Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
Biol Reprod. 2023 Sep 12;109(3):367-380. doi: 10.1093/biolre/ioad065.
Cyclic regression of the ovarian corpus luteum, the endocrine gland responsible for progesterone production, involves rapid matrix remodeling. Despite fibroblasts in other systems being known for producing and maintaining extracellular matrix, little is known about fibroblasts in the functional or regressing corpus luteum. Vast transcriptomic changes occur in the regressing corpus luteum, among which are reduced levels of vascular endothelial growth factor A (VEGFA) and increased expression of fibroblast growth factor 2 (FGF2) after 4 and 12 h of induced regression, when progesterone is declining and the microvasculature is destabilizing. We hypothesized that FGF2 activates luteal fibroblasts. Analysis of transcriptomic changes during induced luteal regression revealed elevations in markers of fibroblast activation and fibrosis, including fibroblast activation protein (FAP), serpin family E member 1 (SERPINE1), and secreted phosphoprotein 1 (SPP1). To test our hypothesis, we treated bovine luteal fibroblasts with FGF2 to measure downstream signaling, type 1 collagen production, and proliferation. We observed rapid and robust phosphorylation of various signaling pathways involved in proliferation, such as ERK, AKT, and STAT1. From our longer-term treatments, we determined that FGF2 has a concentration-dependent collagen-inducing effect, and that FGF2 acts as a mitogen for luteal fibroblasts. FGF2-induced proliferation was greatly blunted by inhibition of AKT or STAT1 signaling. Our results suggest that luteal fibroblasts are responsive to factors that are released by the regressing bovine corpus luteum, an insight into the contribution of fibroblasts to the microenvironment in the regressing corpus luteum.
黄体的周期性退化，即负责孕激素产生的内分泌腺，涉及到快速的基质重塑。尽管其他系统中的成纤维细胞以产生和维持细胞外基质而闻名，但对于功能退化的黄体中的成纤维细胞知之甚少。退化黄体中发生广泛的转录组变化，其中血管内皮生长因子 A（VEGFA）水平降低，孕激素下降和微血管不稳定后 4 和 12 小时 FGF2 表达增加。我们假设 FGF2 激活黄体成纤维细胞。诱导黄体退化过程中转录组变化的分析显示，成纤维细胞激活和纤维化的标志物（包括成纤维细胞激活蛋白（FAP）、丝氨酸蛋白酶抑制剂家族 E 成员 1（SERPINE1）和分泌型磷蛋白 1（SPP1））升高。为了验证我们的假设，我们用 FGF2 处理牛黄体成纤维细胞以测量下游信号、I 型胶原产生和增殖。我们观察到参与增殖的各种信号通路（如 ERK、AKT 和 STAT1）的快速和强烈磷酸化。从我们的长期处理中，我们确定 FGF2 具有浓度依赖性的胶原诱导作用，并且 FGF2 是黄体成纤维细胞的有丝分裂原。AKT 或 STAT1 信号通路的抑制极大地减弱了 FGF2 诱导的增殖。我们的结果表明，黄体成纤维细胞对退化牛黄体释放的因子有反应，这深入了解了成纤维细胞对退化黄体微环境的贡献。
