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VEGF blockade inhibits angiogenesis and reepithelialization of endometrium

Xiujun Fan^*, Sacha Krieg^*, Calvin J. Kuo, Stanley J. Wiegand, Marlene Rabinovitch, Maurice L. Druzin^*, Robert M. Brenner^¶, Linda C. Giudice^|| and Nihar R. Nayak^*,1

^* Department of Obstetrics and Gynecology,

Department of Medicine, and

Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA;

Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA;

^¶ Oregon National Primate Research Center, Beaverton, Oregon, USA; and

^|| Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California, USA

¹Correspondence: Department of Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Drive, HH-333, Stanford, CA 94305, USA. E-mail: nayakn{at}stanford.edu

Despite extensive literature on vascular endothelial growth factor (VEGF) expression and regulation by steroid hormones, the lack of clear understanding of the mechanisms of angiogenesis in the endometrium is a major limitation for use of antiangiogenic therapy targeting endometrial vessels. In the current work, we used the rhesus macaque as a primate model and the decidualized mouse uterus as a murine model to examine angiogenesis during endometrial breakdown and regeneration. We found that blockade of VEGF action with VEGF Trap, a potent VEGF blocker, completely inhibited neovascularization during endometrial regeneration in both models but had no marked effect on preexisting or newly formed vessels, suggesting that VEGF is essential for neoangiogenesis but not survival of mature vessels in this vascular bed. Blockade of VEGF also blocked reepithelialization in both the postmenstrual endometrium and the mouse uterus after decidual breakdown, evidence that VEGF has pleiotropic effects in the endometrium. In vitro studies with a scratch wound assay showed that the migration of luminal epithelial cells during repair involved signaling through VEGF receptor 2–neuropilin 1 (VEGFR2-NP1) receptors on endometrial stromal cells. The leading front of tissue growth during endometrial repair was strongly hypoxic, and this hypoxia was the local stimulus for VEGF expression and angiogenesis in this tissue. In summary, we provide novel experimental data indicating that VEGF is essential for endometrial neoangiogenesis during postmenstrual/postpartum repair.—Fan, X., Krieg, S., Kuo, C. J., Wiegand, S. J., Rabinovitch, M., Druzin, M. L., Brenner, R. M., Giudice, L. C., Nayak, N. R. VEGF blockade inhibits angiogenesis and reepithelialization of endometrium.

Key Words: VEGF Trap • luminal epithelium • rhesus macaque • mouse • hypoxia