BK channel differences in near‐term fetal and adult ovine small pulmonary arteries

Abstract

Pulmonary vasodilatation at birth underlies the fetal transition to lung breathing. Failure to vasodilate causes persistent pulmonary hypertension of newborn, persistent patency of the ductus arteriosus and foramen ovale, and bronchopulmonary dysplasia‐related hypoxia, often with dire consequences. The mechanism of pulmonary vasodilatation at birth is poorly understood. Pulmonary artery smooth muscle cells (PASMCs) isolated from 4th and 5th order resistance vessels of ovine near‐term fetus exhibited resting membrane potentials 8 mV more depolarized than adult (P<0.05), consistent with vasoconstriction. Whole‐cell Kv current densities for voltage‐clamped fetal and adult PASMCs were similar. In contrast, large‐conductance, calcium‐activated K+ (BK) channel current densities for fetal cells were significantly lower than adult at +20 to +60 mV, but equal to adult at higher potentials. By Western immunoblots, fetal PASMCs expressed twice the pore‐forming BKα subunit protein as adult, but only half as much accessary BKβ□ subunit. By flow cytometry, cell surface βl expression was also significantly lower in fetal PASMCs. Since optimal BK channel activity occurs at 1:1 β‐to‐α stoichiometry, our results suggested the near‐term fetus expressed BK β:α ratios about ¼ that of adult. These findings suggest near‐term fetal PASMCs are more depolarized than adult due to lower BK activity and lower BKβ□ subunit expression. In agreement with BKα protein levels, BKα mRNA levels were two‐fold higher in near‐term fetus than in adult by qRT‐PCR. However, in contrast to BKβ□ protein levels, BKβ□ mRNA levels were two‐fold higher in near‐term fetus than adult. These findings suggest that BKβ□ mRNA levels may be poised to express higher levels of BKβ□ protein at birth in order to enhance BK channel activity and promote pulmonary vasodilatation upon transition to lung breathing.Support or Funding InformationNational Institutes of Health Grants HD‐003807‐41 and HD031226‐20 (to LDL)