Sinclair Centre for Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Front Immunol. 2024 Aug 2;15:1403669. doi: 10.3389/fimmu.2024.1403669. eCollection 2024.
Senescence refers to a cellular state marked by irreversible cell cycle arrest and the secretion of pro-inflammatory and tissue-remodeling factors. The senescence associated secretory phenotype (SASP) impacts the tissue microenvironment and provides cues for the immune system to eliminate senescent cells (SCs). Cellular senescence has a dual nature; it can be beneficial during embryonic development, tissue repair, and tumor suppression, but it can also be detrimental in the context of chronic stress, persistent tissue injury, together with an impairment in SC clearance. Recently, the accumulation of SCs has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH), a progressive condition affecting the pre-capillary pulmonary arterial bed. PAH is characterized by endothelial cell (EC) injury, inflammation, and proliferative arterial remodeling, which leads to right heart failure and premature mortality. While vasodilator therapies can improve symptoms, there are currently no approved treatments capable of reversing the obliterative arterial remodeling. Ongoing endothelial injury and dysfunction is central to the development of PAH, perpetuated by hemodynamic perturbation leading to pathological intimal shear stress. The precise role of senescent ECs in PAH remains unclear. Cellular senescence may facilitate endothelial repair, particularly in the early stages of disease. However, in more advanced disease the accumulation of senescent ECs may promote vascular inflammation and occlusive arterial remodeling. In this review, we will examine the evidence that supports a role of endothelial cell senescence to the pathogenesis of PAH. Furthermore, we will compare and discuss the apparent contradictory outcomes with the use of interventions targeting cellular senescence in the context of experimental models of pulmonary hypertension. Finally, we will attempt to propose a framework for the understanding of the complex interplay between EC injury, senescence, inflammation and arterial remodeling, which can guide further research in this area and the development of effective therapeutic strategies.
衰老指细胞不可逆的细胞周期停滞和促炎及组织重塑因子分泌的一种细胞状态。衰老相关分泌表型（SASP）影响组织微环境，并为免疫系统清除衰老细胞（SCs）提供线索。细胞衰老具有双重性质；在胚胎发育、组织修复和肿瘤抑制中是有益的，但在慢性应激、持续组织损伤以及SCs 清除受损的情况下则是有害的。最近，SCs 的积累被认为与肺动脉高压（PAH）的发病机制有关，PAH 是一种影响毛细血管前肺动静脉床的进行性疾病。PAH 的特征是内皮细胞（EC）损伤、炎症和增殖性动脉重塑，导致右心衰竭和过早死亡。虽然血管扩张剂治疗可以改善症状，但目前尚无能够逆转闭塞性动脉重塑的批准治疗方法。持续的内皮损伤和功能障碍是 PAH 发展的核心，由导致病理性内膜切应力的血流动力学扰动所维持。衰老 EC 在 PAH 中的确切作用仍不清楚。细胞衰老可能有助于内皮修复，特别是在疾病的早期阶段。然而，在更严重的疾病中，衰老 EC 的积累可能会促进血管炎症和闭塞性动脉重塑。在这篇综述中，我们将检查支持内皮细胞衰老在 PAH 发病机制中起作用的证据。此外，我们将比较和讨论在肺动脉高压实验模型中使用针对细胞衰老的干预措施所产生的明显矛盾的结果。最后，我们将尝试提出一个理解 EC 损伤、衰老、炎症和动脉重塑之间复杂相互作用的框架，这可以指导该领域的进一步研究和有效治疗策略的制定。
