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.
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