title: Pulmonary artery smooth muscle cell proliferation and migration in fetal lambs acclimatized to high-altitude long-term hypoxia: role of histone acetylation.
abstract: High-altitude long-term hypoxia (LTH) is known to induce pulmonary arterial smooth muscle cell (PASMC) proliferation in the fetus, leading to pulmonary arterial remodeling and pulmonary hypertension of the newborn. The mechanisms underlying these conditions remain enigmatic however. We hypothesized that epigenetic alterations in fetal PASMC induced by high-altitude LTH may play an important role in modulating their proliferation during pulmonary arterial remodeling. To test this hypothesis, we have analyzed epigenetic alterations in the pulmonary vasculature of fetal lambs exposed to high-altitude LTH [pregnant ewes were kept at 3,801 m altitude from ~40 to 145 days gestation] or to sea level atmosphere. Intrapulmonary arteries were isolated, and fetal PASMC were cultured from both control and LTH fetuses. Compared with controls, in LTH fetus pulmonary arteries measurements of histone acetylation and global DNA methylation demonstrated reduced levels of global histone 4 acetylation and DNA methylation, accompanied by the loss of the cyclin-dependent kinase inhibitor p21. Treatment of LTH fetal PASMCs with histone deacetylase (HDAC) inhibitor trichostatin A decreased their proliferation rate, in part because of altered expression of p21 at both RNA and protein level. In PASMC of LTH fetuses, HDAC inhibition also decreased PDGF-induced cell migration and ERK1/2 activation and modulated global DNA methylation. On the basis of these observations, we propose that epigenetic alterations (reduced histone acetylation and DNA methylation) caused by chronic hypoxia leads to fetal PASMC proliferation and vessel remodeling associated with vascular proliferative disease and that this process is regulated by p21.
authors.affiliation: Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. qiwei@uic.edu
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Yang
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Lu
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Ramchandran
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Longo
authors.forename: J Usha
authors.initials: JU
authors.lastname: Raj
mesh_terms: D000064:Acclimatization; D000107:Acetylation; D000531:Altitude; D000818:Animals; D059447:Cell Cycle Checkpoints; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic; D005260:Female; D005311:Fetal Hypoxia / Q000378:metabolism / Q000473:pathology*; D005333:Fetus / Q000473:pathology; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology*; D012756:Sheep; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D010456:Peptides, Cyclic; D010982:Platelet-Derived Growth Factor; D016159:Tumor Suppressor Protein p53; C102351:apicidin; C012589:trichostatin A