Notch signalling in smooth muscle cells during development and disease

The Notch signalling pathway is a highly conserved cell-cell signalling mechanism that plays a central role in the development and maturation of most vertebrate organs. In vertebrates, Notch receptors, several ligands, and components of the downstream signalling machinery are expressed in the vessel. Over the past decade, numerous studies have highlighted the critical role of the Notch pathway in the vasculature. The goal of this review is to summarize our current understanding of the contribution of Notch signalling in smooth muscle cells to vascular development and physiology. We further discuss the growing clinical importance of this pathway in human pathological conditions involving the vasculature, namely cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Alagille syndrome, and pulmonary arterial hypertension.     

The circadian protein period 1 contributes to blood pressure control and coordinately regulates renal sodium transport genes

The circadian clock protein period 1 (Per1) contributes to the regulation of expression of the α subunit of the renal epithelial sodium channel at the basal level and in response to the mineralocorticoid hormone aldosterone. The goals of the present study were to define the role of Per1 in the regulation of additional renal sodium handling genes in cortical collecting duct cells and to evaluate blood pressure (BP) in mice lacking functional Per1. To determine whether Per1 regulates additional genes important in renal sodium handling, a candidate gene approach was used. Immortalized collecting duct cells were transfected with a nontarget small interfering RNA or a Per1-specific small interfering RNA. Expression of the genes for α-epithelial sodium channel and Fxyd5, a positive regulator of Na, K-ATPase activity, decreased in response to Per1 knockdown. Conversely, mRNA expression of caveolin 1, Ube2e3, and ET-1, all negative effectors of epithelial sodium channel, was induced after Per1 knockdown. These results led us to evaluate BP in Per1 KO mice. Mice lacking Per1 exhibit significantly reduced BP and elevated renal ET-1 levels compared with wild-type animals. Given the established role of renal ET-1 in epithelial sodium channel inhibition and BP control, elevated renal ET-1 is one possible explanation for the lower BP observed in Per1 KO mice. These data support a role for the circadian clock protein Per1 in the coordinate regulation of genes involved in renal sodium reabsorption. Importantly, the lower BP observed in Per1 KO mice compared with wild-type mice suggests a role for Per1 in BP control as well.