The β3 subunit contributes to vascular calcium channel upregulation and hypertension in angiotensin II-infused C57BL/6 mice

Abstract

Voltage-gated L-type Ca2+(Cav1.2) channels in vascular smooth muscle cells are a predominant Ca2+influx pathway that mediates arterial tone. Channel biogenesis is accomplished when the pore-forming α1C subunit coassembles with regulatory Cavβ subunits intracellularly, and the multiprotein Cav1.2 channel complex translocates to the plasma membrane to form functional Ca2+channels. We hypothesized that the main Cavβ isoform in vascular smooth muscle cells, Cavβ3, is required for the upregulation of arterial Cav1.2 channels during the development of hypertension, an event associated with abnormal Ca-dependent tone. Cav1.2 channel expression and function were compared between second-order mesenteric arteries 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 mesenteric arteries of Ang II-infused WT mice showed increased Cav1.2 channel expression and accentuated Ca-mediated contractions compared with saline-infused WT mice. In contrast, Cav1.2 channels failed to upregulate in mesenteric arteries of Ang II-infused Cavβ3 mice, and Ca-dependent reactivity was normal in these arteries. Basal systolic blood pressure was not significantly different between WT and Cavβ3 mice (98 ± 2 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 systolic blood pressure of Cavβ3 mice averaged 149 ± 4 mm Hg compared with 180 ± 5 mm Hg in WT mice. Thus, the Cavβ3 subunit is a critical regulatory protein required to upregulate arterial Cav1.2 channels and fully develop Ang II-dependent hypertension in C57BL/6 mice. © 2012 American Heart Association, Inc.