Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynecology, Karolinska Institutet and Karolinska University Hospital, 14186 Huddinge, Sweden.
Department of Life, Health and Environmental Sciences, University of L'Aquila, Via Vetoio, 67100 L'Aquila, Italy.
Int J Mol Sci. 2023 Feb 7;24(4):3318. doi: 10.3390/ijms24043318.
In this study, the effects of aging and parity on VEGF-A/VEGFR protein content and signaling in the mice ovaries were determined. The research group consisted of nulliparous (virgins, V) and multiparous (M) mice during late-reproductive (L, 9-12 months) and post-reproductive (P, 15-18 months) stages. Whilst ovarian VEGFR1 and VEGFR2 remained unchanged in all the experimental groups (LM, LV, PM, PV), protein content of VEGF-A and phosphorylated VEGFR2 significantly decreased only in PM ovaries. VEGF-A/VEGFR2-dependent activation of ERK1/2, p38, as well as protein content of cyclin D1, cyclin E1, and Cdc25A were then assessed. In ovaries of LV and LM, all of these downstream effectors were maintained at a comparable low/undetectable level. Conversely, the decrease recorded in PM ovaries did not occur in the PV group, in which the significant increase of kinases and cyclins, as well phosphorylation levels mirrored the trend of the pro-angiogenic markers. Altogether, the present results demonstrated that, in mice, ovarian VEGF-A/VEGFR2 protein content and downstream signaling can be modulated in an age- and parity-dependent manner. Moreover, the lowest levels of pro-angiogenic and cell cycle progression markers detected in PM mouse ovaries sustains the hypothesis that parity could exert a protective role by downregulating the protein content of key mediators of pathological angiogenesis.
本研究旨在确定衰老和产次对小鼠卵巢中 VEGF-A/VEGFR 蛋白含量和信号转导的影响。研究小组由未产（处女，V）和经产（M）小鼠组成，处于生殖后期（L，9-12 个月）和生殖后期（P，15-18 个月）阶段。虽然卵巢 VEGFR1 和 VEGFR2 在所有实验组（LM、LV、PM、PV）中保持不变，但仅在 PM 卵巢中 VEGF-A 和磷酸化 VEGFR2 的蛋白含量显著降低。然后评估了 VEGF-A/VEGFR2 依赖性 ERK1/2、p38 的激活以及细胞周期蛋白 D1、E1 和 Cdc25A 的蛋白含量。在 LV 和 LM 的卵巢中，所有这些下游效应物都保持在类似的低/无法检测到的水平。相反，在 PM 卵巢中记录到的减少在 PV 组中并未发生，在该组中，激酶和细胞周期蛋白的显著增加以及磷酸化水平与促血管生成标志物的趋势一致。总之，本研究结果表明，在小鼠中，卵巢 VEGF-A/VEGFR2 蛋白含量和下游信号转导可以以年龄和产次依赖的方式进行调节。此外，在 PM 小鼠卵巢中检测到的最低水平的促血管生成和细胞周期进展标志物支持了这样的假设，即产次可以通过下调病理性血管生成关键介质的蛋白含量发挥保护作用。
