Ovarian premature aging: VIP as key regulator of fibro-inflammation and foamy macrophages generation

CASTAGNOLA, LARA; GALLINO, LUCILA; SCHAFIR, ANA; VOTA, DAIANA; GRASSO, ESTEBAN; GORI, SOLEDAD; WASCHEK, JAMES; PARBORELL, FERNANDA; PÉREZ LEIRÓS, CLAUDIA; HAUK, VANESA; RAMHORST, ROSANNA

MOLECULAR AND CELLULAR ENDOCRINOLOGY.

ELSEVIER IRELAND LTD

Año: 2025 vol. 599

0303-7207

Ovarian aging is associated with fibro-inflammation, contributing to the decline in oocyte count and quality.Given the immunomodulatory properties of the vasoactive intestinal peptide (VIP) in the reproductive tract, weinvestigated its role in maintaining ovarian immune homeostasis and preventing premature aging. We evaluatedyoung VIP knockout (KO) mice, comparing them to young wild type (WT) females, for signs of premature aging.Histological staining revealed aberrant ovarian morphology in VIP KO mice, characterized by increased atreticfollicles and decreased ovarian reserve compared to WT controls. Moreover, VIP KO ovaries showed reducedvascularization, increased collagen deposition and elevated ROS and IL-1β levels. Foamy macrophages weresignificantly predominant, indicating premature aging in young VIP KO ovaries. To determine potential mechanisms behind these pathogenic changes, we conditioned peritoneal macrophages from young WT or VIP KOmice in vitro with ovarian-conditioned media from young WT or VIP KO mice to mimic the respective ovarianmicroenvironment. When WT or VIP KO peritoneal macrophages were conditioned with ovarian media fromtheir respective genotypes, lipid droplet accumulation increased compared to control medium. In cross-genotypeexperiments, WT macrophages conditioned with media from VIP KO ovaries selectively accumulated higherlevels of lipid droplets, whereas no differences were observed in VIP KO macrophages conditioned with WTovarian media. This suggests that VIP KO macrophages are uniquely sensitized to the inflammatory environmentof VIP KO ovaries, implicating both ovarian factors and macrophage status. These findings highlight the role ofVIP in preventing fibro-inflammation, thereby preserving ovarian health and preventing premature aging