Molecular Balance of Capillary Tube Formation versus Regression in Wound Repair: Role of Matrix Metalloproteinases and Their Inhibitors

In this review, we discuss the identification of distinct matrix metalloproteinases (MMPs) and their inhibitors that differentially control the processes of capillary tube formation (morphogenesis) versus capillary tube regression in three-dimensional (3D) collagen matrices. This work directly relates to both granulation tissue formation and regression during wound repair. The membrane metalloproteinase, MT1-MMP (MMP-14), is required for endothelial cell (EC) tube formation using in vitro assays that mimic vasculogenesis or angiogenic sprouting in 3D collagen matrices. These events are markedly blocked by small interfering RNA (siRNA) suppression of MT1-MMP in ECs or by addition of tissue inhibitor of metalloproteinases (TIMPs)-2, -3, and -4 but not TIMP-1. In contrast, MMP-1 and MMP-10 are strongly induced during EC tube formation to regulate the process of tube regression (following activation by serine proteases) rather than formation. TIMP-1, which selectively inhibits soluble MMPs, blocks tube regression by inhibiting MMP-1 and MMP-10 while having no influence on EC tube formation. siRNA suppression of MMP-1 and MMP-10 markedly blocks tube regression without affecting tube formation. Furthermore, we discuss that pericyte-induced stabilization of EC tube networks in our model system appears to occur through EC-derived TIMP-2 and pericyte-derived TIMP-3 to block both the capillary tube formation and regression pathways.