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Hypoxia Amplifies the Proliferative Capacity of Distal Human Pulmonary Artery Smooth-Muscle Cells^*

^* From Imperial College London (Drs. Growcott and Wharton), Hammersmith Campus, London; and Pfizer Global Research & Development (Dr. Banner), Sandwich, Kent, UK.

Correspondence to: Ellena J. Growcott, MD, Experimental Medicine and Toxicology, Imperial College London, Hammersmith Campus, London W12 0NN, UK

Hypoxia is an important factor in pulmonary hypertension and vascular remodeling. We sought to determine whether the growth capabilities of human pulmonary artery smooth-muscle cells (PASMCs) differ when isolated and grown under normoxic (95% ambient air, 5% CO₂) and hypoxic conditions (2% O₂, 93% N₂, 5% CO₂). Cells from explants of the same distal (< 1 mm external diameter) pulmonary artery segments (n = 6 patients) were used at passage 3 to 12, and responses to growth factors and prostacyclin analogues (cicaprost and iloprost) were determined by measuring [methyl-³H]-thymidine incorporation, cell number, and intracellular cyclic adenosine monophosphate (cAMP) levels. DNA synthesis was greater in hypoxia—compared to normoxia-derived PASMCs—following stimulation with 5 ng/mL platelet-derived growth factor-BB (9.1 ± 2.8-fold vs 4.2 ± 1.2-fold increase, p < 0.05) [mean ± SD] and 5% fetal bovine serum (15.4 ± 3.8-fold vs 4.4 ± 0.8-fold increase, p < 0.05). A similar differential response occurred with epidermal growth factor and insulin-like growth factor-1. In contrast, the inhibitory potency of prostacyclin analogues on DNA synthesis and cell proliferation was reduced in hypoxia, compared to normoxia-derived PASMCs. For example, inhibition of platelet-derived growth factor-stimulated DNA synthesis by cicaprost (1 nmol) was attenuated in hypoxic compared to normoxic cells (34 ± 2% vs 64 ± 2%, p < 0.05) and was associated with reduced intracellular cAMP levels (4.8 ± 0.4 pmol vs 16.4 ± 4.2 pmol cAMP/10⁵ cells after 60 min; p < 0.02). The attenuated responses to cicaprost were reversed, at least in part, by co-treatment with cAMP-specific phosphodiesterase type 4 inhibitors roflumilast (100 nmol; 29.5 ± 2.6 pmol vs 28.0 ± 1.5 pmol cAMP/10⁵ cells) and cilomilast. In conclusion, human PASMCs exhibit a proliferative phenotype when derived and grown in a hypoxic environment. Reducing cAMP hydrolysis, for example, by inhibiting phosphodiesterase type 4 activity, may represent a strategy for regulating PASMC proliferation and vascular remodeling in pulmonary hypertension.

	Footnotes

 
Abbreviations: cAMP = cyclic adenosine monophosphate; PASMC = pulmonary artery smooth-muscle cell

Funded by a BBSRC-CASE Award and BHF.

This Article Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Growcott, E. J. Articles by Wharton, J. Search for Related Content PubMed PubMed Citation Articles by Growcott, E. J. Articles by Wharton, J.