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.

Figure 1. Schematic diagram depicting potential mechanisms involved in the development of PAH

AVD=apoptotic volume decrease; CaM=calmodulin; DAG=diacylglycerol; E_m=membrane potential; EGF=epidermal growth factor; GPCR=G protein-coupled receptor; HHV=human herpes virus; IP₃=inositol 1,4,5-trisphosphate; MLC=myosin light chain; MLCK=myosin light chain kinase; PDGF=platelet-derived growth factor; PKC=protein kinase C; PLC=phospholipase C; ROS=reactive oxygen species; RTK=receptor tyrosine kinase; SR=sarcoplasmic reticulum.