Orphan nuclear receptor TR 3 / Nur 77 regulates VEGF-A – induced angiogenesis through its transcriptional activity

JEM © The Rockefeller University Press $8.00 Vol. 203, No. 3, March 20, 2006 719–729 www.jem.org/cgi/doi/10.1084/jem.20051523 719 To grow beyond minimal size, tumors must induce the formation of new blood vessels (1, 2). They do so by secreting angiogenic factors, including basic fi broblast growth factor (bFGF), platelet-derived growth factor B, and members of the vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) family (3). Among these, VPF/VEGF (VEGF-A) is thought to be the most important for several reasons. It is expressed abundantly by most human and animal tumors and is able by itself to induce typical tumor blood vessels. In addition, when neutralized, the growth of VEGF-A–expressing tumors is strikingly inhibited (3, 4). VEGF-A is a multifunctional cytokine that acts through receptors that are expressed on vascular endothelium as well as on some other cell types. After interaction with VEGF-A, endothelial cells undergo extensive reprogramming of protease, integrin, and glucose transporter expression; are stimulated to migrate and divide; and are protected from apoptosis and senescence (4, 5). In addition, VEGF-A and other VPF/VEGF family members are the only angiogenic cytokines identifi ed thus far that render microvessels hyperpermeable to circulating macromolecules, a characteristic property of tumor and other angiogenic blood vessels (3). Although extensive eff orts have been made to delineate the mechanisms by which VEGF induces angiogenesis, little is known about the transcriptional events that regulate this important process. We therefore set out to identify endothelial cell immediate-early response genes whose expression was induced by VEGF-A with the thought that such genes might play key downstream roles in regulating angiogenesis. We performed DNA microarrays on cultured human umbilical vein endothelial cells (HUVECs) stimulated with VEGF-A165 and found that several genes were up-regulated. Among the most highly induced was TR3 (mouse homologue Nur77), an immediate-early response <doi>10.1084/jem.20051523</doi><aid>20051523</aid>Orphan nuclear receptor TR3/Nur77 regulates VEGF-A–induced angiogenesis through its transcriptional activity

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