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的异质性。我们已经报道，在围产期(胎儿期和新生儿即刻)，肺动和静脉都非常活跃，静脉对总肺血管阻力有显着贡献。在子宫中，整个血管树都暴露在胎儿血液的低氧分压下。然而，出生后，静脉立即暴露在含氧血液中，而动脉继续暴露在脱氧血液中。因此，我们假设，在出生后观察到的肺动静脉功能行为的异质性可能部分是由于肺动静脉暴露于氧气引起的不同效应。我们的具体目标是基于我们的初步数据，这些数据表明，暴露在氧气中可以增强cGMP依赖的蛋白激酶(PKG)介导的肺静脉血管扩张，但不会增强动脉血管扩张。基于这一观察，我们的主要假设是，肺动和静脉SMC对氧分压变化的反应产生的活性物质的数量和类型(S)不同，从而导致动脉和静脉中不同的细胞信号事件和反应。我们认为，氧对cGMP介导的肺动静脉松弛的影响存在异质性，其背后的机制可能为肺动、静脉的异质性反应提供了共同的解释。在这项提案中，我们将确定活性氧物种在肺动、静脉异质性行为中的作用。我们将测定肺动、静脉平滑肌产生活性氧和氮物种的类型(S)、数量和部位(S)，并测定这些活性物种对肺动、静脉PKG蛋白含量、活性和依赖PKG的松弛反应的影响。我们还将确定活性氧物种对肺动脉和静脉平滑肌中PKG基因表达的影响。

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.