Novel antiangiogenic agents for use in contraception

Abstract

Angiogenesis and vascular development are fundamental to the development of a receptive endometrium that permits implantation. The underlying hypothesis of this project is that implantation in primates and in humans is dependent on vascular remodeling in the endometrium and that the identification of agents that can disrupt this process prior to embryo attachment will lead to the development of new post coital contraceptives. To identify suitable targets for postcoital contraception, we studied the expression in endometrium of the vascular endothelial growth factor (VEGF) and angiopoietin families of angiogenic regulators. We produced a neutralizing antibody to VEGF-A, and this was shown to inhibit implantation in rhesus monkeys, apparently through direct antagonism of the action of VEGF-A in the endometrium. This demonstrated 'proof of principle' that agents antagonizing molecules that regulate angiogenesis can be developed as contraceptive agents. A second objective was to identify new contraceptive targets. We have developed microarrays to compare receptive endometrium with endometrium-rendered nonreceptive by a number of experimental strategies. We have identified over 100 RNA transcripts that are acutely regulated by administration of the antiprogestin RU486 to women, and 20 transcripts altered by antagonizing the action of VEGF-A in endometrium. These transcripts represent new potential targets for development of novel postcoital contraceptives.