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STATE-OF-THE-ART PAPER

Cellular and Molecular Basis of Pulmonary Arterial Hypertension

Nicholas W. Morrell, MA, MD^_*,_*, Serge Adnot, MD, PhD, Stephen L. Archer, MD, Jocelyn Dupuis, MD, PhD, Peter Lloyd Jones, PhD^||, Margaret R. MacLean, PhD^¶, Ivan F. McMurtry, PhD^#, Kurt R. Stenmark, MD^_**, Patricia A. Thistlethwaite, MD, PhD, Norbert Weissmann, PhD, Jason X.-J. Yuan, MD, PhD and E. Kenneth Weir, MD^||||

^_* Pulmonary Vascular Diseases Unit, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
Medical School of Créteil, Hôpital Henri Mondor, Créteil, France
University of Chicago, Chicago, Illinois
Research Center of the Montreal Heart Institute, Department of Medicine, University of Montreal, Montreal, Québec, Canada
^|| University of Pennsylvania, Penn/CMREF Center for Pulmonary Arterial Hypertension Research, Philadelphia, Pennsylvania
^¶ Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland
^# Departments of Pharmacology and Medicine and Center for Lung Biology, University of South Alabama, Mobile, Alabama
^_** Developmental Lung Biology Laboratory and Pediatric Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
Department of Cardiothoracic Surgery, University of California, San Diego, La Jolla, California
University of Giessen Lung Center, Department of Internal Medicine II/V, Justus-Liebig-University, Giessen, Germany
Department of Medicine, University of California San Diego, La Jolla, California
^|||| University of Minnesota, Veterans Affairs Medical Center, Minneapolis, Minnesota

Manuscript received February 6, 2009; accepted April 15, 2009.

^_* Reprint requests and correspondence: Dr. Nicholas W. Morrell, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom (Email: nwm23{at}cam.ac.uk).

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.

Key Words: pulmonary arterial hypertension • cellular • molecular basis

Abbreviations and Acronyms   ALK = activin-receptorlike kinase   Ang = angiopoeitin   BMP = bone morphogenetic protein   BMPR = bone morphogenetic protein receptor   cGMP = cyclic guanosine monophosphate   EC = endothelial cell   ECM = extracellular matrix   enMT = endothelial mesenchymal transition   eNOS = endothelial nitric oxide synthase   GTPase = guanosine triphosphatase   5-HT = hydroxytryptamine (serotonin)   5-HTT = hydroxytryptamine (serotonin) transporter   IPAH = idiopathic pulmonary arterial hypertension   MLC = myosin light chain   MLCK = myosin light chain kinase   MLCP = myosin light chain phosphatase   NO = nitric oxide   PA = pulmonary artery   PAEC = pulmonary artery endothelial cell   PAH = pulmonary arterial hypertension   PAI = plasminogen-activator inhibitor   PAK = p21-activated kinase   PASMC = pulmonary artery smooth muscle cell   PGI2 = prostacyclin   PH = pulmonary hypertension   PK = protein kinase   ROCK = Rho kinase   SMC = smooth muscle cell   TGF = transforming growth factor   TRPC = canonical transient receptor potential

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