FSH促进绝经后动脉粥样硬化形成的效应及其机制研究

The incidence rate of atherosclerosis (AS) increases in postmenopausal women, which is partially attributed to the low level of estrogen. On the other side, the serum level of follicle stimulating hormone (FSH) sharply rises after menopause, which may represent the possible mechanism for the high incidence rate of AS. Recent years evidence is accumulating for the biological actions of FSH in extra-glandular system. However, no report is found on the role of FSH implicated in the pathophysiological process of AS. In this regard, our preliminary results indicated that FSH receptor (FSHR) is expressed in cardiovascular system, suggesting that this system is the target of FSH. From this point of view, we plan to investigate the pro-atherogenesis effect of FSH and to reveal the underlying mechanisms. To achieve these aims, we will generate female mice deficient in both apolipoprotein E (ApoE) and FSHR (ApoE-/- + FSHR -/-) to confirm the pro-atherogenesis effect of FSH. On the basis of this, we will observe the regulatory effect of FSH on vascular cell adhesion molecule-1 (VCAM-1) expression in cultured human endothelial cells, which may provide possible explanation for the pro-atherogenesis effect exerted by FSH. VCAM-1 is the critical adhesion molecule that promotes AS progression by inducing monocyte-endothelial cell adhesion. Therefore, the effect of FSH on endothelial morphology and functions as well as on monocyte-endothelial cell adhesion will be characterized. Moreover, the signaling pathways that account for the regulatory effect of FSH on VCAM-1 expression will be determined. The present project will provide new insight to explain the high incidence rate of AS in postmenopausal women, suggesting that the interference with FSH or its dowmstream signalings will be the novel strategy to prevent AS initiation and progression in postmenopausal women.

女性在绝经后动脉粥样硬化（AS）发病率上升，这一现象部分归咎于雌激素水平的低下。另一方面，绝经后卵泡刺激素（FSH）水平上升，这同样可能是AS发病率增高的原因。近年来FSH在性腺系统之外的作用渐受关注，但迄今为止，尚未有FSH与AS相关的报道。我们的预实验发现心血管系统表达FSH受体（FSHR），提示该系统为FSH的作用靶点。在此基础上，本项目拟探讨FSH对AS形成的影响及其机制。内容包括：1、在ApoE及FSHR双基因敲除小鼠模型上，明确FSH促AS形成的效应。2、研究其内皮机制，即FSH促血管内皮粘附分子-1（VCAM-1）表达的效应。3、在整体和细胞水平上，观察FSH对内皮形态、功能的影响及其促单核细胞-内皮粘附的作用。4、揭示FSH上调VCAM-1表达的信号通路。本项目从FSH促AS形成这一新思路开展研究，提示对FSH及下游信号进行干预，将成为预防绝经后女性AS发生、发展的新途径。

女性绝经后动脉粥样硬化（AS）的发病率上升，这一现象部分归咎于雌激素水平的低下。另一方面，绝经后卵泡刺激素（FSH）水平上升，这同样可能是AS发生的原因。近年来，FSH在性腺系统之外的作用渐受关注，但迄今尚未有FSH与AS相关的报道。在本基金资助下，我们取得的结果有：1、RT-PRC、western blot和免疫荧光结果均表明，在培养的脐静脉血管内皮细胞（HUVECs）上存在有FSH受体（FSHR）。2、FSH可浓度和时间依赖性促进血管内皮粘附分子-1（VCAM-1）的mRNA和蛋白表达。3、FSH可通过激活NF-kappa B信号通路，上调VCAM-1 mRNA和蛋白表达。4、FSHR位于细胞质膜caveolae中，且与caveolin-1、Gαs相互交联。Caveolin-1、Gαs对于其下游信号至关重要，可介导促进腺苷酸环化酶激活，促进cAMP产生，激活PKA，进而进一步激活PI3K/Akt/mTOR信号通路激活NF-kappa B信号。5、FSH促进上述信号通路单核细胞与内皮细胞的粘附。6、FSH促进动脉粥样斑块的形成。7、在绝经后妇女血清中，FSH水平与VCAM-1水平呈正相关。综上所述，本研究揭示：FSH可通过位于caveolae中的FSHR介导，激活PKA/PI3K/Akt/mTOR/NF-kappa B信号通路，上调VCAM-1表达，促进单核内皮粘附，进而促进动脉粥样硬化发生。本项目在国内外首次揭示了FSH对心血管系统的损伤效应，并提示对FSH及下游信号进行干预，将成为预防绝经后女性动脉粥样硬化发生、发展的新途径。