Why the study?
The impact of individual ryanodine receptor isoforms on adaptive vascular responses was largely unknown.
RyR2-mediated Ca2+-release events in vascular smooth muscle cells specifically regulate myogenic tone and arterial adaptation to pressure changes, suggesting RyR2 as a potential therapeutic target in hypertension.
RyR2 shapes Ca2+ signaling in resistance arteries; leaves open whether isoform-selective targeting alters myogenic tone or hypertension.
Background Hypertension is the major risk factor for cardiovascular disease, the most common cause of death worldwide. Resistance arteries are capable of adapting their diameter independently in response to pressure and flow‐associated shear stress. Ryanodine receptors (RyRs) are major Ca 2+ ‐release channels in the sarcoplasmic reticulum membrane of myocytes that contribute to the regulation of contractility. Vascular smooth muscle cells exhibit 3 different RyR isoforms (RyR1, RyR2, and RyR3), but the impact of individual RyR isoforms on adaptive vascular responses is largely unknown. Herein, we generated tamoxifen‐inducible smooth muscle cell–specific RyR2‐deficient mice and tested the hypothesis that vascular smooth muscle cell RyR2s play a specific role in elementary Ca 2+ signaling and adaptive vascular responses to vascular pressure and/or flow. Methods and Results Targeted deletion of the Ryr2 gene resulted in a complete loss of sarcoplasmic reticulum–mediated Ca 2+ ‐release events and associated Ca 2+ ‐activated, large‐conductance K + channel currents in peripheral arteries, leading to increased myogenic tone and systemic blood pressure. In the absence of RyR2, the pulmonary artery pressure response to sustained hypoxia was enhanced, but flow‐dependent effects, including blood flow recovery in ischemic hind limbs, were unaffected. Conclusions Our results establish that RyR2‐mediated Ca 2+ ‐release events in VSCM s specifically regulate myogenic tone (systemic circulation) and arterial adaptation in response to changes in pressure (hypoxic lung model), but not flow. They further suggest that vascular smooth muscle cell–expressed RyR2 deserves scrutiny as a therapeutic target for the treatment of vascular responses in hypertension and chronic vascular diseases.
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Kaßmann et al. (2019) studied Hypertension / Vascular adaptive responses. Targeted deletion of the Ryr2 gene in smooth muscle cells vs. Wild-type / control mice was evaluated on Sarcoplasmic reticulum-mediated Ca2+-release events (Ca2+ sparks) and associated Ca2+-activated large-conductance K+ channel currents.
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