Role of the DLL4-NOTCH System in PGF2alpha-Induced Luteolysis in the Pregnant Rat

HERNANDEZ F; PELUFFO MC; STOUFFER RL; IRUSTA G; TESONE M

BIOLOGY OF REPRODUCTION

SOC STUDY REPRODUCTION

Año: 2011 vol. 84 p. 859 - 865

0006-3363

We investigated the expression and cell localization ofNOTCH1, NOTCH4, and the delta-like ligand DLL4 in corpusluteum (CL) from pregnant rats during prostaglandin F2alpha(PGF2alpha)-induced luteolysis. We also examined serumprogesterone (P4) and CL proteins related to apoptosis afterlocal administration of the notch inhibitor N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT).Specific staining for NOTCH1 and NOTCH4 receptors wasdetected predominantly in large and small luteal cells. Furthermore,in line with the fact that the notch intracellular domain istranslocated to the nucleus, where it regulates gene expression,staining was evident in the nuclei of luteal cells. In addition, wedetected diffuse cytoplasmic immunostaining for DLL4 in smalland large luteal cells, in accordance with the fact that DLL4undergoes proteolytic degradation after receptor binding. ThemRNA expression of Notch1, Notch4, and Dll4 in CL isolated onDay 19 of pregnancy decreased significantly after administrationof PGF2alpha. Consistent with the mRNA results, administrationof PGF2alpha to pregnant rats on Day 19 of pregnancydecreased the protein fragment corresponding to the cleavedforms of NOTCH1/4 CL receptors. In contrast, no significantchanges were detected in protein levels for the ligand DLL4. Thelocal intrabursal administration of DAPT decreased serum P4levels and increased luteal levels of active caspase 3 and theBAX:BCL2 ratio 24 h after the treatment. These results support aluteotropic role for notch signaling to promote luteal cellviability and steroidogenesis, and they suggest that the luteolytichormone PGF2alpha may act in part by reducing the expressionof some notch system members