Endothelial cells in the pathogenesis of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a devastating disease that involves pulmonary vasoconstriction, small vessel obliteration, large vessel thickening and obstruction, and development of plexiform lesions. PAH vasculopathy leads to progressive increases in pulmonary vascular resistance, right heart failure and, ultimately, premature death. Besides other cell types that are known to be involved in PAH pathogenesis (e.g. smooth muscle cells, fibroblasts and leukocytes), recent studies have demonstrated that endothelial cells (ECs) have a crucial role in the initiation and progression of PAH. The EC-specific role in PAH is multi-faceted and affects numerous pathophysiological processes, including vasoconstriction, inflammation, coagulation, metabolism and oxidative/nitrative stress, as well as cell viability, growth and differentiation. In this review, we describe how EC dysfunction and cell signalling regulate the pathogenesis of PAH. We also highlight areas of research that warrant attention in future studies, and discuss potential molecular signalling pathways in ECs that could be targeted therapeutically in the prevention and treatment of PAH.

Figure 1.

(A) PHD2 deficiency in endothelial cells and hematopoietic cells induces obliterative vascular remodeling recapitulating the histopathological features of clinical PAH. Representative micrographs of Russel-Movat pentachrome staining demonstrating thickening of the intima, medial, and adventitial, and occlusion of the large and small vessels (black arrowheads) in 3.5 mo. old Egln1^Tie2Cre mice (Middle 2). Br, bronchus; V, vessel. Scale bar: 50 μm. Anti-CD31 immunohistochemistry showing multiple-channel lesions positive for the endothelial marker CD31 (red arrows) (Right). Scale bar: 50 μm. Figure adapted with permission from Dai, et al. [17]. (B-E) Factors regulating endothelial cell functions contributing to pulmonary vascular remodeling and PAH. (B) Factors regulating pulmonary EC apoptosis and survival in the pathogenesis of PAH. (C) Factors regulating pulmonary EC proliferation and migration contributing to PAH. (D) Factors affecting pulmonary EC metabolism (glycolysis switch) and epigenetic regulation. (E) Factors regulating EndoMT contributing to PAH. Abbreviations: AMPK, AMP-activated protein kinase; BMPR2, bone morphogenic protein receptor 2; Cav1, caveolin 1; CLIC4, chloride intracellular channel 4; FGF2, fibroblast growth factor 2; GDF11, growth differentiation factor 11; GrzB, granzyme B; HIF2α, hypoxia-inducible factor 2α; HIMF, hypoxia-induced mitogenic factor; IL, interleukin; ITSN 1s, intersectin 1 short; MEF2, myocyte enhancer factor 2; miRNA, micro RNA; mTOR, mammalian target of rapamycin; Nep, neprilysin; PCD4, programmed cell death 4; PDGFB, platelet-derived growth factor-BB; PHD2, prolyl hydroxylase 2; PI3K, phosphoinositide 3-kinase; PPARγ, peroxisome proliferator-activated receptor γ; PTPL1, protein tyrosine phosphatase; TGFβ, transforming growth factor β; VEGF, vascular endothelial growth factor.

Figure 2:. Cross-talk between pulmonary endothelial cells and other cells leads to obliterative pulmonary vascular remodeling and progressive vasoconstriction and thereby PAH.

Various environmental factors, mechanical damage, and genetic predisposition converge on pulmonary vascular ECs leading to EC injury and dysfunction which affect EC activation, survival, proliferation, migration, metabolic and epigenetic status resulting in EC-apoptosis-resistant hyperproliferation, EndoMT, and releases of vascular tone modulators, angiocrine factors, cytokine and chemokines which mediate crosstalk between ECs and SMCs, leukocytes, (myo)fibroblasts. Together, EC dysfunction induces obliterative pulmonary vascular remodeling and vasoconstriction resulting in PAH. Thus, targeting altered EC signalings will provide novel effective therapeutic approaches for inhibiting/reversing obliterative vascular remodeling and PAH. Abbreviations: EC, endothelial cell; EndoMT, endothelial-to-mesenchymal transition; PH, pulmonary hypertension; SMC, smooth muscle cell.