Conte J G, Tellechea M L, Park B, Ballerini M G, Jaita G, Peluffo M C
Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.
Instituto de Investigaciones Biomédicas (INBIOMED), Facultad de Medicina CONICET- Universidad de Buenos Aires, Buenos Aires, Argentina.
Front Cell Dev Biol. 2023 Apr 4;11:1161813. doi: 10.3389/fcell.2023.1161813. eCollection 2023.
The epidermal growth factor receptor (EGFR) signaling pathway is one of the main pathways responsible for propagating the luteinizing hormone (LH) signal throughout the cumulus cells and the oocyte. Recently, we have proposed the C-C motif chemokine receptor 2 (CCR2) and its main ligand (monocyte chemoattractant protein-1, MCP1) as novel mediators of the ovulatory cascade. Our previous results demonstrate that the gonadotropins (GNT), amphiregulin (AREG), and prostaglandin E2 (PGE2) stimulation of periovulatory gene mRNA levels occurs, at least in part, through the CCR2/MCP1 pathway, proposing the CCR2 receptor as a novel mediator of the ovulatory cascade in a feline model. For that purpose, feline cumulus-oocyte complexes (COCs) were cultured in the presence or absence of an EGFR inhibitor, recombinant chemokine MCP1, and gonadotropins [as an inducer of cumulus-oocyte expansion (C-OE), and oocyte maturation] to further assess the mRNA expression of periovulatory key genes, C-OE, oocyte nuclear maturation, and steroid hormone production. We observed that MCP1 was able to revert the inhibition of mRNA expression by an EGFR inhibitor within the feline COC. In accordance, the confocal analysis showed that the GNT-stimulated hyaluronic acid (HA) synthesis, blocked by the EGFR inhibitor, was recovered by the addition of recombinant MCP1 in the C-OE culture media. Also, MCP1 was able to revert the inhibition of progesterone (P4) production by EGFR inhibitor in the C-OE culture media. Regarding oocyte nuclear maturation, recombinant MCP1 could also revert the inhibition triggered by the EGFR inhibitor, leading to a recovery in the percentage of metaphase II (MII)-stage oocytes. In conclusion, our results confirm the chemokine receptor CCR2 as a novel intermediate in the ovulatory cascade and demonstrate that the EGFR/AREG and the CCR2/MCP1 signaling pathways play critical roles in regulating feline C-OE and oocyte nuclear maturation, with CCR2/MCP1 signaling pathway being downstream EGFR/AREG pathway within the ovulatory cascade.
表皮生长因子受体（EGFR）信号通路是负责在整个卵丘细胞和卵母细胞中传递促黄体生成素（LH）信号的主要通路之一。最近，我们提出C-C基序趋化因子受体2（CCR2）及其主要配体（单核细胞趋化蛋白-1，MCP1）作为排卵级联反应的新型介质。我们之前的结果表明，促性腺激素（GNT）、双调蛋白（AREG）和前列腺素E2（PGE2）对排卵相关基因mRNA水平的刺激至少部分是通过CCR2/MCP1通路发生的，这表明在猫模型中CCR2受体是排卵级联反应的新型介质。为此，在有或没有EGFR抑制剂、重组趋化因子MCP1和促性腺激素[作为卵丘-卵母细胞扩张（C-OE）和卵母细胞成熟的诱导剂]的情况下培养猫的卵丘-卵母细胞复合体（COC），以进一步评估排卵相关关键基因的mRNA表达、C-OE、卵母细胞核成熟和类固醇激素产生。我们观察到MCP1能够逆转EGFR抑制剂对猫COC中mRNA表达的抑制作用。相应地，共聚焦分析表明，EGFR抑制剂阻断的GNT刺激的透明质酸（HA）合成，通过在C-OE培养基中添加重组MCP1得以恢复。此外，MCP1能够逆转EGFR抑制剂对C-OE培养基中孕酮（P4）产生的抑制作用。关于卵母细胞核成熟，重组MCP1也能够逆转EGFR抑制剂引发的抑制作用，导致中期II（MII）期卵母细胞百分比的恢复。总之，我们的结果证实趋化因子受体CCR2是排卵级联反应中的新型中间体，并表明EGFR/AREG和CCR2/MCP1信号通路在调节猫的C-OE和卵母细胞核成熟中起关键作用，CCR2/MCP1信号通路在排卵级联反应中位于EGFR/AREG通路的下游。
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