Oxygen tension modulates the expression of pulmonary vascular BKCa channel α and β subunits

At birth, the lung environment changes from low to relatively high O 2 tension. Pulmonary blood flow increases and pulmonary artery pressure decreases. Recent data suggests that pulmonary vascular calcium-sensitive potassium channel (BK Ca) activation mediates perinatal pulmonary vasodilation. While BK Ca channel expression is developmentally regulated, the molecular mechanisms responsible for BK Ca expression remain unknown. We tested the hypothesis that the low O 2 tension environment of the normal fetus modulates BK Ca channel expression. We analyzed BK Ca expression under conditions of hypoxia and normoxia both in vitro and in vivo. BK Ca α subunit mRNA expression increased 2-fold in ovine pulmonary artery smooth muscle cell (PA SMC) primary cultures maintained in hypoxia. In vivo BK Ca expression was similarly affected by hypoxia. When adult Sprague-Dawley rats were placed in hypobaric hypoxic chambers for three weeks, hypoxic animals showed an increase of 3-fold in the expression of BK Ca α and more than 2-fold in the expression of BK Ca β1-subunit mRNA. Immunochemical staining was consistent with the genetic data. To assess transcriptional activation of the β subunit of the BK Ca , both BK Ca β1 and β2 subunit-luciferase (K Ca β:luc+) reporter genes were constructed. Hypoxia increased PA SMC K Ca β1:luc+ reporter expression by 3-fold and K Ca β2:luc+ expression by 35%. Fetal PA SMC treated with the Hypoxia-inducible Factor-1 mimetic deferoxamine showed a 63% and 41% increase in BK Ca channel α and β1 subunit expression respectively. Taken together, these results suggest that oxygen tension modulates BK Ca channel subunit mRNA expression, and the regulation is, at least in part, at the transcriptional level.