St. Michael's Hospital, Canada.
Pharmacol Ther. 2010 Apr;126(1):1-8. doi: 10.1016/j.pharmthera.2009.12.006. Epub 2010 Feb 1.
Pulmonary arterial hypertension (PAH) is a progressive and lethal disease that has a strong female predominance, often affecting the young. Current therapies are mostly vasodilator agents, and while mainly addressing the endothelial dysfunction that has been widely reported in this disease, they may be less effective in treating arterial remodeling. The lung pathology of PAH is characterized by medial hypertrophy and intimal hyperplasia of muscular arteries as well as plexiform lesions, that lead to a widespread narrowing or obliteration of the pulmonary arteriolar bed. However, the pathogenesis of the functional and structural abnormalities of the lung microcirculation in PAH is poorly understood. Perhaps the greatest advancement in the last decade has been the discovery of the "PAH gene," bone morphogenetic receptor 2 (Bmpr2), however how the loss-of-function mutations in Bmpr2 lead to PAH is unclear. The BMPR2 pathway has recently been shown to mediate survival signaling in endothelial cells (EC), and thus the reduced activity will favor endothelial apoptosis, likely increasing the susceptibility to endothelial injury in response to various environmental triggers. EC apoptosis has been implicated as an initiating event in experimental PAH, leading either directly to the degeneration of pre-capillary arterioles or to the selection of hyperproliferative, apoptosis-resistant ECs that may contribute to "angioproliferative" plexiform lesions. The idea that EC apoptosis may play a central role in the initiation and progression of PAH suggests that therapeutic strategies aimed at endothelial repair and regeneration of ECs may be uniquely effective in the treatment of this disease. Preclinical evaluation and validation on the use of endothelial progenitor cells (EPCs) for the prevention and reversal of experimental PAH is reviewed and the design of a "first in man" clinical trial to assess the safety and efficacy of a combined EPC and endothelial NO-synthase gene therapy for patients that are refractory to standard therapies is discussed.
肺动脉高压（PAH）是一种进行性和致命性疾病，具有强烈的女性优势，通常影响年轻人。目前的治疗方法主要是血管扩张剂，虽然主要针对这种疾病中广泛报道的内皮功能障碍，但它们在治疗动脉重塑方面可能效果较差。PAH 的肺病理学特征是肌性动脉的中膜肥厚和内膜增生以及丛状病变，导致肺小动脉床广泛狭窄或闭塞。然而，PAH 中肺微循环的功能和结构异常的发病机制尚不清楚。也许过去十年中最大的进展是发现了“PAH 基因”，骨形态发生受体 2（Bmpr2），然而 Bmpr2 功能丧失突变如何导致 PAH 尚不清楚。BMPR2 途径最近被证明在内皮细胞（EC）中介导存活信号，因此活性降低将有利于内皮细胞凋亡，可能增加对各种环境触发因素的内皮损伤的易感性。EC 凋亡已被牵连为实验性 PAH 的起始事件，直接导致毛细血管前小动脉退化，或导致增殖、抗凋亡的 EC 选择，可能导致“血管增殖性”丛状病变。EC 凋亡可能在 PAH 的起始和进展中发挥核心作用的观点表明，旨在修复内皮细胞和促进 EC 再生的治疗策略可能在治疗这种疾病方面具有独特的效果。本文综述了内皮祖细胞（EPC）在预防和逆转实验性 PAH 中的应用的临床前评估和验证，并讨论了一项“首例人体”临床试验的设计，以评估联合 EPC 和内皮一氧化氮合酶基因治疗对标准治疗无效的患者的安全性和疗效。
