Functional Heterogeneity of Pulmonary Arteries and Veins

在肺循环中，动脉和静脉表现出结构和功能 异质性，在组织，细胞和分子水平。我们报道过在围产期 （在胎儿期和新生儿期），肺动脉和肺静脉都非常脆弱。 血管活性，静脉对总肺血管阻力有显著贡献。在子宫内， 整个血管树都暴露在胎儿血液的低氧分压下。但紧接着 出生时，静脉暴露于含氧血液，而动脉继续暴露于含氧血液。 缺氧的血液因此，我们假设，观察到的功能行为的异质性， 出生后时期的肺动脉和肺静脉可能部分地由差异效应解释 由肺动脉和静脉中的氧气暴露引起。我们的具体目标是基于我们的 初步数据表明，暴露于氧气增加cGMP依赖性蛋白激酶 （PKG）介导的肺静脉血管舒张，但动脉中不存在。根据这一观察，我们 主要假设是肺内产生的活性物质的量和类型 动脉与静脉SMC对氧分压变化的反应不同，导致不同的 动脉和静脉中的细胞信号事件和反应。我们认为，我们的机制背后， 观察到氧对cGMP介导的肺血管舒张的影响存在异质性， 动脉和静脉可能提供了肺内异质性反应的共同解释， 动脉和静脉。在这个提议中，我们将确定活性氧在细胞中的作用。 肺动脉和静脉的异质性行为。我们将确定类型（S），数量和地点 (s)肺动脉和静脉平滑肌产生活性氧和氮类 并确定这些活性物质对PKG蛋白量、活性和PKG依赖性的影响。 肺动脉和静脉的舒张反应。我们还将确定活性氧的作用 PKG基因在肺动脉和静脉平滑肌中的表达。

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.