title: Cellular and molecular basis of pulmonary arterial hypertension.
abstract: 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 [Ca(2+)] 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.
authors: Pulmonary Vascular Diseases Unit, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. Electronic address: nwm23@cam.ac.uk.
authors: Nicholas W
authors: NW
authors: Morrell
authors: Medical School of Créteil, Hôpital Henri Mondor, Créteil, France.
authors: Serge
authors: S
authors: Adnot
authors: University of Chicago, Chicago, Illinois.
authors: Stephen L
authors: SL
authors: Archer
authors: Research Center of the Montreal Heart Institute, Department of Medicine, University of Montreal, Montreal, Québec, Canada.
authors: Jocelyn
authors: J
authors: Dupuis
authors: University of Pennsylvania, Penn/CMREF Center for Pulmonary Arterial Hypertension Research, Philadelphia, Pennsylvania.
authors: Peter
authors: P
authors: Lloyd Jones
authors: Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland.
authors: Margaret R
authors: MR
authors: MacLean
authors: Departments of Pharmacology and Medicine and Center for Lung Biology, University of South Alabama, Mobile, Alabama.
authors: Ivan F
authors: IF
authors: McMurtry
authors: Developmental Lung Biology Laboratory and Pediatric Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado.
authors: Kurt R
authors: KR
authors: Stenmark
authors: Department of Cardiothoracic Surgery, University of California, San Diego, La Jolla, California.
authors: Patricia A
authors: PA
authors: Thistlethwaite
authors: University of Giessen Lung Center, Department of Internal Medicine II/V, Justus-Liebig-University, Giessen, Germany.
authors: Norbert
authors: N
authors: Weissmann
authors: Department of Medicine, University of California San Diego, La Jolla, California.
authors: Jason X-J
authors: JX
authors: Yuan
authors: University of Minnesota, Veterans Affairs Medical Center, Minneapolis, Minnesota.
authors: E Kenneth
authors: EK
authors: Weir
mesh_terms: D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D011464:Epoprostenol / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D059630:Mesenchymal Stem Cells / Q000502:physiology; D014655:Vascular Resistance / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000502:physiology
chemical_list: D011464:Epoprostenol; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; D020741:rho GTP-Binding Proteins