Overexpression of Caveolin-1 Inhibits Endothelial Cell Proliferation by Arresting the Cell Cycle at G0/G1 Phase

Abstract

Angiogenesis, the development of new blood vessels from pre-existing capillary, is required for tumor growth and metastasis. The process is not fully understood yet, but involves endothelial cell proliferation, migration and differentiation. Recently, we have shown that over-expression of caveolin-1, a putative transformation suppressor gene, inhibits VEGFR-2 and MEK-1-mediated mitogenic signal to the nucleus. Conversely, angiogenic activators suppress caveolin-1 expression in endothelial cells. However, whether caveolin-1 expression affects endothelial cell proliferation is not clear. In the present study, we infect human endothelial cells with adenovirus expressing caveolin-1 and show that transient over-expression of caveolin-1 dramatically inhibits the proliferation of human endothelial cells. Consistent with caveolin-1 functioning as an inhibitor for protein kinases, over-expression of caveolin-1 inhibits the activity of VEGFR-2 (KDR) and down-stream p42/44 MAP kinase. Furthermore, over-expression of caveolin-1 prevents VEGF-induced down-regulation of the cyclin-dependent kinase inhibitor p27kip1and Rb phosphorylation, and subsequently arrests endothelial cells in the G0/G1 phase. Thus, our results suggest that caveolin-1, as a negative regulator of endothelial cell proliferation, may be a potential target for the control of angiogenesis.