Chronic hypoxia decreases KVchannel expression and function in pulmonary artery myocytes

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Abstract
Activity of voltage-gated K+(KV) channels regulates membrane potential ( Em) and cytosolic free Ca2+concentration ([Ca2+]cyt). A rise in [Ca2+]cytin pulmonary artery (PA) smooth muscle cells (SMCs) triggers pulmonary vasoconstriction and stimulates PASMC proliferation. Chronic hypoxia (Po230–35 mmHg for 60–72 h) decreased mRNA expression of KVchannel α-subunits (Kv1.1, Kv1.5, Kv2.1, Kv4.3, and Kv9.3) in PASMCs but not in mesenteric artery (MA) SMCs. Consistently, chronic hypoxia attenuated protein expression of Kv1.1, Kv1.5, and Kv2.1; reduced KVcurrent [ IK(V)]; caused Emdepolarization; and increased [Ca2+]cytin PASMCs but negligibly affected KVchannel expression, increased IK(V), and induced hyperpolarization in MASMCs. These results demonstrate that chronic hypoxia selectively downregulates KVchannel expression, reduces IK(V), and induces Emdepolarization in PASMCs. The subsequent rise in [Ca2+]cytplays a critical role in the development of pulmonary vasoconstriction and medial hypertrophy. The divergent effects of hypoxia on KVchannel α-subunit mRNA expression in PASMCs and MASMCs may result from different mechanisms involved in the regulation of KVchannel gene expression.