Gestational Hyperandrogenism in Cardiovascular Programming

心血管疾病(CVD)是世界范围内主要的死亡原因之一，占所有死亡原因的32.2% 美国的死亡人数。令人信服的人类流行病学数据表明，子宫内的不良反应 环境导致宫内生长受限，这与心血管疾病风险增加和 左心室肥厚。研究发现，产前暴露于过量的睾丸素(T)会对 在发育规划的良好验证的绵羊模型中对多个器官系统进行编程。产前T 在该模型中，过量导致男女胎儿宫内发育迟缓，并最终导致胰岛素抵抗，左心室增加 成年雌性子代体重与高血压(产前T对心脏代谢的影响 对雄性后代的结果尚未进行研究)。考虑到心血管疾病中存在的性别二形性 死亡率和发病率洞察性二型性在左脑发育中的作用至关重要 使心脏肥厚能够制定针对性别的预防策略。在这方面，产前 T模型提供了一个有价值的资源来确定疾病在多大程度上过度暴露性激素 国家(多囊卵巢综合征、先天性肾上腺增生症或环境化学物质与 胎儿发育过程中的类固醇生成潜力程序不利的心脏组织重构导致 成年期心血管疾病死亡率增加。我们的初步数据提供了产前T过多导联的证据 成年雌性后代的病理性左心室重构，从而使我们能够探索潜在的 机制和特定性别的功能结果。此应用程序的目标是标识 宫内暴露过多T程序对心脏重构和易感性不利的机制(S) 成人生活中的心脏病，并辨别这个节目中可能存在的性别差异。我们 假设产前T过多会导致不良的左心室结构和功能改变。 寿命和这些变化将由参与维持的途径的表观遗传修改驱动 左心室的形态和功能导致在以后的生活中对侮辱的敏感性增加。建议数 研究将深入了解宫内睾酮过高导致左心功能不良的机制 重构，2)产前T过多的长期心脏功能和结构后果，3)性别 产前心脏编程的差异。通过这些研究获得的知识将有助于确定 有针对性地治疗左心室肥厚和心力衰竭的策略，并具有翻译相关性。

Cardiovascular disease (CVD) is one of the leading causes of death worldwide accounting for 32.2% of all deaths in the United States. Compelling epidemiological data in human has shown that adverse in utero environment leads to intrauterine growth restriction that has been associated with increased risk of CVD and left ventricular hypertrophy. Prenatal exposure to excess testosterone (T) has been found to adversely program multiple organ systems in the well-validated sheep model of developmental programming. Prenatal T excess induces IUGR in both sexes in this model and culminates in insulin resistance, increased left ventricular mass and hypertension in the female offspring in adulthood (the impact of prenatal T on cardiometabolic outcomes in the male offspring has not been studied). Considering the sexual dimorphism that exists in CVD mortality and morbidity it is critically important to gain an insight into the role sexual dimorphism plays in left ventricular hypertrophy to enable development of sex-specific prevention strategies. In this regard, the prenatal T model provides a valuable resource to determine to what extent excess sex steroid exposure via disease states (Polycystic ovary syndrome, Congenital adrenal hyperplasia, or environmental chemicals with steroidogenic potential during fetal development programs adverse cardiac tissue remodeling resulting in increased mortality from CVD in adulthood. Our preliminary data provide evidence that prenatal T excess leads to pathological left ventricular remodeling in adult female offspring thus allowing us to probe underlying mechanisms and sex-specific functional outcomes. The objective of this application is to identify the mechanism(s) by which in utero exposure to excess T programs adverse cardiac remodeling and susceptibility to cardiac disease during adult life and to discern sex differences that might exist in this programming. We hypothesize that prenatal T excess will lead to adverse left ventricular structural and functional changes over the lifespan and these changes will be driven by epigenetic modifications of pathways involved in maintaining left ventricular morphology and function leading to increased susceptibility to insult later in life. The proposed studies will provide insight into the 1) mechanisms by which excess T in-utero leads to adverse left ventricular remodeling, 2) long term cardiac functional and structural consequences of prenatal T excess and 3) sex differences in prenatal cardiac programming. Knowledge gained through these studies will help identify strategies targeted toward treatment for LVH and heart failure and of translational relevance.