Abstract P164: Pronethalol Reduces Sox2 To Ameliorate Vascular Calcification

Abstract

Vascular calcification is present in most people over 60 years of age and results in severe complications that increase all-cause mortality of cardiovascular disease, diabetes mellitus and chronic kidney disease. Previous studies demonstrated that endothelial induction of SRY (sex determining region Y)-box 2 (Sox2) triggered endothelial-mesenchymal transitions (EndMTs) and drove endothelial cells (ECs) towards osteoblastic differentiation. The excess Sox2 induced mesenchymal markers and promoted ECs to acquire mesenchymal potential and undergo osteogenic differentiation. Recently, we reported that beta-adrenergic receptor antagonists (beta-blockers) decreased Sox2 expression in cerebrovascular endothelium and limited arteriovenous malformations. In this study, we hypothesize that the beta-blockers suppress Sox2 also in arterial endothelium to limit vascular calcification. To test this hypothesis, we used the Mgp -/- mouse model, where the elastic arteries start to calcify at 1-2 weeks of age and exhibit severe calcification at 4 weeks of age. We treated Mgp -/- mice with pronethalol for two weeks starting at 2 weeks of age and revealed that the pronethalol treatment significantly ameliorated the aortic calcification in Mgp -/- aortas. To examine the time-course of the pronethalol effect on calcification, we started the pronethalol treatment at three different time points, at 1, 2 and 3 weeks of age. The treatments all ended at 5 weeks of age. The results showed that the total aortic calcium was immediately reduced if the pronethalol was started at 1 or 2 weeks of age and was maintained at low levels as the treatment continued. When the treatment was started at 3 weeks of age, it still reduced the aortic calcium but to a lesser degree. To determine if pronethalol limits vascular calcification also in atherosclerosis and diabetes, we treated Apoe -/- mice and Ins2 Akita/+ mice with pronethalol. Aortic calcium and histology showed that pronethalol reduced the atherosclerotic lesion calcification and decreased the calcification in Ins2 Akita/+ mice. Together, the results suggest that the beta-blocker pronethalol reduces Sox2 expression in the arterial endothelium, thereby limiting EndMTs and vascular calcification.