Abstract 064: Transactivation of Egfr by Tgfβ Induces Hypertension by Increasing Arteriolar Myogenic Response

Emilin1 (E1) is a protein of the extracellular matrix regulating TGFβ bioavailability through proTGFβ proteolysis. E1 KO mice are hypertensive with increased TGFβ activation. As E1 is expressed in vessels from embryonic life to adulthood, is still unknown whether the E1 KO phenotype results from a developmental defect or lack of homeostatic role in the adult. To dissect this issue, we used a conditional gene targeting inactivating E1 in smooth muscle cells (SMCs) of adult mice, by the use of E1flox/flox and tamoxifen (TAM) inducible Cre recombinase specific for SMCs. When E1fl/fl mice carrying the Smmhc-CreERT2 were given TAM blood pressure significantly increased (SBP: 123±2 vs basal condition 104±3;***p< 0.001) as well as myogenic tone (MT) of resistance arteries (16.3±0.7 vs basal condition 11.4±0.1 % at 125 mmHg). How increased TGFβ signaling in SMCs could determine an increased MT is still unknown. Relevant to this, we found that the higher TGFβ signaling in E1 KO SMCs stimulates heparin binding epidermal growth factor (HB-EGF) and subsequent transactivation of the EGF receptor, a mechanism typically implied in potentiating MT. When mesenteric resistance arteries from E1 were subjected to step-increases in intraluminal pressure, EGFR inhibition rescued the increased MT. At the molecular level, TGFβ-induced EGFR transactivation resulted into the activation of transient receptor potential classical type 6 (TRPC6) and melastatin type 4 (TRPM4) channels. To put our data into translational perspective, we measured MT of resistance arteries isolated from hypertensive patients and normotensive subjects, finding increased MT (HT 16.4±0.7; NT 11±0.4;***p< 0.001) and TGFβ signaling in the former group. By using a neutralizing anti-TGFβ or an anti-EGFR we found a normalization of the increased MT (HT+anti-TGFβ 11±1.3; NT+anti-TGFβ 11.2±1.2;***p< 0.001 and HT+anti-EGFR 9±0.6; NT+anti-EGFR 10.8±1.1;***p< 0.001), thus confirming the relevance of TGFβ-EGFR pathway in humans. Taken together these data suggest that primary increase of MT induced by TGFβ-EGFR transactivation can cause hypertension and that higher TGFβ signaling and MT are common alterations of resistance arteries of hypertensive patients.