Diversity of ryanodine receptor 1-mediated Ca 2+ signaling in systemic and pulmonary artery smooth muscle cells.

Aims: Ryanodine receptor-1 (RyR1) is essential for skeletal muscle cell functions. However, its roles in vascular smooth muscle cells (SMCs) are well recognized. This study aims to determine the potential physiological importance and difference in systemic and pulmonary artery SMCs (SASMCs and PASMCs).
Methods: Local and global Ca ²⁺ release were measured using a laser scanning confocal microscope and wide-field fluorescence microscope; membrane currents were recorded using a patch clamp recording; muscle contraction was determined using an organ bath system; RyR protein expression was assessed using immunofluorescence staining. Homozygous and heterozygous RyR1 gene knockout (RyR1 ^-/- and RyR1 ^+/- ) mice were used to determine its specific functions.
Key Findings: Ca ²⁺ sparks were more prominently decreased in RyR1 ^-/- ASMCs than in PASMCs. Caffeine induced a smaller increase in [Ca ²⁺ ] _i in both RyR1 ^+/+ and RyR1 ^-/- ASMCs than in PASMCs. High K ⁺ produced a reduced [Ca ²⁺ ] _i increase in RyR1 ^-/- PASMCs and ASMCs as well as a reduced contraction in RyR1 ^+/- pulmonary artery and aortic tissues. ATP elicited a smaller increase in [Ca ²⁺ ] _i in RyR1 ^-/- ASMCs and PASMCs with a greater inhibition in ASMCs. Norepinephrine-elicited muscle contraction was reduced in RyR1 ^+/- aortic and pulmonary arteries. IP ₃ dialysis-induced Ca ²⁺ release was much smaller in RyR1 ^+/- ASMCs and PASMCs. Hypoxia-induced large Ca ²⁺ and contractile responses were inhibited in RyR1 ^+/- PASMCs. However, hypoxic exposure did not evoke a notable increase in [Ca ²⁺ ] _i in ASMCs.
Significance: Our findings for the first time provide clear genetic evidence for the functional importance and difference of RyR1 in systemic and pulmonary artery SMCs.
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