围绝经期和绝经后妇女高FSH水平引发的血管功能紊乱及其肾上腺介导的发病机制研究

Vasofunctional disturbances, like tidal fever, is a common manifestation in perimenopause women and might be a pathophysiological basis of many cardiovascular diseases. Studies have found that higher levels of epinephrine and norepinephrine in hypertensive women in menopause may suggest their participation in the pathogenesis of hypertension in this group of patients. But the relationship between menopause and cardiovascular diseases has not been fully understood. As FSH secretion is negatively regulated by estrogenic feedback, a high circulating FSH level invariably accompanies hypogonadism. FSH has thus been regarded as a supportive marker for the onset of reproductive aging. However, it has never been tested whether FSH might directly stimulate the medulla of adrenal gland to execrate much epinephrine and norepinephrine to cause hypertension or other cardiovascular diseases associated with hypogonadism. We found, for the first time, that FSHR was expressed in the endocrine cells in rat medulla of adrenal gland. This finding suggested that FSHR may regulate the production or secretion of epinephrine and norepinephrine. Together with the risk of cardiovascular diseases increase seen in women during their menopause, we hypothesized that FSHR might be involved in the regulation of epinephrine and norepinephrine production in the endocrine cells in medulla of adrenal gland, and that the high circulating FSH level in women of reproductive aging might result in abnormal epinephrine and norepinephrine levels as seen in menopause. In the present project, we will test this possibility and assess: (1) the association of serum levels of epinephrine & norepinephrine, the onset of tidal fever, blood pressure and the risk of cardiovascular diseases with serum FSH level in women of reproductive aging; (2) the production of epinephrine & norepinephrine in medulla of adrenal gland and the relevant intracellular mechanism stimulated by FSH. Pathophysiologically, the research may give firm that the vasofunctional disturbance, even the cardiovascular diseases in menopause and hypogonadism, which has been attributed solely to declining sex hormone levels, may result at least in significant part from elevated circulating FSH.

潮热、出汗等血管功能紊乱表现是围绝经期妇女常见现象，也可能是绝经后妇女快速、高发心血管疾病的病理生理基础，具体机制不清。肾上腺素（E）和去甲肾上腺素（NE）是代表性心血管活性因子；血液循环中E/NE主要来自肾上腺髓质。我们前期研究发现：大鼠肾上腺髓质表达促卵泡激素（FSH）受体，FSH可以促进肾上腺髓质内分泌细胞分泌E/NE。这提示围绝经期及绝经后妇女的高FSH水平，可能通过刺激肾上腺髓质分泌过多的E/NE，引发相应的血管功能紊乱、甚至严重心血管疾病。本项目拟就该假说深入研究：临床评估生殖衰老女性FSH水平与血清E/NE水平、潮热发作频度、高血压/冠心病发病的关联；细胞和动物模型研究FSH刺激肾上腺髓质细胞后相应的E/NE合成、分泌及细胞内效应机制；揭示围绝经期及绝经后妇女高FSH水平引发血管功能紊乱、甚至严重心血管疾病的肾上腺（介导/发病）机制，为相关疾病的防治提供新理论和可靠科学依据。

潮热、出汗等血管功能紊乱表现是围绝经期妇女常见现象，也是绝经后妇女快速、高发心血管疾病的病理生理基础，其具体机制不清。去甲肾上腺素（NE）和肾上腺素（EPI）是代表性心血管活性因子，血液循环中E/NE主要来自肾上腺髓质。围绝经期和绝经后女性去甲肾上腺素和肾上腺素均明显上升，其具体原因不清。通过本研究我们对围绝经期和绝经后妇女血清FSH水平与E/NE水平的相关性以及与潮热发作频度、高血压病、冠心病发病的相关性进行分析；在动物模型和人细胞系进行相应的的核查获取分子水平和组织学证据；并对FSH对大鼠肾上腺髓质细胞系合成和分泌肾上腺素/去甲肾上腺素的效应进行观察；深入研究了FSH促进肾上腺髓质合成/分泌肾上腺素/去甲肾上腺素的分子调节机制。我们的研究结果发现：围绝经期和绝经后妇女血清FSH水平与去甲肾上腺素和肾上腺素水平升高有关联，并首次证实FSH受体人和大鼠肾上腺髓质内分泌细胞表达FSH受体，并进一步证实FSH促进肾上腺内分泌细胞合成和分泌肾上腺素和去甲肾上腺素，完整阐述了FSH作用于肾上腺髓质内分泌细胞FSH受体，激活MAPK途径、AKT途径、CREB途径和钙信号途径启动相应基因表达，促进肾上腺素和去甲肾上腺素分泌的细胞内分子调节机制。通过本研究揭示围绝经期及绝经后妇女高FSH水平引发血管功能紊乱、甚至严重心血管疾病的肾上腺（介导/发病）机制，为相关疾病的防治提供了新理论和科学依据。