State-of-the-Art Paper
Cellular and Molecular Basis of Pulmonary Arterial Hypertension

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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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