Endothelial cells induce expression of Notch3 in vascular support cells

Abstract

The communication of endothelial cells and vascular support cells (pericytes and smooth muscle cells) is crucial for the assembly and subsequent function of blood vessels. To assess the significance of this heterotypic interaction on gene expression, we screened for factors that were modulated by coculturing of these different cell types. We identified Notch3 as one gene that is strongly induced in fibroblasts, pericytes, and smooth muscle cells upon coculture with endothelial cells. Notch3 belongs to an evolutionarily conserved family of transmembrane receptors that are known to govern cell fate decisions and differentiation in diverse cell types. In particular, Notch3, the causative gene of the neurovascular disorder CADSASIL, has been linked to smooth muscle differentiation. To investigate the mechanism that governs Notch3 induction by endothelial cells, we employed chemical inhibitors to select signaling pathways. Interestingly, Notch3 upregulation was completely abolished by the Notch signaling inhibitor DAPT, raising the possibility that Notch3 acts through an autoregulatory loop. Our study provides compelling evidence that during blood vessel formation the expression of Notch3 in pericytes and smooth muscle cells is modulated by endothelial cells, and this serves to facilitate the differentiation of vascular support cells leading to stable blood vessels. Supported by NIH HL076428.