Developmental Regulation of O2 Sensing in the Lung

描述（由申请人提供）：出生时，肺血管舒张与氧张力升高有关。当肺动脉（PA）压力不降低时，新生儿持续性肺动脉高压（PPHN）的结果。PPHN的特征是肺血管张力和反应性增加，以及对围产儿血管舒张剂刺激（包括氧气）的不完全反应。我们实验室的数据表明，肺循环通过钙敏感K+通道（BKCa）激活响应氧张力的急性增加，该通道是由发育调节的红胺敏感储存的Ca2+释放介导的。尽管氧在围产期肺血管舒张中起着至关重要的作用，但在PPHN中氧感应是如何受损的仍然未知。初步数据表明，在绵羊PPHN模型中，肺动脉平滑肌细胞（PA SMC） BKCa通道表达、氧传感和细胞内Ca2+稳态受到损害。目前的提议验证了在PPHN动物模型中，肺动脉平滑肌细胞氧感知受损，从而减弱围产期肺血管舒张的工作假设。具体目的是检验假设，在围产儿肺动脉高压的绵羊模型：目的1。通过对BKCa通道激活的直接和间接影响，O2传感受到损害；和Aim 2。BKCa通道亚基表达调控PA SMC O2感知。本申请中提出的研究将确定肺循环对血管扩张剂刺激的反应减弱（PPHN的标志）是否由PA SMC BKCa表达和/或功能受损引起。这些研究的完成可能会确定特定的分子靶点，以开发新的基于K+通道的策略来解决一个非常困难的临床问题。调节BKCa通道亚基表达增强肺血管舒张的策略可能更广泛地适用于其他血管疾病。

DESCRIPTION (provided by applicant): 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.