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Oxygen tension modulates the expression of pulmonary vascular BK_Ca channel - and -subunits

¹Pediatrics, University of Minnesota, Minneapolis, Minnesota; ²Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; and ³Pediatrics, Stanford University Medical School, Palo Alto, California

Submitted 30 June 2005 ; accepted in final form 18 October 2005

At birth, the lung environment changes from low to relatively high O₂ tension. Pulmonary blood flow increases and pulmonary artery pressure decreases. Recent data suggest that pulmonary vascular calcium-sensitive K⁺ channel (BK_Ca) activation mediates perinatal pulmonary vasodilation. Although BK_Ca channel expression is developmentally regulated, the molecular mechanisms responsible for BK_Ca expression remain unknown. We tested the hypothesis that the low-O₂ 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 -subunit mRNA expression increased twofold in ovine pulmonary artery smooth muscle cell (PASMC) 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 3 wk, hypoxic animals showed an increase of threefold in the expression of BK_Ca - and more than twofold in the expression of BK_{Ca 1}-subunit mRNA. Immunochemical staining was consistent with the genetic data. To assess transcriptional activation of the -subunit of the BK_Ca, both BK_{Ca 1}- and ₂-subunit luciferase (K_Ca :luc⁺) reporter genes were constructed. Hypoxia increased PASMC K_{Ca 1}:luc⁺ reporter expression by threefold and K_{Ca 2}:luc⁺ expression by 35%. Fetal PASMC treated with the hypoxia-inducible factor-1 mimetic deferoxamine showed a 63 and 41% increase in BK_Ca channel - and ₁-subunit expression, respectively. 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.

hypoxia; oxygen sensing; hypoxia-inducible factor-1

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