P 7 . 2 Oral presentation Integrin α 7 β 1 is a redoxregulated target of hydrogen peroxide in vascular smooth muscle cell adhesion

Emilin-1 is an extracellular matrix protein highly expressed in the cardiovascular system by endocardium, right ventricle myocytes, endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and adventitial fibroblasts. One prominent function of Emilin-1 is the regulation of systemic blood pressure. Emilin-1 deficiency results into systemic hypertension, accompanied by narrowing and structural alterations of the arterial tree due to increase of TGF-β signaling. The protein indeed inhibits TGF-β activation by blocking the proteolytic cleavage of the proTGF-β precursor into the LAP/TGF-β complex. We have investigated whether hypertension is causally related to abnormal behavior of VSMCs or ECs. We have addressed the question using a phenotype-rescue approach by expressing the protein in either ECs or VSMCs or in all cells of the arterial wall of Emilin1-/mice. Hypertensive phenotype of Emilin1-/mice was only rescued by transgenes expressed in VSMCs while ECs specific production of recombinant Emilin-1 did not rescue blood pressure phenotype. Pharmacological anti-TGF-β treatment of Emilin1 null mice normalized blood pressure. Therefore not only TGF-β regulation is key to Emilin1-/hypertension, but also increased TGF-β activity must be continuously operating in order to maintain higher blood pressure. This result prompted us to look for functional alterations of mutated vessels that could be responsible for the hypertensive phenotype. Arteriolar myogenic response to perfusion pressure is a pivotal element in blood pressure control and is a peculiar feature of VSMCs. We found that resistance arteries of Emilin1-/mice exhibited an increased myogenic response to mechanical stress. Interestingly, VSMCsand ECsspecific transgene expression revealed that the increased myogenic response of Emilin1-/mice was dependent on production of Emilin-1 in VSMCs, in line with that observed for the hypertensive phenotype. In summary, the results clarify that VSMCs Emilin-1 is a main regulator of resting blood pressure levels by controlling the myogenic response in resistance arteries. P7.2 Oral presentation