Role of ryanodine receptor Ca2+ channels in adaptative vascular processes

点击翻译按钮获取中文摘要

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Resistance arteries can adapt their vessel diameter independently by pressure and by flow. Ryanodine receptors (RyRs) are major Ca2+ release channels in the sarcoplasmic reticulum (SR) membrane of myocytes contributing to contractility. Vascular smooth muscle cells (VSMCs) exhibit three different RyR isoforms (RyR1, 2, 3), but their function is largely unknown. We generated tamoxifen-inducible smooth muscle cell (SM) specific RyR2 deficient mice. We will test the hypothesis that VSMC RyR2s play a specific role in elementary Ca2+ signaling and adaptive vascular responses to vascular pressure and/or flow. Using SM RyR2 deficient mice, we will study the role of RyR2 in local (sparks) and global Ca2+ handling in arterial smooth muscle cells affecting vascular tone. Besides Cav1.2-L-type channels, there are additional Ca2+ influx pathways (e.g. Cav3.2, TRPC6) to trigger Ca2+ sparks. It is unclear what role these signal components play and how they are involved in triggering the Ca2+ sparks. Confocal calcium imaging and patch clamp current recordings on isolated VSMCs, myography and video microscopy of isolated arteries, collateral artery recruitment, flow and ischemic vascular remodeling and blood pressure measurements will be performed. Our studies are aimed to identify a specific contribution of RyR2 in mediating VSMC Ca2+ sparks relevant for regulating myogenic tone and systemic arterial adaptation in response to changes in pressure, but not flow. The role of the CaV3.2/TRPC6-RyR2 axis is clarified in these processes. Our studies will provide new insights into adaptive mechanisms of arterial compliance during hypertension and other chronic vascular diseases and identification of novel therapeutic targets. During hypertension and other chronic vascular diseases and identification of novel therapeutic targets.