Molecular pathogenesis of pulmonary arterial hypertension

Abstract

Recent clinical and experimental studies are redefining the cellular and molecular bases of pulmonary arterial hypertension (PAH). The genetic abnormalities first identified in association with the idiopathic form of PAH--together with a vast increase in our understanding of cell signaling, cell transformation, and cell-cell interactions; gene expression; microRNA processing; and mitochondrial and ion channel function--have helped explain the abnormal response of vascular cells to injury. Experimental and clinical studies now converge on the intersection and interactions between a genetic predisposition involving the BMPR2 signaling pathway and an impaired metabolic and chronic inflammatory state in the vessel wall. These deranged processes culminate in an exuberant proliferative response that occludes the pulmonary arterial (PA) lumen and obliterates the most distal intraacinar vessels. Here, we describe emerging therapies based on preclinical studies that address these converging pathways.

Figure 1. Vascular abnormalities associated with PAH.

This schema depicts the abnormalities throughout the pulmonary circulation: abnormal muscularization of distal and medial precapillary arteries, loss of precapillary arteries, thickening of large PAs, and neointimal formation that is particularly occlusive in vessels less than 500–100 μM and in plexiform lesions therein.

Figure 2. Factors that converge in the molecular pathogenesis of PAH.

This schema focuses on the interactions among inflammation, altered cellular metabolism, and genetic/epigenetic abnormalities in the pathogenesis of PAH.