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BOR - Papers in Press, published online ahead of print February 9, 2005.
Biol Reprod 2005, 10.1095/biolreprod.104.037143
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BIOLOGY OF REPRODUCTION 72, 1352–1358 (2005)
DOI: 10.1095/biolreprod.104.037143
© 2005 by the Society for the Study of Reproduction, Inc.

Local Delivery of Angiopoietin-2 into the Preovulatory Follicle Terminates the Menstrual Cycle in Rhesus Monkeys1

Fuhua Xu 3, and Richard L. Stouffer 2 3,4,5  

Division of Reproductive Sciences, Oregon National Primate Research Center,3 Department of Physiology and Pharmacology,4 Oregon Health & Science University, Portland, Oregon 97239 Department of Environmental and Biomolecular Systems,5 OGI School of Science & Engineering, Oregon Health & Science University, Beaverton, Oregon 97006

The angiopoietin (ANGPT)-receptor (TEK) system plays a crucial role in blood vessel formation and stability. Because the endogenous agonist ANGPT1, antagonist ANGPT2, and TEK are expressed in the primate ovary, experiments were designed to investigate their role at a critical time during tissue remodeling/ angiogenesis in the menstrual cycle (i.e., at midcycle during maturation, ovulation, and luteinization of the dominant follicle). Either vehicle, 20 µg of ANGPT1, 2 µg of ANGPT2 (low-dose), or 20 µg of ANGPT2 (high-dose) was injected directly into the preovulatory follicle of monkeys around the day (–1 to 0) of the midcycle estradiol (E2)/LH peak. Ovaries were evaluated on Day 3 postinjection for follicle rupture, and serum samples were analyzed for levels of E2 and progesterone. Similar to controls, ANGPT1 treatment was followed by ovulation, and elevated progesterone levels during the luteal phase. In contrast, high-dose ANGPT2 treatment prevented follicle rupture, and progesterone levels never rose above baseline in the subsequent 12 days. However, an E2 peak typically occurred 12 days postinjection. Laparoscopy detected a preovulatory follicle on the contralateral (noninjected) ovary. Progesterone levels subsequently increased above baseline in these animals. Thus, exogenous ANGPT2 disrupted maturation of the preovulatory follicle, preventing its ovulation and conversion into the corpus luteum. ANGPT antagonism eliminated the dominant structure, thereby resetting the ovarian cycle, with selection and maturation of the next preovulatory follicle occurring in a timely manner. The data are consistent with a critical role of the ANGPT-TIE1/TEK system in the ovary, notably at the late stages of follicle maturation during the menstrual cycle.

angiogenesis, angiopoietin-1, angiopoietin-2, corpus luteum, follicle, menstrual cycle, ovary, ovulation, preovulatory follicle, rhesus monkeys

1 Supported by grant RF96020 from the World Health Organization/Rockefeller Foundation; and by the National Institutes of Health as part of the Specialized Cooperative Centers Program in Reproduction Research (U54 HD18185, project III), and Primate Centers grant RR00163.

2 Correspondence: Richard L. Stouffer, Division of Reproductive Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006. stouffri{at}ohsu.edu


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Copyright © 2005 by the Society for the Study of Reproduction.