Oxygen tension modulates the expression of pulmonary vascular BKCachannel α- and β-subunits

Abstract

At birth, the lung environment changes from low to relatively high O2tension. Pulmonary blood flow increases and pulmonary artery pressure decreases. Recent data suggest that pulmonary vascular calcium-sensitive K+channel (BKCa) activation mediates perinatal pulmonary vasodilation. Although BKCachannel expression is developmentally regulated, the molecular mechanisms responsible for BKCaexpression remain unknown. We tested the hypothesis that the low-O2tension environment of the normal fetus modulates BKCachannel expression. We analyzed BKCaexpression under conditions of hypoxia and normoxia both in vitro and in vivo. BKCaα-subunit mRNA expression increased twofold in ovine pulmonary artery smooth muscle cell (PASMC) primary cultures maintained in hypoxia. In vivo, BKCaexpression was similarly affected by hypoxia. When adult Sprague-Dawley rats were placed in hypobaric hypoxic chambers for 3 wk, hypoxic animals showed an increase of threefold in the expression of BKCaα- and more than twofold in the expression of BKCaβ1-subunit mRNA. Immunochemical staining was consistent with the genetic data. To assess transcriptional activation of the β-subunit of the BKCa, both BKCaβ1- and β2-subunit luciferase (KCaβ:luc+) reporter genes were constructed. Hypoxia increased PASMC KCaβ1:luc+reporter expression by threefold and KCaβ2:luc+expression by 35%. Fetal PASMC treated with the hypoxia-inducible factor-1 mimetic deferoxamine showed a 63 and 41% increase in BKCachannel α- and β1-subunit expression, respectively. Together, these results suggest that oxygen tension modulates BKCachannel subunit mRNA expression, and the regulation is, at least in part, at the transcriptional level.