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Distinct responses to hypoxia in subpopulations of distal pulmonary artery cells contribute to pulmonary vascular remodeling in emphysema

Research output: Contribution to journalArticle

DOI

Authors

  • L. S. Howard
  • A. Crosby
  • P. Vaughan
  • A. Sobolewski
  • M. Southwood
  • M. L. Foster
  • E. R. Chilvers
  • N. W. Morrell

Organisational units

Abstract

We have shown previously that hypoxia inhibits the growth of distal human pulmonary artery smooth muscle cells (PASMC) isolated under standard normoxic conditions (PASMCnorm). By contrast, a subpopulation of PASMC, isolated through survival selection under hypoxia was found to proliferate in response to hypoxia (PASMChyp). We sought to investigate the role of hypoxia-inducible factor (HIF) in these differential responses and to assess the relationship between HIF, proliferation, apoptosis, and pulmonary vascular remodeling in emphysema. PASMC were derived from lobar resections for lung cancer. Hypoxia induced apoptosis in PASMCnorm (as assessed by TUNEL) and mRNA expression of Bax and Bcl-2, and induced proliferation in PASMChyp (as assessed by 3H-thymidine incorporation). Both observations were mimicked by dimethyloxallyl glycine, a prolyl-hydroxylase inhibitor used to stabilize HIF under normoxia. Pulmonary vascular remodeling was graded in lung samples taken from patients undergoing lung volume reduction surgery for severe heterogenous emphysema. Carbonic anhydrase IX expression in the medial compartment was used as a surrogate of medial hypoxia and HIF stabilization and increased with increasing vascular remodeling. In addition, a mixture of proliferation, assessed by proliferating-cell nuclear antigen, and apoptosis, assessed by active caspase 3 staining, were both higher in more severely remodeled vessels. Hypoxia drives apoptosis and proliferation via HIF in distinct subpopulations of distal PASMC. These differential responses may be important in the pulmonary vascular remodeling seen in emphysema and further support the key role of HIF in hypoxic pulmonary hypertension.

Details

Original languageEnglish
Pages (from-to)241-249
Number of pages9
JournalPulmonary Circulation
Volume2
Issue number2
DOIs
Publication statusPublished - 1 Apr 2012
Peer-reviewedYes

Keywords

    Research areas

  • hypoxia, hypoxia-inducible factor, pulmonary arterial hypertension

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