Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by (mal)adaptive remodeling of the pulmonary vasculature, which is associated with inflammation, fibrosis, thrombosis, and neovascularization. Vascular remodeling in PAH is associated with cellular metabolic and inflammatory reprogramming that induce profound endothelial and smooth muscle cell phenotypic changes. Multiple signaling pathways and regulatory loops act on metabolic and inflammatory mediators which influence cellular behavior and trigger pulmonary vascular remodeling in vivo. This review discusses the role of bioenergetic and inflammatory impairments in PAH development.
Highlights
Pulmonary hypertension (PH) is a progressive disease characterized by increased pulmonary vascular resistance (PVR) leading to right heart hypertrophy and death due to right heart failure [1]
This assertion was based on the fact that PASMCs from hypoxiaexposed rats show an increased expression of TRPC1 and TRPC6 mRNA and proteins, and these channels were increased in PASMCs from normoxic animals cultured under hypoxic conditions (4% O2 ; 60 h) [92], validating that the presence of hypoxia-inducible factors 1α (HIF-1α) in PASMCs is necessary for the development of PH
In the hypoxia-induced PH model, platelet-derived growth factor (PDGF) activates the PI3Ks/AKT pathway resulting in cyclic adenosine monophosphate response element-binding protein depletion in PASMCs, which in turn induces switching of PASMCs from a contractile to a synthetic phenotype
Summary
Pulmonary hypertension (PH) is a progressive disease characterized by increased pulmonary vascular resistance (PVR) leading to right heart hypertrophy and death due to right heart failure [1]. PAH is characterized by increases in PVR that are mostly due to (mal)adaptive remodeling of the pulmonary vasculature, which is associated with inflammation, fibrosis, thrombotic lesions, medial hypertrophy, and intimal proliferation. Due to its complexity and being constituted by several associated clinical disorders, PAH is subdivided in: idiopathic PAH (group 1.1); heritable PAH (group 1.2); drugand toxin-induced PAH (group 1.3); PAH associated with various conditions including connective tissue diseases, such as HIV infection, portal hypertension, and congenital heart disease (group 1.4); PAH in long-term responders to calcium channel blockers (group 1.5); PAH with venous/capillary involvement (group 1.6); and persistent PH of the newborn (group 1.7) [5]. Other hereditary causes of PAH involve TGF-β superfamily genes including ALK1/ACVRL1 (a heterodimeric partner of BMPR2), BMP9. We will summarize current data on the mechanisms that control metabolic and inflammatory events in endothelial cells (ECs) and smooth muscle cells (SMCs) as essential pathways leading to pulmonary vascular remodeling in PAH
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