Human endothelial cells can be induced to form capillary-like tubular networks in collagen gels. We have used this in vitro model and representational difference analysis to identify genes involved in the formation of new blood vessels. HESR1 (HEY-1/HRT-1/CHF-2/gridlock), a basic helix-loop-helix protein related to the hairy/enhancer of split/HES family, is absent in migrating and proliferating cultures of endothelial cells but is rapidly induced during capillary-like network formation. HESR1 is detectable in all adult tissues and at high levels in well vascularized organs such as heart and brain. Its expression is also enriched in aorta and purified capillaries. Overexpression of HESR1 in endothelial cells down-regulates vascular endothelial cell growth factor receptor-2 (VEGFR2) mRNA levels and blocks proliferation, migration, and network formation. Interestingly, reduction of expression of HESR1 by antisense oligonucleotides also blocks endothelial cell network formation in vitro. Finally, HESR1 expression is altered in several breast, lung, and kidney tumors. These data are consistent with a temporal model for HESR1 action where down-regulation at the initiation of new vessel budding is required to allow VEGFR2-mediated migration and proliferation, but re-expression of HESR1 is necessary for induction of tubular network formation and continued maintenance of the mature, quiescent vessel.The formation of new blood vessels by angiogenesis is critical to development of normal tissues as well as growth of solid tumors (1, 2). Angiogenesis is a multistep sequence of distinct cellular processes beginning with degradation of extracellular matrix, then proliferation, and migration of endothelial cells (EC), 1 followed by lumen formation and functional maturation (3, 4). Currently, two families of EC-specific growth factors are known to regulate these steps. The vascular endothelial growth factors (VEGFs), together with the more widely expressed and pleiotropic fibroblast growth factors (FGFs), promote EC migration, proliferation, and tube formation (5-9). The second family is composed of angiopoietins (Ang) 1-5, of which Ang-1 and Ang-2, acting through the Tie-2 receptor tyrosine kinase, are known to be critical for the later processes of vessel maturation and stabilization (10 -12). The VEGFs, which can drive all of the early stages of angiogenesis, act through two tyrosine kinase receptors, VEGFR1 (flt-1) (13) and VEGFR2 (KDR/ flk-1) (14). EC also express neuropilin-1 and neuropilin-2, which only bind the VEGF 165 isoform (15).Although transcription factors such as HIF and Tfeb are known to mediate EC responses to specific angiogenic inducers (hypoxia and placental growth, respectively (16, 17)), downstream events coordinating EC responses to general angiogenic growth factors remain unknown. In particular, it is not clear how sequential cellular processes can be triggered by continued or repeated exposure to the same stimulus, although a model for reiterative signaling has been proposed to explain FGFinduced branc...
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