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Ovulatory Induction of SCG2 in Human, Nonhuman Primate, and Rodent Granulosa Cells Stimulates Ovarian Angiogenesis

Journal article
Authors P. R. Hannon
D. M. Duffy
K. L. Rosewell
Mats Brännström
J. W. Akin
T. E. Curry
Published in Endocrinology
Volume 159
Issue 6
Pages 2447-2458
ISSN 0013-7227
Publication year 2018
Published at Institute of Clinical Sciences, Department of Obstetrics and Gynecology
Pages 2447-2458
Language en
Keywords endothelial growth-factor, human chorionic-gonadotropin, subsequent, luteal function, dense core vesicles, secretogranin-ii, luteinizing-hormone, preovulatory follicle, rhesus-monkeys, neuropeptide, secretoneurin, progesterone antagonist, Endocrinology & Metabolism, ammell jg, 1990, journal of histochemistry & cytochemistry, v38, p949
Subject categories Obstetrics and gynaecology


The luteinizing hormone (LH) surge is essential for ovulation, but the intrafollicular factors induced by LH that mediate ovulatory processes (e.g., angiogenesis) are poorly understood, especially in women. The role of secretogranin II (SCG2) and its cleaved bioactive peptide, secretoneurin (SN), were investigated as potential mediators of ovulation by testing the hypothesis that SCG2/SN is induced in granulosa cells by human chorionic gonadotropin (hCG), via a downstream LH receptor signaling mechanism, and stimulates ovarian angiogenesis. Humans, nonhuman primates, and rodents were treated with hCG in vivo resulting in a significant increase in the messenger RNA and protein levels of SCG2 in granulosa cells collected early during the periovulatory period and just prior to ovulation (humans: 12 to 34 hours; monkeys: 12 to 36 hours; rodents: 4 to 12 hours post-hCG). This induction by hCG was recapitulated in an in vitro culture system utilizing granulosa-lutein cells from in vitro fertilization patients. Using this system, inhibition of downstream LH receptor signaling pathways revealed that the initial induction of SCG2 is regulated, in part, by epidermal growth factor receptor signaling. Further, human ovarian microvascular endothelial cells were treated with SN (1 to 100 ng/mL) and subjected to angiogenesis assays. SN significantly increased endothelial cell migration and new sprout formation, suggesting induction of ovarian angiogenesis. These results establish that SCG2 is increased in granulosa cells across species during the periovulatory period and that SN may mediate ovulatory angiogenesis in the human ovary. These findings provide insight into the regulation of human ovulation and fertility.

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