Partial HIF-1α deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia

Chronic hypoxia depolarizes and reduces K⁺ current in pulmonary arterial smooth muscle cells (PASMCs). Our laboratory previously demonstrated that hypoxia-inducible factor-1 (HIF-1) contributed to the development of hypoxic pulmonary hypertension. In this study, electrophysiological parameters were measured in PASMCs isolated from intrapulmonary arteries of mice with one null allele at the Hif1α locus encoding HIF-1α [Hif1α(+/-)] and from their wild-type [Hif1α(+/+)] littermates after 3 wk in air or 10% O₂. Hematocrit and right ventricular wall and left ventricle plus septum weights were measured. Capacitance, K⁺ current, and membrane potential were measured with whole cell patch clamp. Similar to our laboratory's previous results, hypoxia-induced right ventricular hypertrophy and polycythemia were blunted in Hif1α(+/-) mice. Hypoxia increased PASMC capacitance in Hif1α(+/+) mice but not in Hif1α(+/-) mice. Chronic hypoxia depolarized and reduced K+ current density in PASMCs from Hif1α(+/+) mice. In PASMCs from hypoxic Hif1α(+/-) mice, no reduction in K⁺ current density was observed, and depolarization was significantly blunted. Thus partial deficiency of HIF-1α is sufficient to impair hypoxia-induced depolarization, reduction of K⁺ current density, and PASMC hypertrophy.