent to these processes, and activate a variety of cell surface molecules. The process of blood vessel formation, in particular, is regulated by what is widely classified as the angiogenic switch: a mixture of both pro- and antiangiogenic factors that function to counteract each other unless the stimuli from one side exceeds the other to disrupt the quiescent state. Although it was initially thought that MMPs were strictly proangiogenic, new functions for this proteolytic family, such as mediating vascular regression and generating matrix fragments with antiangiogenic capacities, have been discovered in the last decade. These findings cast MMPs as multifaceted pro- and antiangiogenic effectors. The purpose of this review is to introduce the reader to the general structure and characterization of the MMP family and to discuss the temporal and spatial regulation of their gene expression and enzymatic activity in the following crucial steps associated with angiogenesis: degradation of the vascular basement membrane, proliferation and invasion of endothelial cells within the subjacent ECM, organization into immature tubules, maturation of these nascent vessels, and the pruning and regression of the vascular network.