Hot topics in the mechanisms of pulmonary arterial hypertension disease: cancer‐like pathobiology, the role of the adventitia, systemic involvement, and right ventricular failure

Abstract

In order to intervene appropriately and develop disease-modifying therapeutics for pulmonary arterial hypertension, it is crucial to understand the mechanisms of disease pathogenesis and progression. We herein discuss four topics of disease mechanisms that are currently highly debated, yet still unsolved, in the field of pulmonary arterial hypertension. Is pulmonary arterial hypertension a cancer-like disease? Does the adventitia play an important role in the initiation of pulmonary vascular remodeling? Is pulmonary arterial hypertension a systemic disease? Does capillary loss drive right ventricular failure? While pulmonary arterial hypertension does not replicate all features of cancer, anti-proliferative cancer therapeutics might still be beneficial in pulmonary arterial hypertension if monitored for safety and tolerability. It was recognized that the adventitia as a cell-rich compartment is important in the disease pathogenesis of pulmonary arterial hypertension and should be a therapeutic target, albeit the data are inconclusive as to whether the adventitia is involved in the initiation of neointima formation. There was agreement that systemic diseases can lead to pulmonary arterial hypertension and that pulmonary arterial hypertension can have systemic effects related to the advanced lung pathology, yet there was less agreement on whether idiopathic pulmonary arterial hypertension is a systemic disease per se. Despite acknowledging the limitations of exactly assessing vascular density in the right ventricle, it was recognized that the failing right ventricle may show inadequate vascular adaptation resulting in inadequate delivery of oxygen and other metabolites. Although the debate was not meant to result in a definite resolution of the specific arguments, it sparked ideas about how we might resolve the discrepancies by improving our disease modeling (rodent models, large-animal studies, studies of human cells, tissues, and organs) as well as standardization of the models. Novel experimental approaches, such as lineage tracing and better three-dimensional imaging of experimental as well as human lung and heart tissues, might unravel how different cells contribute to the disease pathology.

Astragaloside IV attenuates hypoxia‑induced pulmonary vascular remodeling via the Notch signaling pathway

“…The pathogenesis of PAH is relatively complex and is not completely understood ( 13 ). Pulmonary vascular remodeling is an important marker of the degree of severity and progression in PAH, which is primarily due to the imbalance between pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis ( 14 , 15 ).…”

Endothelial Basement Membrane Components and Their Products, Matrikines: Active Drivers of Pulmonary Hypertension?

“…In contrast, laminin lead to cytoplasmic retainment of YAP [ 4 ]. YAP is one of the key components of the mechanosensing machinery, and it is increasingly being connected to PAH pathology [ 169 , 178 ]—for example, by being part of the pro-proliferative Hippo-YAP/Tafazzin- integrin-linked kinase 1 (TAZ- ILK1) circuit involved in mediating the hyperproliferation of vascular cells in PAH [ 169 , 179 , 180 ].…”

Endothelial platelet‐derived growth factor‐mediated activation of smooth muscle platelet‐derived growth factor receptors in pulmonary arterial hypertension

“…[8][9][10] The altered activation of growth factorinduced pathways drives concentric pulmonary arterial remodeling, pulmonary arteriole muscularization, and obliterative intimal lesions predominantly resulting in the elevation of pulmonary vascular resistance. 11 Platelet-derived growth factor (PDGF) plays an essential role in regulating cell proliferation, differentiation, and migration. 12,13 The increased level of PDGF-AA and PDGF-BB in serum and PASMC has been demonstrated in patients with PAH and animals with experimental pulmonary hypertension (PH).…”