PPAR gamma represses VEGF expression in human endometrial cells: implications for uterine angiogenesis

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 PPAR\(\upgamma\). The action of natural and synthetic PPAR\(\upgamma\) 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 PPAR\(\upgamma\) protein. Treatment of transformed and primary endometrial cells with rosiglitazone, a synthetic PPAR\(\upgamma\) agonist, or prostaglandin 15-deoxy-Δ12-14 J2, a naturally occurring eicosanoid ligand, decreased VEGF protein secretion. In transiently transfected Ishikawa cells, rosiglitazone repressed VEGF gene promoter-luciferase activation with an IC50 ∼ ∼ 50 nM. Truncated and mutated VEGF promoter constructs revealed that the PPAR\(\upgamma\)-regulated domain is a direct repeat (DR)-1 motif –443 bp upstream of the transcriptional start site. Conclusions: PPAR\(\upgamma\) ligands repress VEGF gene expression via a PPAR\(\upgamma\)-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. Similar content being viewed by others

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The authors thank Drs Olga Genbacev and Susan Fisher for useful comments and access to their hypoxia cell culture chamber and Dr Fritz Wieser for advice and assistance. LLP was supported by funds from the University Hospital Maastricht. J-LV, MKT, DZ, LLW, and RNT were supported by NIH grants R01-HD33238 and R01-HL73469. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Peeters, L., Vigne, JL., Tee, M. et al. PPAR\(\upgamma\) represses VEGF expression in human endometrial cells: Implications for uterine angiogenesis. Angiogenesis 8, 373–379 (2006). https://doi.org/10.1007/s10456-005-9027-4 Received: Accepted: Published: Issue date: DOI: https://doi.org/10.1007/s10456-005-9027-4