The β3 Subunit Contributes to Vascular Calcium Channel Upregulation and Hypertension in Angiotensin II-infused C57BL/6 Mice

摘要

Voltage-gated L-type Ca²⁺ (Cav1.2) channels in vascular smooth muscle cells (VSMCs) are a predominant Ca²⁺ influx pathway that mediates arterial tone. Channel biogenesis is accomplished when the pore-forming α1C subunit co-assembles with regulatory Cavβ subunits intracellularly, and the multi-protein Cav1.2 complex translocates to the plasma membrane to form functional Ca²⁺ channels. We hypothesized that the main Cavβ isoform in VSMCs, Cavβ3, is required for the upregulation of arterial Cav1.2 channels during the development of hypertension, an event associated with abnormal Ca²⁺-dependent tone. Cav1.2 channel expression and function was compared between 2^nd order mesenteric arteries (MA) of C57BL/6 wild-type (WT) and Cavβ3^-/- mice infused with saline (control) or angiotensin II (Ang II) for 2 weeks to induce hypertension. The MA of Ang II-infused WT mice showed increased Cav1.2 channel expression and accentuated Ca²⁺-mediated contractions compared to saline-infused WT mice. In contrast, Cav1.2 channels failed to upregulate in MA of Ang II-infused Cavβ3^-/- mice and Ca²⁺-dependent reactivity was normal in these arteries. Basal systolic blood pressure (SBP) was not significantly different between WT and Cavβ3^-/- mice (98±2 mm Hg and 102±3 mm Hg, respectively), but the Cavβ3^-/- mice showed a blunted pressor response to Ang II infusion. Two weeks after the start of Ang II administration, the SBP of Cavβ3^-/- mice averaged 149±4 mm Hg compared to 180±5 mm Hg in WT mice. Thus, the Cavβ3 subunit is a critical regulatory protein required to upregulate arterial Ca_v1.2 channels and fully develop angiotensin II –dependent hypertension in C57BL/6 mice.