Estradiol Metabolites Treatment Pulmonary Hypertension

问题范围：严重肺动脉高压（PH）是一种罕见但致命的疾病。这种孤儿疾病的特点是肺循环压力进行性增加，小尺寸肺动脉血管重构，包括内皮细胞（ECs）的增殖。目前，治疗方案很少，而且现有的治疗方案疗效不佳。背景：先前的动物实验和一些人类观察性研究表明，雌二醇（E2）可能会减弱PH的发展；然而，所采用的动物模型并不能模拟人类的PH值，临床结果也不明确，E2的作用是由E2本身介导还是通过其下游代谢物介导，目前还没有研究。此外，目前尚不清楚E2对肺EC生长的直接或间接（通过代谢物）影响是否介导了雌二醇在ph中的有益作用。初步研究：雌二醇被CYP1A1代谢为2-羟基雌二醇（2HE）， 2HE通过COMT转化为2-甲氧基雌二醇（2ME）。在许多研究中，我们已经表明2ME在体内抑制血管（介质）重塑，并减弱单根碱诱导的ph的发展。雌二醇和2ME对ECs有不同的作用；然而，它们对严重PH患者内皮重塑的影响尚未研究。假设：我们假设雌二醇通过其代谢为2-甲氧基雌二醇的机制减轻严重的PH， E2和2ME对EC增殖和内皮重塑的影响不同。因此，2ME可能在严重PH中提供高效的保护。为了验证我们的假设，我们将使用严重PH的大鼠模型，模拟在人类严重PH形式中看到的关键变化。具体目的：我们将解决以下问题：1)内源性/外源性雌二醇是否通过涉及其下游代谢物的机制减弱严重PH的发展，以及2ME是否减弱严重PH的发展？2) E2代谢的改变是否影响EC增殖，E2和2ME对对照和重度PH动物EC增殖的影响是否不同？意义：该项目将提供可能最终导致开发安全有效的治疗人类严重肺动脉高压的方法的信息。

DESCRIPTION (provided by applicant): Problem Area: Severe pulmonary hypertension (PH) is a rare but deadly disease. This orphan disease is characterized by progressive increase in pressure in pulmonary circulation and vascular remodeling of small size pulmonary arteries that include proliferation of endothelial cells (ECs). Currently, there are few therapeutic options, and those available have poor efficacy. Background: Previous animal experiments and some observational studies in humans suggest that estradiol (E2) may attenuate the development of PH; however, the animal models employed do not mimic human PH, the clinical findings are ambiguous, and whether the effects of E2 are mediated by E2 per se or via its downstream metabolites has not been examined. Also, it is unclear whether direct or indirect (via metabolites) effects of E2 on pulmonary EC growth mediate the putative beneficial effects of estradiol in PH. Preliminary Studies: Estradiol is metabolized by CYP1A1 to 2-hydroxyestradiol (2HE) and 2HE is converted to 2-methoxyestradiol (2ME) via COMT. In a number of studies we have shown that 2ME inhibits vascular (media) remodeling in vivo and attenuates the development of monocrotaline-induced PH. Estradiol and 2ME have divergent effects on ECs; however, their effects on endothelial remodeling in severe PH have not been studied. Hypothesis: We hypothesize that estradiol attenuates severe PH via a mechanism that involves its metabolism to 2- methoxyestradiol and that E2 and 2ME differently affect EC proliferation and endothelial remodeling. Thereby, 2ME may offer highly efficacious protection in severe PH. To test our hypothesis we will use a rat model of severe PH that mimics the key alterations seen in the severe form of PH in humans. Specific Aims: We will address the following questions: 1) Does endogenous/exogenous estradiol attenuate the development of severe PH by a mechanism that involves its downstream metabolites, and does 2ME attenuate the development of severe PH? 2) Do alterations of E2 metabolism affect EC proliferation and do E2 and 2ME differently affect the proliferation of ECs from control and severe PH animals? Significance: This project will provide information that may ultimately lead to the development of safe and effective modalities for the treatment of severe pulmonary hypertension in humans.