Figure 1. Direct and indirect effects of homocysteine on angiogenesis.

Lines with arrows indicate permissive actions, and lines with end bars indicate inhibitory actions. Red lines indicate the contributions of the work of Jacovina and colleagues (17) to these pathways. Homocysteine (HC) induces tissue factor (TF) expression on the endothelial cell and inhibits annexin A2–dependent plasminogen (PGN) activation by TPA. In addition, homocysteine increases plasminogen activator inhibitor-1 (PAI-1) expression to impair further fibrinolysis. By activating tissue factor expression, homocysteine promotes local generation of thrombin, which converts fibrinogen (FGN) to fibrin, impairs fibrinolysis by increasing TAFI, and activates factor XIII (FXIII). FXIIIa, in turn, not only crosslinks fibrin, but also crosslinks the integrin α_Vβ₃ to VEGFR2, which stimulates angiogenesis. Thrombin, along with factor Xa (FXa), activates MMPs (to aMMPs) to promote endothelial cell migration and angiogenesis. Offsetting these indirect angiogenic effects of thrombin are its inhibitory effects, which include factor XIIIa–mediated inhibition of thrombospondin-1 (TSP-1) and the generation of angiogenesis inhibitors endostatin and angiostatin by MMPs acting on collagen 18 and plasminogen, respectively. α_Vβ₃-VEGFR2, factor XIIIa–crosslinked α_Vβ₃-VEGFR2; A2, annexin A2; FDP, fibrin degradation product; Pn, plasmin.