Novel Negative Regulator of Angiogenesis

摘要

Vascular endothelial growth inhibitor (VEGI), a novel cytokine of the TNF-superfamily, is produced predominantly by endothelial cells and exhibits potent anti-angiogenic and anti- cancer activities (Zhai et al., Int. J. Cancer, 82:131, 1999). We report here that the effect of VEGI on endothelial cells is cell-cycle dependent: it mediates an early G1 arrest in quiescent cells, but induces apoptotic death in proliferating cells. VEGI inhibits DNA synthesis in GO-synchronized adult bovine aortic endothelial (ABAE) cells, which do not express VEGI themselves. The inhibition was reversible once VEGI was removed from the culture media. VEGI treated GO-cells lacked typical markers of late G1 phase, such as the hyperphosphorylation of the retinoblastoma gene product (pRB) and the upregulation of the c-myc gene, suggesting an early G1 arrest. In contrast, exposure of ABAE cells of logarithmic growth phase to VEGI resulted in apoptotic cell death. Consistently, VEGI expression in human umbilical cord vein endothelial cells (HUVEC) was found to be markedly upregulated in confluent cells when compared to proliferating cells. These findings support the view that VEGI may play a role in the maintenance of the low turn over rate of the endothelium of an established vasculature.