Functional Heterogeneity of Pulmonary Arteries and Veins

肺动脉和静脉的功能异质性

• 批准号: 7091636
• 负责人: J. Usha RAJ
• 金额: $ 44.85万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-22 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091636
• 关键词: biological signal transduction; cGMP dependent protein kinase; cell cell interaction; cesarean section; embryo /fetus; enzyme activity; free radical oxygen; free radicals; gene expression; nitrogen; oxygen tension; protein quantitation /detection; pulmonary artery; pulmonary circulation; pulmonary veins; respiratory oxygen; sheep; smooth muscle; vasodilation

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.

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。我们报告说，在围产期（在胎儿生命和新生儿时期）肺动脉和静脉都非常血管活性，并且静脉对总肺血管耐药性有显着贡献。 在子宫内，整个血管树暴露于胎儿血的低氧张力。 但是，出生后立即将静脉暴露于含氧血液中，而动脉继续暴露于脱氧血液中。 因此，我们假设在产后期间观察到的肺动脉和静脉功能行为的异质性可能部分用肺动脉和静脉中的氧气暴露引起的差异作用来解释。 我们的具体目的是基于我们的初步数据，该数据表明，暴露于氧气增强CGMP依赖性蛋白激酶（PKG）介导的肺静脉中的血管舒张，但在动脉中却没有。 基于这一观察结果，我们的主要假设是在肺动脉动脉和静脉SMC中产生的反应性物种的数量和类型响应氧气张力的变化而不同，从而导致动脉和静脉中的不同细胞信号事件和反应。 我们认为，我们观察到的机制是，氧对CGMP介导的肺动脉和静脉中CGMP介导的弛豫的异质性可能为肺动脉和静脉异质反应提供了共同的解释。 在此提案中，我们将确定活性氧在肺动脉和静脉异质行为中的作用。 我们将确定肺动脉和静脉平滑肌中活性氧和氮种的产生的类型，数量和部位，并确定这些反应性物种对肺动脉和静脉中PKG蛋白质量，活性和PKG依赖性弛豫反应的影响。 我们还将确定活性氧对肺动脉和静脉平滑肌中PKG基因表达的作用。