Functional Heterogeneity of Pulmonary Arteries and Veins

描述（由申请人提供）： 在肺循环中，动脉和静脉在组织、细胞和分子水平上表现出结构和功能异质性。我们已经报道，在围产期（在胎儿期和新生儿期）肺动脉和静脉都是非常血管活性的，静脉对总肺血管阻力有显着的贡献。 在子宫内，整个血管树都暴露在胎儿血液的低氧分压下。 然而，出生后，静脉立即暴露于含氧血液，而动脉继续暴露于脱氧血液。 因此，我们推测，观察到的异质性在出生后的肺动脉和静脉的功能行为，可能在一定程度上解释了不同的影响，诱导肺动脉和静脉的氧暴露。 我们的具体目标是基于我们的初步数据，这些数据表明，暴露于氧气会增强肺静脉中cGMP依赖性蛋白激酶（PKG）介导的血管舒张，但不会增强动脉中的血管舒张。 基于这一观察结果，我们的主要假设是，肺动脉与静脉SMC中响应氧张力变化而产生的反应性物质的量和类型不同，导致动脉和静脉中不同的细胞信号传导事件和反应。 我们认为，我们观察到的肺动脉和静脉中cGMP介导的舒张的氧效应存在异质性，这一机制可能为肺动脉和静脉中的异质性反应提供了一个共同的解释。 在这个提议中，我们将确定活性氧在肺动脉和静脉的异质性行为中的作用。 我们将确定肺动脉和静脉平滑肌中产生活性氧和氮的类型、数量和部位，并确定这些活性物质对肺动脉和静脉中PKG蛋白量、活性和PKG依赖性舒张反应的影响。 我们还将确定活性氧对肺动脉和静脉平滑肌PKG基因表达的作用。

DESCRIPTION (provided by applicant): In the pulmonary circulation, arteries and veins demonstrate structural and functional heterogeneity, at the tissue, cellular and molecular level. We have reported that in the perinatal period (during fetal life and in the immediate newborn period) both pulmonary arteries and veins are very vasoactive and that veins contribute significantly to total pulmonary vascular resistance. In utero, the entire vascular tree is exposed to the low oxygen tension of fetal blood. However, immediately after birth, veins are exposed to oxygenated blood whereas the arteries continue to be exposed to de-oxygenated blood. We therefore hypothesize that the observed heterogeneity in functional behavior of pulmonary arteries and veins in the postnatal period may in part be explained by differential effects induced by oxygen exposure in pulmonary arteries and veins. Our specific aims are based on our preliminary data which demonstrate that exposure to oxygen augments cGMP-dependent protein kinase (PKG)-mediated vasodilation in pulmonary veins but NOT in arteries. Based on this observation, our main hypothesis is that the amount and type(s) of reactive species that are generated in pulmonary arterial versus venous SMC in response to changes in oxygen tension are different, resulting in different cell signaling events and responses in arteries and veins. We believe that the mechanisms behind our observation that there is heterogeneity in oxygen effects on cGMP-mediated relaxation in pulmonary arteries and veins might provide a common explanation for heterogeneous responses in pulmonary arteries and veins. In this proposal, we will determine the role of reactive oxygen species in the heterogeneous behavior of pulmonary arteries and veins. We will determine the type(s), amount and site(s) of production of reactive oxygen and nitrogen species in pulmonary artery and vein smooth muscle and determine the effect of these reactive species on PKG protein amount, activity and PKG-dependent relaxation responses in pulmonary arteries and veins. We will also determine the role of reactive oxygen species on PKG gene expression in pulmonary artery and vein smooth muscle.