Defining the role of Notch3 in smooth muscle differentiation and blood vessel formation

Abstract

The heterotypic communication of endothelial cells and mural cells (pericytes, smooth muscle cells or fibroblasts) is crucial for the assembly and subsequent function of blood vessels. We have demonstrated that Notch3 is strongly induced in mural cells upon coculture with endothelial cells in vitro. To assess the significance of Notch3 on blood vessel formation, we silenced Notch3 by siRNA in mural cells and cocultured them with endothelial cells in a 3‐dimensional angiogenesis assay. Interestingly, deletion of Notch3 decreased endothelial‐promoted smooth muscle differentiation and attenuated mural cell‐enhanced angiogenesis. In vivo, Notch3 is selectively expressed in mural cells, including retinal pericytes, and our data show that Notch3 deficient mice exhibit decreased expression of smooth muscle α‐actin and enlarged arteries in retinas. Furthermore, preliminary results indicate that Notch3 expression is perturbed in a mouse model of retinopathy of prematurity (ROP). Our study provides evidence that during blood vessel formation the expression of Notch3 in mural cells is modulated by endothelial cells, which in turn serves to facilitate the differentiation of mural cells and regulate blood vessel formation. Supported by NIH HL076428.