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1 Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
2 Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado, USA
* To whom correspondence should be addressed. E-mail: resni004{at}umn.edu.
At birth, the lung environment changes from low to relatively high O2 tension. Pulmonary blood flow increases and pulmonary artery pressure decreases. Recent data suggests that pulmonary vascular calcium-sensitive potassium channel (BKCa) activation mediates perinatal pulmonary vasodilation. While BKCa channel expression is developmentally regulated, the molecular mechanisms responsible for BKCa expression remain unknown. We tested the hypothesis that the low O2 tension environment of the normal fetus modulates BKCa channel expression. We analyzed BKCa expression under conditions of hypoxia and normoxia both in vitro and in vivo. BKCa 
subunit mRNA expression increased 2-fold in ovine pulmonary artery smooth muscle cell (PA SMC) primary cultures maintained in hypoxia. In vivo BKCa 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 BKCa and more than 2-fold in the expression of BKCa 
1 subunit mRNA. Immunochemical staining was consistent with the genetic data. To assess transcriptional activation of the subunit of the BKCa, both BKCa 1 and 2 subunit-luciferase (KCa :luc+) reporter genes were constructed. Hypoxia increased PA SMC KCa 1:luc+ reporter expression by 3-fold and KCa 2:luc+ expression by 35%. Fetal PA SMC treated with the Hypoxia-inducible Factor-1 mimetic deferoxamine showed a 63% and 41% increase in BKCa channel and 1 subunit expression respectively. Taken together, these results suggest that oxygen tension modulates BKCa channel subunit mRNA expression, and the regulation is, at least in part, at the transcriptional level.
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