Endometrial vasculature supports physiological uterine growth, embryonic implantation and endometrial pathology. Vascular endothelial growth factor (VEGF) is regulated by diverse developmental and hormonal signals, including eicosanoid ligands of PPARgamma. The action of natural and synthetic PPARgamma ligands on VEGF expression in primary and transformed human endometrial cell cultures was established by quantifying endogenous gene expression and transfected VEGF gene reporters. VEGF promoter-luciferase constructs were truncated and mutated to map functional sequences. Endometrial tissues and cells express PPARgamma protein. Treatment of transformed and primary endometrial cells with rosiglitazone, a synthetic PPARgamma agonist, or prostaglandin 15-deoxy-Delta12-14 J(2), a naturally occurring eicosanoid ligand, decreased VEGF protein secretion. In transiently transfected Ishikawa cells, rosiglitazone repressed VEGF gene promoter-luciferase activation with an IC(50) approximately approximately 50 nM. Truncated and mutated VEGF promoter constructs revealed that the PPARgamma-regulated domain is a direct repeat (DR)-1 motif -443 bp upstream of the transcriptional start site.
Conclusions: PPARgamma ligands repress VEGF gene expression via a PPARgamma-responsive element (PPRE) in the VEGF gene promoter. Agonists of this nuclear receptor might be exploited pharmacologically to inhibit pathological vascularization in complications of pregnancy, endometriosis and endometrial adenocarcinoma.