STAT5a/b contribute to sex bias in vascular disease: A neuroendocrine perspective.
STAT5a/b contribute to sex bias in vascular disease: A neuroendocrine perspective.
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STAT5a/b 导致血管疾病中的性别偏见：神经内分泌的观点。
DOI：
10.1080/21623996.2015.1090658
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Miller,EdmundJ
中科院分区：
文献类型：
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作者：
Sehgal,PravinB;Yang,Yang-Ming;Yuan,Huijuan;Miller,EdmundJ
先前的研究已经阐明了由下丘脑（生长激素释放激素，GHRH）-垂体（生长激素，GH）-STAT5a/b 轴组成的神经内分泌机制，该轴是肝脏中性别偏向基因表达的基础。现在已经确定，男性与女性的 GHRH 分泌模式，以及循环 GH 水平的模式（分别为“脉冲式”与“更连续性”），导致肝细胞中 PY-STAT5a/b 的不同模式激活，导致数百个下游基因组的性别偏见基因表达。本综述概述了支持血管疾病肺动脉高压 (PH) 中基于 STAT5a/b 的性别偏见机制的新数据。 PH 中令人费解的观察结果包括其在女性中的患病率高出 2-4 倍，但在许多啮齿动物模型中男性占主导地位，并且矛盾的是，在此类模型中雌激素对 PH 的发展有抑制作用。我们观察到，条件性删除小鼠中的 STAT5a/bin 血管平滑肌细胞 (SMC)，可将慢性缺氧诱导的 PH 的雄性主导模型转变为雌性主导表型。在人类特发性肺动脉高压中，男性和女性晚期闭塞性肺动脉病变细胞中的 STAT5a/b 和 PY-STAT5 均减少。先前的肝脏数据与新的 PH 相关数据的并置引起了人们对下丘脑-GH-STAT5 轴的关注，它是下丘脑水平雌激素的主要目标。这一假设解释了人类和啮齿动物模型中 PH 性别偏见的许多令人困惑的方面。 STAT5锚定的性别偏见机制扩展到血管疾病强调了中枢神经内分泌过程在不同组织和细胞类型中产生性别二态性的贡献。
Previous studies have elucidated a neuroendocrine mechanism consisting of the hypothalamus (growth hormone releasing hormone, GHRH) – pituitary (growth hormone, GH) – STAT5a/b axis that underlies sex-biased gene expression in the liver. It is now established that male vs female patterned secretion of GHRH, and thus of circulating GH levels (“pulsatile” vs “more continuous” respectively), leading to differently patterned activation of PY-STAT5a/b in hepatocytes results in sex-biased gene expression of cohorts of hundreds of downstream genes. This review outlines new data in support of a STAT5a/b-based mechanism of sex bias in the vascular disease pulmonary hypertension (PH). Puzzling observations in PH include its 2-4-fold higher prevalence in women but a male-dominance in many rodent models, and, paradoxically, inhibition of PH development by estrogens in such models. We observed that conditional deletion ofSTAT5a/bin vascular smooth muscle cells (SMC) in mice converted the male-dominant model of chronic hypoxia-induced PH into a female-dominant phenotype. In human idiopathic PH, there was reduced STAT5a/b and PY-STAT5 in cells in late-stage obliterative pulmonary arterial lesions in both men and women. A juxtaposition of the prior liver data with the newer PH-related data drew attention to the hypothalamus-GH-STAT5 axis, which is the major target of estrogens at the level of the hypothalamus. This hypothesis explains many of the puzzling aspects of sex bias in PH in humans and rodent models. The extension of STAT5-anchored mechanisms of sex bias to vascular disease emphasizes the contribution of central neuroendocrine processes in generating sexual dimorphism in different tissues and cell types.