fibrin and Corneal-Neovascularization

When plasma levels of homocysteine (HC), a thiol amino acid formed upon methionine demethylation, exceed 12 muM, individuals are at increased risk of developing large vessel atherothrombosis and small vessel dysfunction. The annexin A2 complex (termed "A2") is the cell surface coreceptor for plasminogen and TPA and accelerates the catalytic activation of plasmin, the major fibrinolytic agent in mammals. We previously showed that HC prevents A2-mediated, TPA-dependent activation of plasminogen in vitro by disulfide derivatization of the "tail" domain of A2. We also demonstrated that fibrinolysis and angiogenesis are severely impaired in A2-deficient mice. We now report here that, although hyperhomocysteinemic mice had a normal coagulation profile and normal platelet function, fibrin accumulated in their tissues due to reduced perivascular fibrinolytic activity and angiogenesis was impaired. A2 isolated from hyperhomocysteinemic mice failed to fully support TPA-dependent plasmin activation. However, infusion of hyperhomocysteinemic mice with fresh recombinant A2, which localized to neoangiogenic endothelial cells, resulted in normalization of angiogenesis and disappearance of peri- and intravascular fibrin. We therefore conclude that hyperhomocysteinemia impairs postnatal angiogenesis by derivatizing A2, preventing perivascular fibrinolysis, and inhibiting directed endothelial cell migration. These findings provide a mechanistic explanation for microvascular dysfunction and macrovascular occlusion in individuals with hyperhomocysteinemia.

Topics: Animals; Annexin A2; Cell Movement; Corneal Neovascularization; Diet; Endothelial Cells; Fibrin; Fibrinolysis; Homocysteine; Hyperhomocysteinemia; Male; Methionine; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Recombinant Proteins

The chemokine stromal cell-derived factor-1 (SDF-1) has been shown to be involved in cell migration. As the receptor CXCR-4 is expressed on endothelial cells and upregulated by angiogenic factors, we were prompted to study the effect of SDF-1 on angiogenesis in endothelial cells from microvasculature. This study demonstrates that SDF-1 induces an angiogenic effect in vitro, primarily in a tridimensional fibrin gel. The increase in capillary tube formation was evident after a 10-day incubation with SDF-1. This was associated with a mild increase in VEGF production by microvascular endothelial cells (ELISA and rt-PCR) and a potent chemotactic effect. SDF-1 also induced an in vivo angiogenic activity as shown in the model of the rabbit corneal pocket. However, the angiogenesis was located in an area rich in inflammatory cells. The results of our study suggest that these data underline the potential role of SDF-1 in angiogenesis as the microvascular endothelial cells were greatly involved in this process.

Topics: Animals; Anti-HIV Agents; Capillaries; Cell Division; Cell Line; Chemokine CXCL12; Chemokines, CXC; Chemotaxis; Cornea; Corneal Neovascularization; Endothelial Growth Factors; Endothelium, Vascular; Fibrin; Fibroblast Growth Factor 2; Humans; In Vitro Techniques; Lymphokines; Microcirculation; Neovascularization, Physiologic; Rabbits; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors