Heterogeneous Gene Expression and Functional Activity of Ryanodine Receptors in Resistance and Conduit Pulmonary as well as Mesenteric Artery Smooth Muscle Cells

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Abstract
Background: Hypoxia causes heterogeneous contractile responses in resistance and conduit pulmonary as well as systemic (mesenteric) artery smooth muscle cells (RPASMCs, CPASMCs and MASMCs), but the underlying mechanisms are largely unknown. In this study, we aimed to investigate whether the gene expression and functional activity of ryanodine receptors (RyRs) would be different in these 3 cell types. Methods: RyR mRNA expression, Ca2+ sparks and [Ca2+]i were measured by real-time quantitative RT-PCR, laser scanning confocal microscopy and wide-field fluorescence microscopy, respectively. Results: All 3 RyR subtype (RyR1, RyR2 and RyR3) mRNAs are expressed in RPASMCs, CPASMCs and MASMCs, but their expression levels are different. Spontaneous Ca2+ sparks (functional events of RyRs) show distinct frequency, amplitude, duration, size and kinetics in these 3 cell types. Similarly, activation of RyRs by caffeine, 4-chloro-m-cresol or high K+ induces differential Ca2+ release. Moreover, hypoxia-induced increase in [Ca2+]i is largest in MASMCs relative to CPSAMCs and smallest in RPASMCs. Conclusion: This study provides comprehensive evidence that RyRs are heterogeneous in gene expression and functional activity in RPASMCs, CPASMCs and MASMCs, which may contribute to the diversity of excitation-contraction coupling and hypoxic Ca2+ responses in different vascular smooth muscle cells.

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