Bioactive sphingolipid ceramide-1-phophate (C1P) protects against age-related ovarian dysfunction/decline in female mice
Leopoldina Scotti (AR), Natalia Pascuali (AR), Mariana Di Pietro (AR), Gonzalo Oubiña (AR), Débora Cohen (AR), Dalhia Abramovich (AR), Fernanda Parborell (AR)
[Scotti] Instituto de Biología y Medicina Experimental (IBYME - CONICET), [Pascuali] Instituto de Biología y Medicina Experimental (IBYME - CONICET), [Di Pietro] Instituto de Biología y Medicina Experimental (IBYME - CONICET), [Oubiña] Instituto de Biología y Medicina Experimental (IBYME - CONICET), [Cohen] Instituto de Biología y Medicina Experimental (IBYME - CONICET), [Abramovich] Instituto de Biología y Medicina Experimental (IBYME - CONICET), [Parborell] Instituto de Biología y Medicina Experimental (IBYME - CONICET)
Context: As many women postpone childbearing over 38 years, large portions of aged female become infertile. Ovarian aging is dominated by the progressive loss of primordial follicles and a decline in oocyte quality. Activation of ovarian angiogenesis has emerged as a new strategy to halt age-related decline of ovarian response. Bioactive sphingolipids such as C1P, a proangiogenic and antiapoptotic factor, are key regulators of cell homeostasis. Objective: To study whether C1P can improve the ovarian response and angiogenesis in aged female mice. Methods: Aged female mice (26-31 weeks) received C1P (10µl/ovary; 50µM) under the bursa of one ovary and vehicle on the other, and were sacrificed 48h later. Young mice (6-9 weeks) were used as control. Ovaries were isolated. Main Outcome Measure(s): Histological and immunohistochemical analysis (VW and α-SMA; endothelial and periendothelial cell markers, respectively), radioimmunoassay (E2 and P4 concentrations) and western blot (pFoxo3a/Foxo3a and AMH; ovarian reserve markers) were performed. Results: The % of primary (PF), preantral (PrF) and antral follicles (AF) in aged mice were lower than in young mice (p<0.05). C1P treatment increased the % of PrF and AF in aged mice (p<0.05). The % of atretic follicles (AtrF) in aged mice was higher than in young mice (p<0.01) and C1P decreased the % of AtrF (p<0.05) in aged mice. C1P increased the concentration of ovarian E2 and P4 (p<0.05) and AMH levels in aged mice, while decreasing pFoxo3a/Foxo3a ratio (p<0.05). The endothelial and periendothelial cell areas increased in ovaries from aged mice treated with C1P (p<0.05). Conclusion: C1P administration in aged mice improves the ovarian response, possibly by preserving the ovarian reserve and increasing the ovarian angiogenesis. These results may have potential clinical implications in the treatment of age-related infertility.