At birth, pulmonary vasodilation occurs in association with an increase in oxygen tension. When pulmonary artery (PA) pressure does not decrease, persistent pulmonary hypertension of the newborn (PPHN) results. PPHN is characterized by increased pulmonary vascular tone and reactivity, and an incomplete response to perinatal vasodilator stimuli, including oxygen. Data from our laboratory have demonstrated that the pulmonary circulation responds to an acute increase in oxygen tension via calcium-sensitive K+ channel (BKCa) activation mediated by Ca2+ release from a developmentally regulated ryanodine-sensitive store. Despite the critical importance of oxygen in mediating perinatal pulmonary vasodilation, how oxygen sensing is compromised in PPHN remains unknown. Preliminary data indicate that in an ovine model of PPHN, pulmonary artery smooth muscle cell (PA SMC) BKCa channel expression, oxygen sensing and intracellular cellular Ca2+ homeostasis are compromised. The present proposal tests the working hypothesis that in an animal model of PPHN, pulmonary artery smooth muscle cell oxygen sensing is compromised, thereby attenuating perinatal pulmonary vasodilation.
The specific aims are to test the hypotheses that in an ovine model of perinatal pulmonary hypertension:
Aim 1. O2 sensing is compromised through both direct and indirect effects on BKCa channel activation;
and Aim 2. BKCa channel subunit expression modulates PA SMC O2 sensing. The studies proposed in the present application will determine whether the attenuated response of the pulmonary circulation to vasodilator stimuli, the hallmark of PPHN, results from compromised PA SMC BKCa expression and/or function. Completion of the proposed studies may identify specific molecular target for the development of novel K+ channel based strategies to address a profoundly difficult clinical problem. The strategy of modulating BKCa channel subunit expression to enhance pulmonary vasodilation may be more broadly applicable to other vascular diseases. ? ?
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