Cellular and molecular basis of pulmonary arterial hypertension.
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.
Morrell
Nicholas W
NW
Pulmonary Vascular Diseases Unit, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. Electronic address: nwm23@cam.ac.uk.
Adnot
Serge
S
Medical School of Créteil, Hôpital Henri Mondor, Créteil, France.
Archer
Stephen L
SL
University of Chicago, Chicago, Illinois.
Dupuis
Jocelyn
J
Research Center of the Montreal Heart Institute, Department of Medicine, University of Montreal, Montreal, Québec, Canada.
Lloyd Jones
Peter
P
University of Pennsylvania, Penn/CMREF Center for Pulmonary Arterial Hypertension Research, Philadelphia, Pennsylvania.
MacLean
Margaret R
MR
Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland.
McMurtry
Ivan F
IF
Departments of Pharmacology and Medicine and Center for Lung Biology, University of South Alabama, Mobile, Alabama.
Stenmark
Kurt R
KR
Developmental Lung Biology Laboratory and Pediatric Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado.
Thistlethwaite
Patricia A
PA
Department of Cardiothoracic Surgery, University of California, San Diego, La Jolla, California.
Weissmann
Norbert
N
University of Giessen Lung Center, Department of Internal Medicine II/V, Justus-Liebig-University, Giessen, Germany.
Yuan
Jason X-J
JX
Department of Medicine, University of California San Diego, La Jolla, California.
Weir
E Kenneth
EK
University of Minnesota, Veterans Affairs Medical Center, Minneapolis, Minnesota.
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
D011464:Epoprostenol; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; D020741:rho GTP-Binding Proteins