Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital; Key Laboratory of Cardiovascular Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
Theranostics. 2017 Oct 17;7(19):4671-4688. doi: 10.7150/thno.21216. eCollection 2017.
Postmenopausal atherosclerosis (AS) has for decades been attributed to estrogen deficiency. Although the follicular stimulating hormone (FSH) levels rise sharply in parallel, the direct effect of FSH on AS has never been investigated. In this study, we explored the possible role of FSH in the development of AS. This was a prospective cohort study of 48 healthy premenopausal and 15 postmenopausal women. ApoE knockout mice were used as atherosclerosis model and human umbilical vascular endothelial cells (HUVECs) were cultured as cell model. Serum hormones and vascular cell adhesion molecule-1 (VCAM-1) levels were measured. Real-time PCR, histology for atherosclerotic lesions, immunofluorescence, luciferase assay, transfection experiments, flow chamber adhesion assay and western blot were performed. In ApoE knockout mice, administration of FSH increased the atherosclerotic lesions and serum VCAM-1 concentration. Importantly, in blood samples of postmenopausal women, we detected significantly higher levels of FSH and VCAM-1 compared with those from premenopausal women, and there was a positive correlation between these two molecules. In cultured HUVECs, FSH receptor (FSHR) mRNA and protein expression were detected and FSH enhanced VCAM-1 expression. This effect was mediated by the activation of nuclear factor κB (NF-κB), which was sequentially enhanced by the activation of PI3K/Akt/mTOR cascade. FSH first enhanced Gα activity resulting in elevated cAMP level and PKA activity, which relayed the signals from FSHR to the PI3K/Akt/mTOR cascade. Furthermore, FSHR was detected in endothelial caveolae fraction and interacted with caveolin-1 and Gα. The disruption of caveolae or the silencing of caveolin-1 blocked FSH effects on signaling activation and VCAM-1 expression, suggesting the existence of a functional signaling module in membrane caveolae. Finally, FSH increased human monocyte adhesion to HUVECs which was reversed by the VCAM-1 neutralizing antibody. FSHR was located in the membrane caveolae of HUVECs and FSH promoted VCAM-1 expression via FSHR/Gα /cAMP/PKA and PI3K/Akt/mTOR/NF-κB pathway. This may contribute to the deleterious role of FSH in the development of AS in postmenopausal women.
绝经后动脉粥样硬化（AS）数十年来一直归因于雌激素缺乏。尽管卵泡刺激素（FSH）水平急剧上升，但 FSH 对 AS 的直接作用从未被研究过。在这项研究中，我们探讨了 FSH 在 AS 发展中的可能作用。这是一项前瞻性队列研究，纳入了 48 名健康绝经前和 15 名绝经后女性。使用载脂蛋白 E 基因敲除（ApoE -/-）小鼠作为动脉粥样硬化模型，培养人脐静脉内皮细胞（HUVECs）作为细胞模型。测量血清激素和血管细胞黏附分子-1（VCAM-1）水平。进行实时 PCR、动脉粥样硬化病变的组织学检查、免疫荧光、荧光素酶检测、转染实验、流式细胞室黏附实验和 Western blot。在 ApoE -/- 小鼠中，FSH 的给药增加了动脉粥样硬化病变和血清 VCAM-1 浓度。重要的是，在绝经后女性的血液样本中，我们检测到 FSH 和 VCAM-1 水平明显高于绝经前女性，并且这两种分子之间存在正相关。在培养的 HUVECs 中，检测到 FSH 受体（FSHR）mRNA 和蛋白表达，并且 FSH 增强了 VCAM-1 的表达。这种作用是通过核因子 κB（NF-κB）的激活介导的，NF-κB 被 PI3K/Akt/mTOR 级联的激活依次增强。FSH 首先增强 Gα 活性，导致 cAMP 水平和 PKA 活性升高，从而将信号从 FSHR 传递到 PI3K/Akt/mTOR 级联。此外，在血管内皮细胞 caveolae 部分检测到 FSHR，并与 caveolin-1 和 Gα 相互作用。破坏 caveolae 或沉默 caveolin-1 阻断了 FSH 对信号转导激活和 VCAM-1 表达的作用，表明在膜 caveolae 中存在功能性信号模块。最后，FSH 增加了人单核细胞对 HUVECs 的黏附，而 VCAM-1 中和抗体可逆转这种作用。FSHR 位于 HUVECs 的膜 caveolae 中，FSH 通过 FSHR/Gα /cAMP/PKA 和 PI3K/Akt/mTOR/NF-κB 通路促进 VCAM-1 的表达。这可能有助于 FSH 在绝经后女性 AS 发展中的有害作用。
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