Cellular and Molecular Basis of Pulmonary Arterial Hypertension

Nicholas W. Morrell, Serge Adnot, Stephen L. Archer, Jocelyn Dupuis, Peter Lloyd Jones, Margaret R. MacLean, Ivan F. McMurtry, Kurt R. Stenmark, Patricia A. Thistlethwaite, Norbert Weissmann, Jason X J Yuan, E. Kenneth Weir

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592 Scopus citations


Pulmonary arterial hypertension (PAH) is caused by functional and structural changes in the pulmonary vasculature, leading to increased pulmonary vascular resistance. The process of pulmonary vascular remodeling is accompanied by endothelial dysfunction, activation of fibroblasts and smooth muscle cells, crosstalk between cells within the vascular wall, and recruitment of circulating progenitor cells. Recent findings have reestablished the role of chronic vasoconstriction in the remodeling process. Although the pathology of PAH in the lung is well known, this article is concerned with the cellular and molecular processes involved. In particular, we focus on the role of the Rho family guanosine triphosphatases in endothelial function and vasoconstriction. The crosstalk between endothelium and vascular smooth muscle is explored in the context of mutations in the bone morphogenetic protein type II receptor, alterations in angiopoietin-1/TIE2 signaling, and the serotonin pathway. We also review the role of voltage-gated K+ channels and transient receptor potential channels in the regulation of cytosolic [Ca2+] and [K+], vasoconstriction, proliferation, and cell survival. We highlight the importance of the extracellular matrix as an active regulator of cell behavior and phenotype and evaluate the contribution of the glycoprotein tenascin-c as a key mediator of smooth muscle cell growth and survival. Finally, we discuss the origins of a cell type critical to the process of pulmonary vascular remodeling, the myofibroblast, and review the evidence supporting a contribution for the involvement of endothelial-mesenchymal transition and recruitment of circulating mesenchymal progenitor cells.

Original languageEnglish (US)
Pages (from-to)S20-S31
JournalJournal of the American College of Cardiology
Issue number1 SUPPL. 1
StatePublished - Jun 30 2009

Bibliographical note

Funding Information:
Dr. Morrell has received research grants from the British Heart Foundation, Cambridge NIHR Biomedical Research Center, and Novartis and has received honoraria for educational lectures from Actelion, GlaxoSmithKline, and Pfizer. Dr. Archer has received grant support from the National Institutes of Health, and has received an honorarium from Gilead. Dr. Dupuis has served as a consultant for Actelion, Pfizer, and Encysive, and is president and a shareholder of PulmoScience Inc. Dr. Jones has received an honorarium from Novartis. Dr. MacLean has received funding from the Biotechnology and Biological Sciences Research Council and the British Heart Foundation. Dr. McMurtry has received a research grant from the National Heart, Lung and Blood Institute. Dr. Thistlethwaite has received grant support from the National Institutes of Health and the Center for Medical Research and Education Fund. Dr. Weissmann has received research grants from the Deutsche Forschungsgemeinschaft “Excellence Cluster Cardio-Pulmonary System,” Bayer HealthCare, Sanofi-Aventis, and Solvay Pharmaceuticals, and has received lecture fees from Nycomed, Sanofi-Aventis, and Solvay Pharmaceuticals. Dr. Yuan has received grant support from the National Institutes of Health. Dr. Weir has received grant support from NIH RO1 HL 65322. Drs. Adnot and Stenmark report no conflicts of interest.


  • cellular
  • molecular basis
  • pulmonary arterial hypertension

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