Abstract
Pulmonary arterial hypertension (PAH) is a rare, complex, and progressive disease that is characterized by the abnormal remodeling of the pulmonary arteries that leads to right ventricular failure and death. Although our understanding of the causes for abnormal vascular remodeling in PAH is limited, accumulating evidence indicates that endothelial cell (EC) dysfunction is one of the first triggers initiating this process. EC dysfunction leads to the activation of several cellular signalling pathways in the endothelium, resulting in the uncontrolled proliferation of ECs, pulmonary artery smooth muscle cells, and fibroblasts, and eventually leads to vascular remodelling and the occlusion of the pulmonary blood vessels. Other factors that are related to EC dysfunction in PAH are an increase in endothelial to mesenchymal transition, inflammation, apoptosis, and thrombus formation. In this review, we outline the latest advances on the role of EC dysfunction in PAH and other forms of pulmonary hypertension. We also elaborate on the molecular signals that orchestrate EC dysfunction in PAH. Understanding the role and mechanisms of EC dysfunction will unravel the therapeutic potential of targeting this process in PAH.
Highlights
Pulmonary hypertension (PH) is a condition that is defined by a mean pulmonary arterial pressure of more than 20 mmHg at rest and 30 mmHg during exercise
The purpose of this review is to provide a state-of-the-art overview on the features and driving forces of endothelial cell (EC) dysfunction in Pulmonary arterial hypertension (PAH) and highlight the current progress made in understanding this phenomenon
We have recently shown that BMP9-induced aberrant endothelial to mesenchymal transition (EndoMT) in PAH pulmonary ECs is dependent on exacerbated pro-inflammatory signaling mediated through IL6 [54]
Summary
Pulmonary hypertension (PH) is a condition that is defined by a mean pulmonary arterial pressure of more than 20 mmHg at rest and 30 mmHg during exercise. Biomedicines 2021, 9, 57 and drug development mainly focus on PAH and CTEPH, which are rarer diseases that mainly affect younger people [5]. PAH is characterized by remodeling of distal pulmonary arteries, causing a progressive increase in vascular resistance. Prolonged or chronic activation of the endothelium leads to EC dysfunction, the loss of homeostatic functions, leading to pathological changes, and it is crucial in the development of cardiovascular diseases and so too in PAH [8,9]. The endothelium switches from a quiescent to an overactive state, where it starts to secrete vasoconstrictive factors, like endothelin (ET-1) [13] and thromboxane [14], and proliferative factors, like vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2) [15], CXCL12 [16], and reduce the secretion of vasodilators, like nitric oxide (NO) and prostacyclin, which indicates that EC dysfunction might play a central role in the pathogenesis of PAH.
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