Combinatory action of XXXX and MAP kinase pathways maintains endothelial-cell integrity.

@entity1 @entity8947 @entity7242 @entity2240 @entity13977 @entity319 @entity3392
Blood vessels normally maintain stereotyped lumen diameters and their stable structures are crucial for vascular function. However, very little is known about the molecular mechanisms controlling the maintenance of vessel diameters and the integrity of endothelial cells. We investigated this issue in @entity3392 embryos by a chemical genetics approach. Small molecule libraries were screened using live Tg(kdrl:GRCFP)(zn1) transgenic embryos in which endothelial cells are specifically labeled with GFP. By analyzing the effects of compounds on the morphology and function of embryonic blood vessels after lumen formation, @entity13977 , a putative @entity7242 kinase inhibitor, was identified as capable of specifically reducing vascular lumen size by interrupting endothelial-cell integrity. The inhibitory effect is not due to @entity7242 or general VEGF signaling inhibition because another @entity7242 inhibitor and @entity7242 morpholino as well as several @entity319 inhibitors failed to produce a similar phenotype. After profiling a panel of 22 representative @entity1 kinases and surveying published data, we selected a few possible new candidates. Combinational analysis of these candidate kinase inhibitors established that @entity13977 induced endothelial collapse by inhibiting both the @entity319 and MAP kinase pathways. More importantly, combinatory use of two clinically approved drugs @entity8947 and @entity2240 produced the same phenotype. This is the first study to elucidate the pathways controlling maintenance of endothelial integrity using a chemical genetics approach, indicating that endothelial integrity is controlled by the combined action of the @entity319 and MAP kinase pathways. Our results also suggest the possible side effect of the combination of two anticancer drugs on the circulatory system.
