Differential expression of thymosin beta-10 by early passage and senescentvascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis

VPF/VEGF acts selectively on the vascular endothelium to enhance permeabili ty, induce cell migration and division, and delay replicative senescence. T o understand the changes in gene expression during endothelial senescence, we investigated genes that were differentially expressed in early vs, late passage (senescent) human dermal endothelial cells (HDMEC) using cDNA array hybridization, Early passage HDMEC cultured with or without VPF/VEGF overe xpressed 9 and underexpressed 6 genes in comparison with their senescent co unterparts. Thymosin beta -10 expression was modulated by VPF/VEGF and was strikingly down-regulated in senescent EC, The beta -thymosins are actin G- sequestering peptides that regulate actin dynamics and are overexpressed in neoplastic transformation. We have also identified senescent EC in the hum an aorta at sites overlying atherosclerotic plaques. These EC expressed sen escence-associated neutral beta -galactosidase and, in contrast to adventit ial microvessel endothelium, exhibited weak staining for thymosin beta -10. ISH performed on human malignant tumors revealed strong thymosin beta -10 expression in tumor blood vessels. This is the first report that T beta -10 expression is significantly reduced in senescent EC, that VPF/VEGF modulat es thymosin beta -10 expression, and that EC can become senescent in vivo, The reduced expression of thymosin beta -10 may contribute to the senescent phenotype by reducing EC plasticity and thus impairing their response to m igratory stimuli.