Effets de l’homocystéine sur les processus angiogéniques et l’invasion tumorale du tissu endothélialin vivo et in vitro

Abstract

Angiogenesis is the formation of new blood vessels from pre-existing vessels, existing in many pathophysiological conditions, including tumorogenesis. In the activation of the endothelial cell (EC),VEGF-A (vascular endothelial growth factor) is the decisive stage of the process. Since homocysteine (Hcy) has an angiotoxic power, the aim of this work is to assess (in vivo and in vitro studies) the effect of this molecule on angiogenesis and tumor invasion involving VEGF and its two powerful signaling effectors: the HIF(hypoxia –inducible factor ) -1α and the OPN (Osteopontin). In the in vivo study, the conception of our Hyperhomocysteinemia model (HH) is confirmed by biochemical study (total Hcy, total protein, CRP and MDA) and histological one (aorta, liver and thymus). We showed that HH potentiated the presence of VEGF-A in thymus, suggesting the installation of a reparative angiogenesis effect, in the same time to an inhibition of VEGF-A and HIF-1α expressions in aortic tissue. In the in vitro study, we evaluated the antiangiogenic effect of Hcy previously revealed in vivo, by exposing HUVECs to cytotoxic and pathophysiological concentrations of Hcy. In fact, the first range revealed a strong inhibition of the proliferation, migration and capillary sprouting associated with senescence and apoptosis of EC. In pathophysiological range, inhibition is always dose -dependent and became completely significant in adenosine condition. Hcy seems to act by an hypomethylation mechanism. In addition, the results of qRT-PCR revealed that Hcy inhibited gene expression of VEGF-A and OPN in dosedependent manner. This study shows a new aspect of antiangiogenic properties of Hcy, by impaired the expression of genes involved in tumor angiogenesis.