Chronic hypoxia functionally upregulated L-type and T-type voltage-dependent Ca2+ channels in the pulmonary artery of mice via increased expression of Cav1.2 and Cav3.2.
Chronic hypoxia selectively upregulates L- and T-type voltage-dependent calcium channels (Cav1.2 and Cav3.2) in the pulmonary artery, contributing to hypoxia-induced pulmonary hypertension in mice.
Hypoxia-induced pulmonary hypertension (HPH) is characterized by sustained pulmonary vasoconstriction and vascular remodeling, both of which are mediated by pulmonary artery smooth muscle cell (PASMC) contraction and proliferation, respectively. An increase in cytosolic Ca²⁺ concentration (Ca²⁺cyt) is a major trigger for pulmonary vasoconstriction and an important stimulus for cell proliferation in PASMCs. Ca²⁺ influx through voltage-dependent Ca²⁺ channels (VDCC) is an important pathway for the regulation of Ca²⁺cyt. The potential role for L- and T-type VDCC in the development of HPH is still unclear. Using a hypoxic-induced pulmonary hypertension mouse model, we undertook this study to identify if VDCC in pulmonary artery (PA) are functionally upregulated and determine which type of VDCC are altered in HPH. Mice subjected to chronic hypoxia developed pulmonary hypertension within 4 wk, and high-K⁺- and U-46619-induced contraction of PA was greater in chronic hypoxic mice than that in normoxic control mice. Additionally, we demonstrate that high-K⁺- and U-46619-induced Ca²⁺ influx in PASMC is significantly increased in the hypoxic group. The VDCC activator, Bay K8864, induced greater contraction of the PA of hypoxic mice than in that of normoxic mice in isometric force measurements. L-type and T-type VDCC blockers significantly attenuated absolute contraction of the PA in hypoxic mice. Chronic hypoxia did not increase high-K⁺- and U-46619-induced contraction of mesenteric artery (MA). Compared with MA, PA displayed higher expression of calcium channel voltage-dependent L-type α1C-subunit (Cav1.2) and T-type α1H-subunit (Cav3.2) upon exposure to chronic hypoxia. In conclusion, both L-type and T-type VDCC were functionally upregulated in PA, but not MA, in HPH mice, which could result from selectively increased expression of Cav1.2 and Cav3.2.
Wan et al. (Sat,) conducted a other in Hypoxia-induced pulmonary hypertension. Chronic hypoxia vs. Normoxic control mice was evaluated on High-K+- and U-46619-induced contraction of pulmonary artery and Ca2+ influx. Chronic hypoxia functionally upregulated L-type and T-type voltage-dependent Ca2+ channels in the pulmonary artery of mice via increased expression of Cav1.2 and Cav3.2.