Pulmonary arterial hypertension (PAH) is a deadly disease, characterized by increased vascular resistance, pulmonary arteriolar loss, and occlusive arterial remodeling, leading to eventual right heart failure. Evidence increasingly points to the pulmonary endothelium as a central actor in PAH. Endothelial cell apoptosis can result directly in distal lung arteriolar pruning and indirectly in the formation of complex and occlusive arterial lesions, reflecting an imbalance between endothelial injury and repair in the development and progression of PAH. Many of the mutations implicated in PAH are in genes, which are predominantly, or solely, expressed in endothelial cells, and the endothelium is a major target for therapeutic interventions to restore BMP signaling. We explore how arterial pruning can promote the emergence of occlusive arterial remodeling mediated by ongoing endothelial injury secondary to hemodynamic perturbation and pathological increases in luminal shear stress. The emerging role of endothelial cell senescence is discussed in the transition from reversible to irreversible arterial remodeling in advanced PAH, and we review the sometimes conflicting evidence that female sex hormones can both protect or promote vascular changes in disease. Finally, we explore the contribution of the endothelium to metabolic changes and the altered inflammatory and immune state in the PAH lung, focusing on the role of excessive TGFβ signaling. Given the complexity of the endothelial pathobiology of PAH, we anticipate that emerging technologies that allow the study of molecular events at a single cell level will provide answers to many of the questions raised in this review.

中文翻译：

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肺动脉高压内皮病理学概念的演变

肺动脉高压 (PAH) 是一种致命疾病，其特征是血管阻力增加、肺小动脉丢失和闭塞性动脉重塑，最终导致右心衰竭。越来越多的证据表明肺内皮细胞是 PAH 的核心因素。内皮细胞凋亡可直接导致远端肺小动脉修剪，间接导致复杂闭塞性动脉病变的形成，反映了内皮损伤与修复在PAH发生发展过程中的失衡。许多与 PAH 相关的突变存在于基因中，这些基因主要或单独在内皮细胞中表达，而内皮细胞是恢复 BMP 信号传导的治疗干预的主要目标。我们探讨了动脉修剪如何促进闭塞性动脉重塑的出现，这是由继发于血流动力学扰动和管腔剪切应力病理性增加的持续内皮损伤介导的。讨论了内皮细胞衰老在晚期 PAH 从可逆到不可逆动脉重塑的转变中的新兴作用，我们回顾了有时相互矛盾的证据，即女性性激素可以保护或促进疾病中的血管变化。最后，我们探讨了内皮对代谢变化的贡献以及 PAH 肺中炎症和免疫状态的改变，重点是过度 TGFβ 信号传导的作用。鉴于 PAH 内皮病理学的复杂性，