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Theranostics 2017; 7(19):4671-4688. doi:10.7150/thno.21216 This issue Cite

Research Paper

Follicular Stimulating Hormone Accelerates Atherogenesis by Increasing Endothelial VCAM-1 Expression

Xiaosa Li^1*, Weiyu Chen^2*, Ping Li^1*, Jinzhi Wei¹, Yang Cheng³, Pei Liu⁴, Qing Yan¹, Xingyan Xu¹, Yuhong Cui¹, Zhengtian Gu³, Tommaso Simoncini⁵, Xiaodong Fu^1✉

1. 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;
2. School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia;
3. Department of Gynecology and Obstetrics, the Municipal First People' s Hospital of Guangzhou, Guangzhou, 510180, Guangdong Province, China;
4. Department of Anesthesiology, the Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, Guangdong Province, China;
5. Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa 56100, Italy.
* These authors contributed equally to this work.

✉ Corresponding author: Xiaodong Fu., M.D., Ph.D., Tel: +86.020.83412002, E-mail: fuxiaodgzhmu.edu.cn

Abstract

Rationale: 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.

Methods: 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.

Results: 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_S 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_S. 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.

Conclusion: FSHR was located in the membrane caveolae of HUVECs and FSH promoted VCAM-1 expression via FSHR/Gα_S /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.

Keywords: Follicular Stimulating Hormone, Vascular Cell Adhesion Molecule-1, Atherosclerosis, Vascular Endothelial Cells, Caveolae.

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