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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075187-04
Application #
7091636
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S1))
Program Officer
Denholm, Elizabeth M
Project Start
2003-09-22
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2008-07-31
Support Year
4
Fiscal Year
2006
Total Cost
$448,504
Indirect Cost
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
Sun, Miranda; Ramchandran, Ramaswamy; Chen, Jiwang et al. (2016) Smooth Muscle Insulin-Like Growth Factor-1 Mediates Hypoxia-Induced Pulmonary Hypertension in Neonatal Mice. Am J Respir Cell Mol Biol 55:779-791
Yang, Qiwei; Sun, Miranda; Ramchandran, Ramaswamy et al. (2015) IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension: Role of epigenetic regulation. Vascul Pharmacol 73:20-31
Chen, Tianji; Zhou, Guofei; Zhou, Qiyuan et al. (2015) Loss of microRNA-17?92 in smooth muscle cells attenuates experimental pulmonary hypertension via induction of PDZ and LIM domain 5. Am J Respir Crit Care Med 191:678-92
Zhou, Guofei; Chen, Tianji; Raj, J Usha (2015) MicroRNAs in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 52:139-51
Ramchandran, Ramaswamy; Raghavan, Aarti; Geenen, David et al. (2014) PKG-1? leucine zipper domain defect increases pulmonary vascular tone: implications in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 307:L537-44
Yang, Q; Dahl, M J; Albertine, K H et al. (2013) Role of histone deacetylases in regulation of phenotype of ovine newborn pulmonary arterial smooth muscle cells. Cell Prolif 46:654-64
Ibe, Joyce Christina F; Zhou, Qiyuan; Chen, Tianji et al. (2013) Adenosine monophosphate-activated protein kinase is required for pulmonary artery smooth muscle cell survival and the development of hypoxic pulmonary hypertension. Am J Respir Cell Mol Biol 49:609-18
Lu, Ziyan; Tian, Yufeng; Salwen, Helen R et al. (2013) Histone-lysine methyltransferase EHMT2 is involved in proliferation, apoptosis, cell invasion, and DNA methylation of human neuroblastoma cells. Anticancer Drugs 24:484-93
Ye, Liping; Liu, Juan; Liu, Huixia et al. (2013) Sulfhydryl-dependent dimerization of soluble guanylyl cyclase modulates the relaxation of porcine pulmonary arteries to nitric oxide. Pflugers Arch 465:333-41
Kang, Kang; Peng, Xiao; Zhang, Xiaoying et al. (2013) MicroRNA-124 suppresses the transactivation of nuclear factor of activated T cells by targeting multiple genes and inhibits the proliferation of pulmonary artery smooth muscle cells. J Biol Chem 288:25414-27

Showing the most recent 10 out of 37 publications