Role of Ryanodine Type 2 Receptors in Elementary Ca2+ Signaling in Arteries and Vascular Adaptive Responses

Abstract

ObjectiveCardiovascular 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 the impact of individual RyR isoforms on vascular adaptive responses is largely unknown.MethodsWe generated tamoxifen‐inducible smooth muscle cell (SM) specific RyR2 deficient mice and tested the hypothesis that VSMC RyR2s play a specific role in elementary Ca2+ signaling and adaptive vascular responses to vascular pressure and/or flow.ResultsTargeted deletion of the Ryr2 gene resulted in a complete loss of SR released Ca2+ sparks and the associated Ca2+ activated potassium (BKCa) channel currents, leading to increased myogenic arterial tone in peripheral arteries and systemic blood pressure. RyR2 deficiency enhanced the pulmonary artery pressure response to sustained hypoxia, but had no effect on flow‐dependent effects, including blood flow recovery in ischemic hind limbs.ConclusionOur results identify a specific contribution of RyR2 in mediating VSMC Ca2+ sparks relevant for regulating myogenic tone (systemic circulation) and arterial adaptation in response to changes in pressure (hypoxic lung model), but not flow. VSMC expressed RyR2 deserves scrutiny as a therapeutic target for the treatment of vascular responses in hypertension and chronic vascular diseases.Support or Funding InformationThis study was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) to M.G and M.W. (SFB‐TR84 C3 and C6), and the Deutsche Akademische Austauschdienst (DAAD) to M.G. and I.S, and the NIH (R37 DK053832, R01 HL121706, PO1 HL095488, R01 HL131181), Fondation Leducq, and the Totman Medical Research Trust to M.T.N., and by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research) to M.G. and M.K. We thank Dr. Kirill Essin for help in Ca2+ spark recordings using line scan imaging. CFG‐P is recipient of Ministerio de Educación Cultura y Deporte, Fundación San Pablo‐CEU and Banco Santander fellowships.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.