Estrogens and development of pulmonary hypertension: interaction of estradiol metabolism and pulmonary vascular disease.
Estrogens and development of pulmonary hypertension: interaction of estradiol metabolism and pulmonary vascular disease.
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DOI：
10.1097/fjc.0b013e3181f9ea8d
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发表时间：
2010-12
影响因子：
3
通讯作者：
Tofovic SP
中科院分区：
文献类型：
--
作者：
Tofovic SP
重度肺动脉高压(PAH)的特征是小口径肺动脉管腔内皮细胞聚集增殖，导致管腔向心性闭塞，形成复杂的血管结构，称为丛状病变。这种衰弱的疾病更多地发生在女性身上，然而在经典的PAH模型中进行的动物研究和有限的临床数据都表明雌激素的保护作用：肺动脉高压中的雌激素悖论。目前对雌激素在肺动脉高压中的作用知之甚少，但有一系列证据有力地表明，17β-雌二醇的血管保护作用主要是通过其下游代谢产物实现的。雌二醇在细胞色素P1A1/细胞色素P1B1的作用下代谢为2-羟基雌二醇(2HE)，2-羟基雌二醇(2HE)在邻苯二酚-O-甲基转移酶作用下转化为2-甲氧基雌二醇(2ME)。2Me被广泛代谢成2-甲氧基雌酮，这是一种没有生物活性但可以转化回2Me的代谢物。2ME没有雌激素样作用，其作用是通过雌激素受体非依赖性机制发挥作用的(S)。值得注意的是，在全身和肺血管内皮细胞、平滑肌细胞和成纤维细胞中，2Me比E2本身具有更强的抗有丝分裂作用。尽管E2和2Me对其他心血管细胞有相似的作用，但对内皮细胞却有相反的作用；即在内皮细胞中，E2是促有丝分裂、促血管生成和抗凋亡的，而2Me是抗分裂、抗血管生成和促凋亡的。这可能对严重的PAH有重要的影响，涉及到单克隆性、抗凋亡的内皮细胞的不受控制的增殖。基于其细胞效应，2Me应该可以延缓疾病的进展，并在严重的PAH中提供保护。相反，由于其促有丝分裂、血管生成和抗凋亡作用(否则在正常的静止内皮细胞中是可取的)，E2甚至可能对PAH中的内皮重构产生不利影响，如果2Me不对抗E2‘S对受损内皮细胞的影响(例如，在由于缺氧、炎症、药物、环境因素或代谢酶基因多态而导致E2向2Me转化减少的情况下)，这一影响可能更加显著。本文就雌激素及其代谢产物在肺血管病变中的作用及实验性PAH的发生发展作一综述，并对PAH中的雌激素悖论提供可能的解释。此外，我们认为雌激素代谢失衡可能导致PAH的发生。最近的动物数据和对PAH患者的研究支持这一概念。
Severe pulmonary arterial hypertension (PAH) is characterized by clustered proliferation of endothelial cells in the lumina of small size pulmonary arteries resulting in concentric obliteration of the lumina and formation of complex vascular structures known as plexiform lesions. This debilitating disease occurs more frequently in women, yet both animal studies in classical models of PAH and limited clinical data suggest protective effects of estrogens: the estrogen paradox in pulmonary hypertension. Little is known about the role of estrogens in PAH, but one line of evidence strongly suggests that the vascular protective effects of 17β-estradiol (estradiol; E2) are mediated largely by its downstream metabolites. Estradiol is metabolized to 2-hydroxyestradiol (2HE) by CYP1A1/CYP1B1, and 2HE is converted to 2-methoxyestradiol (2ME) by catechol-O-methyl transferase. 2ME is extensively metabolized to 2-methoxyestrone, a metabolite that lacks biologic activity but which may be converted back to 2ME. 2ME has no estrogenic activity and its effects are mediated by estrogen receptors-independent mechanism(s). Notably, in systemic and pulmonary vascular endothelial cells, smooth muscle cells, and fibroblasts 2ME exerts stronger anti-mitotic effects than E2 itself. E2 and 2ME, despite having similar effects on other cardiovascular cells, have opposing effects on endothelial cells; that is, in endothelial cells, E2 is pro-mitogenic, pro-angiogenic and anti- apoptotic, whereas 2ME is antimitogenic, anti-angiogenic and pro-apoptotic. This may have significant ramifications in severe PAH that involves uncontrolled proliferation of monoclonal, apoptosis resistant endothelial cells. Based on its cellular effects, 2ME should be expected to attenuate the progression of disease and provide protection in severe PAH. In contrast, E2, due to its mitogenic, angiogenic, and anti-apoptotic effects (otherwise desirable in normal, quiescent endothelial cells), may even adversely affect endothelial remodeling in PAH and this may be even more significant if the E2’s effects on injured endothelium are not opposed by 2ME (e.g., in the event of reduced E2 conversion to 2ME due to hypoxia, inflammation, drugs, environmental factors, or genetic polymorphism of metabolizing enzymes). This review focuses on the effects of estrogens and their metabolites on pulmonary vascular pathobiology and the development of experimental PAH, and offers potential explanation for the estrogen paradox in PAH. Furthermore, we propose that unbalanced estradiol metabolism may lead to the development of PAH. Recent animal data and studies in patients with PAH support this concept.