University Hospital of Padua, Unit of Andrology and Reproductive Medicine, Padua, Italy.
University of Padua, Department of Medicine, Padua, Italy.
Mol Cell Endocrinol. 2024 Dec 1;594:112378. doi: 10.1016/j.mce.2024.112378. Epub 2024 Sep 25.
Follicle-stimulating hormone (FSH) plays a fundamental role in reproduction stimulating ovarian folliculogenesis, Sertoli cells function and spermatogenesis. However, the recent identification of FSH receptor (FSHR) also in extra-gonadal tissues has suggested that FSH activity may not be limited only to fertility regulation, with conflicting results on the possible role of FSH in endothelial cells. The aim of this study was to investigate FSH role on endothelial function in Human Umbilical Vein Endothelial Cells (HUVECs).
Endothelial Nitric oxide synthase (eNOS) expression, eNOS phosphorylation and Nitric Oxide (NO) production resulted increased after the stimulation of HUVEC with recombinant human FSH (rhFSH) at 3.6x10 ng/ml, with increasing Calcium release from intracellular stores. Furthermore, IP production increased after rhFSH stimulation despite PTX treatment and NFAT1 was observed prevalently in nucleus. We observed a statistical difference between untreated cells and cells stimulated with 0.36x10 ng/ml and between cells stimulated with 0.36x10 ng/ml and cells stimulated with 1.8x10 ng/ml at 4 and 8 h by Wound healing assay, respectively. Furthermore, a higher cellular permeability was observed in stimulated cells, with atypical VE-cadherin distribution, as well as filamentous actin.
Our findings suggest that FSH at high concentrations elicits a signalling that could compromise the endothelial membrane. Indeed, VE-cadherin anomalies may severely affect the endothelial barrier, resulting in an increased membrane permeability. Although NO is an important vasodilatation factor, probably an excessive production could impact on endothelial functionality, partially explaining the increased risk of cardiovascular diseases in menopausal women and men with hypogonadism.
卵泡刺激素（FSH）在生殖中起着刺激卵巢卵泡发生、支持细胞功能和精子发生的基本作用。然而，最近在性腺外组织中也发现了 FSH 受体（FSHR），这表明 FSH 的活性可能不仅限于生育调节，FSH 对内皮细胞的可能作用存在矛盾的结果。本研究旨在探讨 FSH 在人脐静脉内皮细胞（HUVEC）中的内皮功能作用。
内皮型一氧化氮合酶（eNOS）表达、eNOS 磷酸化和一氧化氮（NO）产生在重组人 FSH（rhFSH）刺激 HUVEC 至 3.6x10ng/ml 时增加，同时细胞内储存的钙释放增加。此外，尽管 PTX 处理后 IP 产生增加，并且观察到 NFAT1 主要存在于细胞核中。我们观察到未处理细胞与用 0.36x10ng/ml 刺激的细胞之间以及用 0.36x10ng/ml 和 1.8x10ng/ml 刺激的细胞之间在 4 和 8 小时的划痕愈合试验中存在统计学差异。此外，刺激细胞的细胞通透性增加，VE-cadherin 分布异常，以及丝状肌动蛋白。
我们的研究结果表明，高浓度的 FSH 会引发一种信号通路，可能会损害内皮细胞膜。事实上，VE-cadherin 的异常可能会严重影响内皮屏障，导致细胞通透性增加。尽管 NO 是一种重要的血管舒张因子，但过量的产生可能会影响内皮功能，这部分解释了绝经后妇女和性腺功能减退症男性患心血管疾病风险增加的原因。
