The basic helix-loop-helix transcription factor HESR1 regulates endothelial cell tube formation

Human endothelial cells can be induced to form capillary-like tubular netwo rks in collagen gels. We have used this in vitro model and representational difference analysis to identify genes involved in the formation of new blo od vessels. HESR1 (HEY-1/HRT-1/CHF-2/gridlock), a basic helix-loop-helix pr otein related to the hairy/enhancer of split/HES family, is absent in migra ting 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 br ain. Its expression is also enriched in aorta and purified capillaries. Ove rexpression of HESR1 in endothelial cells down-regulates vascular endotheli al cell growth factor receptor-2 (VEGFR2) mRNA levels and blocks proliferat ion, migration, and network formation. Interestingly, reduction of expressi on of HESR1 by antisense oligonucleotides also blocks endothelial cell netw ork formation in vitro. Finally, HESR1 expression is altered in several bre ast, lung, and kidney tumors. These data are consistent with a temporal mod el for HESR1 action where down-regulation at the initiation of new vessel b udding is required to allow VEGFR2-mediated migration and proliferation, bu t re-expression of HESR1 is necessary for induction of tubular network form ation and continued maintenance of the mature, quiescent vessel.