In vascular smooth muscle cells, endothelium-derived NO, ANF, nitrovasodilators and exogenous NO-induced vasodilation by activation of the PKG cascade following increases in intracellular cGMP concentrations. The NO-cGMP-PKG pathway plays a pivotal role in establishing low vascular resistance in the pulmonary circulation. The applicant and others have been studying this pathway and thus far has focused on studies of the enzymes (guanylyl cyclase and phosphodiesterase) that regulate cGMP levels. Studies ar now proposed to determine the mechanisms by which elevated cGMP in vascular smooth muscle cells ultimately result in vasodilation in the developing lung a the time of birth.
Aim 1 will determine the role of PKG in cGMP-mediated vasodilation and the link between the developmental increase in cGMP-induced dilation in the perinatal period and PKG activity will be explored. The specific roles of PKG type 1-alpha and 1-beta isoforms will be determined.
Aim 2 will determine the role of the protein phosphatases, PP1 PP2A, and PP2B, in PKG-mediated vasodilation.
Aim 3 will determine the effect of oxygen tension o PKG and phosphatase activity in the perinatal period. All studies will be conducted in the ovine species, and isolated vessel tension experiments will b complemented with molecular and biochemical studies in the experimental protocols. The investigators have shown that responses of pulmonary arteries may be quite different from those of veins, and experiments will therefore be done in both arteries and veins. Any disturbance in the normal fall in pulmonary vascular resistance at birth results in pulmonary hypertension of th newborn and significant morbidity and mortality. Knowledge derived from these studies could lead to a better understanding of the mechanisms of pulmonary vasodilation at birth and thus to develop strategies to prevent and treat pulmonary hypertension in the perinatal period.
|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|
|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|
|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|
|Gu, Song; Tian, Yufeng; Chlenski, Alexandre et al. (2012) Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma. Anticancer Drugs 23:1054-66|
|Ramchandran, Ramaswamy; Pilipenko, Evgeny; Bach, Laura et al. (2012) Hypoxic regulation of pulmonary vascular smooth muscle cyclic guanosine monophosphate-dependent kinase by the ubiquitin conjugating system. Am J Respir Cell Mol Biol 46:323-30|
|Gou, Deming; Ramchandran, Ramaswamy; Peng, Xiao et al. (2012) miR-210 has an antiapoptotic effect in pulmonary artery smooth muscle cells during hypoxia. Am J Physiol Lung Cell Mol Physiol 303:L682-91|
|Yang, Q; Lu, Z; Singh, D et al. (2012) BIX-01294 treatment blocks cell proliferation, migration and contractility in ovine foetal pulmonary arterial smooth muscle cells. Cell Prolif 45:335-44|
|Xu, Xiaojian; Wang, Shumin; Liu, Juan et al. (2012) Hypoxia induces downregulation of soluble guanylyl cyclase ?1 by miR-34c-5p. J Cell Sci 125:6117-26|
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