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

Lugar: Madison; Año: 2011 vol. 84 p. 859 - 865

0006-3363

We investigated the expression and cell localization of NOTCH1, NOTCH4 and the ligand DlLL4 in corpus luteum (CL) from pregnant rats during PGF2alpha-induced luteolysis. We also examined serum progesterone (P(4)) and CL proteins related to apoptosis after local administration of the notch inhibitor DAPT. Specific staining for NOTCH1 and 4 receptors was detected predominantly in large and small luteal cells. Furthermore, the staining was evident in the nuclei of luteal cells in coincidence with the fact that the notch intracellular domain is translocated to the nucleus, where it regulates gene expression. Additionally, we detected diffuse cytoplasmic immunostaining for DLL4 in small and large luteal cells, in accordance with the information that DLL4 undergoes proteolytic degradation after receptor binding. The mRNA expression of Notch1, Notch4 and Dll4 in CL isolated on Day 19 of pregnancy decreased significantly after the administration of PGF2alpha. Consistent with the mRNA results, administration of PGF2alpha to pregnant rats on Day 19 of pregnancy decreased the protein fragment corresponding to the cleaved forms of NOTCH1/4 CL receptors. In contrast, no significant changes were detected in protein levels for the ligand DLL4. The local intrabursal administration of DAPT decreased serum P(4) levels, increased luteal levels of active CASP3 and the BAX/BCL2 ratio 24 h after the treatment. These results support a luteotropic role for notch signaling to promote luteal cell viability and steroidogenesis, and suggest that the luteolytic hormone PGF2alpha may act in part by reducing the expression of some notch system members.