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Chronic intrauterine pulmonary hypertension selectively modifies pulmonary artery smooth muscle cell gene expression

Departments of ¹Pediatrics and ²Surgery, University of Minnesota Medical School, Minneapolis, Minnesota

Submitted 29 June 2005 ; accepted in final form 6 September 2005

Pulmonary artery smooth muscle cell (PASMC) relaxation at birth results from an increase in cytosolic cGMP, cGMP-dependent and kinase-mediated activation of the Ca²⁺-sensitive K⁺ channel (K_Ca), and closure of voltage-operated Ca²⁺ channels (VOCC). How chronic intrauterine pulmonary hypertension compromises perinatal pulmonary vasodilation remains unknown. We tested the hypothesis that chronic intrauterine pulmonary hypertension selectively modifies gene expression to mitigate perinatal pulmonary vasodilation mediated by the cGMP kinase-K_Ca-VOCC pathway. PASMC were isolated from late-gestation fetal lambs that had undergone either ligation of the ductus arteriosus (hypertensive) or sham operation (control) at 127 days of gestation and were maintained under either hypoxic (25 Torr) or normoxic (120 Torr) conditions in primary culture. We studied mRNA levels for cGMP kinase I (PKG-1), the -chain of VOCC (Ca_v1.2), and the -subunit of the K_Ca channel. Compared with control PASMC, hypertensive PASMC had decreased VOCC, K_Ca, and PKG-1 expression. In response to sustained normoxia, expression of VOCC and K_Ca channel decreased and expression of PKG-1 increased. In contrast, sustained normoxia had no effect on PKG-1 levels and an attenuated effect on VOCC and K_Ca channel expression in hypertensive PASMC. Protein expression of PKG-1 was consistent with the mRNA data. We conclude that chronic intrauterine pulmonary hypertension decreases PKG expression and mitigates the genetic effects of sustained normoxia on pulmonary vasodilation, because gene expression remains compromised even after sustained exposure to normoxia.

fetal; oxygen sensing; nitric oxide

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