Pulmonary artery smooth muscle cell proliferation and migration in fetal lambs acclimatized to high-altitude long-term hypoxia

Role of histone acetylation

Qiwei Yang, Ziyan Lu, Ramaswamy Ramchandran, Lawrence D. Longo, J. Usha Raj

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume303
Issue number11
DOIs
StatePublished - Dec 17 2012

Fingerprint

Acetylation
Histones
Pulmonary Artery
Smooth Muscle Myocytes
Cell Movement
Cell Proliferation
DNA Methylation
Lung
Fetus
Epigenomics
trichostatin A
Fetal Hypoxia
Cyclin-Dependent Kinase Inhibitor p21
Histone Deacetylase Inhibitors
Histone Deacetylases
Hypoxia
Atmosphere
Vascular Diseases
Pulmonary Hypertension
Oceans and Seas

Keywords

  • Epigenetics
  • High-altitude long-term hypoxia
  • Histone deacetylase
  • PDGF
  • p21

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Pulmonary artery smooth muscle cell proliferation and migration in fetal lambs acclimatized to high-altitude long-term hypoxia : Role of histone acetylation. / Yang, Qiwei; Lu, Ziyan; Ramchandran, Ramaswamy; Longo, Lawrence D.; Usha Raj, J.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 303, No. 11, 17.12.2012.

Research output: Contribution to journalArticle

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