Abstract 615: Transactivation of EGFR by TGFβ Induces Hypertension by Increasing Arteriolar Myogenic Response

Abstract

Myogenic tone (MT) is an intrinsic property of arteriolar smooth muscle cells (SMCs) that contract when intraluminal pressure is increased. MT is a relevant physiological mechanism to maintain stable blood flow through important organs like kidney and brain, thus preventing organ damage that could derive from increase in blood pressure (BP). On the other hand, enhancement of the basal MT could raise BP by increasing systemic vascular resistance, thus further contributing to hypertension. Several studies in animal models suggest that primary dysfunctions in SMCs can directly cause abnormalities in BP. However, in hypertensive animal models investigated so far, the increment of MT is accompanied by a stronger response to G protein coupled receptor (GPCR) agonists, thus making it difficult to distinguish whether increased vascular resistance and BP are primary effects of a more robust MT or the consequence of increased reactivity to agonists. Here we show an increased MT in mice deficient of Emilin1 , an extracellular inhibitor of TGFβ signaling, displaying a phenotype of spontaneous hypertension. We also found that the higher TGFβ signaling in Emilin1 deficient SMCs stimulates heparin binding epidermal growth factor (HB-EGF) expression and subsequent transactivation of the EGF receptor. When step-increases in intraluminal pressure are applied to mesenteric resistance arteries (MRA), the combined stimulation of mechanosensor and EGF transactivation results into activation of transient receptor potential classical type 6 (TRPC6) and melastatin type 4 (TRPM4) channels, stimulation of voltage dependent calcium channels (VDCC). To put our data into translational perspective, we measured MT on resistance arteries isolated from hypertensive patients and untreated normotensives, finding increased MT and TGFβ signaling in the former group. In addition, by using an antibody neutralizing EGFR signaling we found a normalization of the increased MT, thus confirming the relevance of TGFβ-EGFR pathway in humans. Overall our results suggest that primary increase of MT induced by TGFβ-EGFR transactivation can cause hypertension and that higher TGFβ-EGFR signaling and MT are common alterations of resistance arteries of hypertensive patients.