Cellular and molecular pathobiology of pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) has a multifactorial pathobiology. Vasoconstriction, remodeling of the pulmonary vessel wall, and thrombosis contribute to increased pulmonary vascular resistance in PAH. The process of pulmonary vascular remodeling involves all layers of the vessel wall and is complicated by cellular heterogeneity within each compartment of the pulmonary arterial wall. Indeed, each cell type (endothelial, smooth muscle, and fibroblast), as well as inflammatory cells and platelets, may play a significant role in PAH. Pulmonary vasoconstriction is believed to be an early component of the pulmonary hypertensive process. Excessive vasoconstriction has been related to abnormal function or expression of potassium channels and to endothelial dysfunction. Endothelial dysfunction leads to chronically impaired production of vasodilators such as nitric oxide and prostacyclin along with overexpression of vasoconstrictors such as endothelin (ET)-1. Many of these abnormalities not only elevate vascular tone and promote vascular remodeling but also represent logical pharmacological targets. Recent genetic and pathophysiologic studies have emphasized the relevance of several mediators in this condition, including prostacyclin, nitric oxide, ET-1, angiopoietin-1, serotonin, cytokines, chemokines, and members of the transforming-growth-factor-beta superfamily. Disordered proteolysis of the extracellular matrix is also evident in PAH. Future studies are required to find which if any of these abnormalities initiates PAH and which ones are best targeted to cure the disease.
Humbert
Marc
M
Service de Pneumologie et Réanimation Respiratoire, Centre des Maladies Vasculaires Pulmonaires, UPRES EA2705, Hôpital Antoine-Béclère, Université Paris-Sud, Clamart, France. humbert@ipsc.u-psud.fr
Morrell
Nicholas W
NW
Archer
Stephen L
SL
Stenmark
Kurt R
KR
MacLean
Margaret R
MR
Lang
Irene M
IM
Christman
Brian W
BW
Weir
E Kenneth
EK
Eickelberg
Oliver
O
Voelkel
Norbert F
NF
Rabinovitch
Marlene
M
D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008967:Molecular Biology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D014655:Vascular Resistance / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology