Robert D. Koos, Ph.D.
Laboratory of Molecular and Cellular Aspects of Development and Angiogenesis in the Ovary and Uterus
The goal of my research is to understand the mechanisms that control developmental events, particularly angiogenesis (the growth of new blood vessels), in the follicle and corpus luteum (CL) of the ovary and the endometrium of the uterus. Blood vessels repeatedly grow and regress during the rapid, hormonally-regulated development of these tissues, unlike in other tissues, during the reproductive cycle and pregnancy, making them excellent systems for the study of this fundamental developmental process. Understanding the factors that regulate normal vascular development is not only crucial to understanding these key reproductive events, but also the abnormal angiogenesis that contributes to the progression of many diseases, including cancer and atherosclerosis. In recent years, we have concentrated our efforts on examining the roles of fibroblast growth factors (FGFs) and vascular endothelial growth factor/vascular permeability factor (VEGF) in this process. Both FGFs and VEGF are endothelial cell mitogens. VEGF is also a potent stimulator of capillary permeability. The latter property is especially relevant to the reproductive system because increased vascular permeability and edema occur in the ovary prior to ovulation and in the uterus in response to estrogen, and is believed to be essential for subsequent tissue remodeling. Using the sensitive and specific technique of quantitative reverse transcription-polymerase chain reaction (RT-PCR), we have recently shown that VEGF expression increases markedly following the ovulatory gonadotropin surge, and immediately before the onset of follicular edema, suggesting that VEGF plays a role in follicle rupture as well as vascularization of the CL. In vitro, VEGF expression by granulosa cells is strongly stimulated by hypoxia, a fundamental stimulus for angiogenesis, and the normal state in the developing follicle and early CL. We have also shown that VEGF expression is rapidly stimulated by estrogen in the uterus, and that the increase immediately precedes uterine edema, suggesting that VEGF induces this response. The continued expression of VEGF in the CL after formation of the luteal vasculature also strongly suggests that its primary function there is maintenance of the high degree of vascular permeability characteristic of that tissue. It also indicates that additional factors, most likely FGFs, are required for the induction of angiogenesis. Our latest studies employ powerful new transgenic techniques - targeted overexpression of truncated FGF receptors (that specifically inhibit FGF action) and targeted overexpression of VEGF, controlled through tetracycline inducible regulatory elements, in transgenic mice - to determine the exact roles of FGFs and VEGF in cell growth and tissue remodeling in the ovary and uterus. In addition to obtaining in-depth knowledge of basic ovarian and uterine physiology, trainees can learn a wide range of cellular and molecular techniques, including cell culture, RNA/DNA isolation, quantitative RT-PCR, DNA cloning, transfection, and transgenic methodologies.
Recent PublicationsKoos RD 1993 Ovarian Angiogenesis. In: The Ovary (E.Y. Adashi and P.C.K. Leung, eds.) pp. 433-453, Raven Press, New York.
Cullinan-Bove K, Koos RD 1993 Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: Rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology 133:829-837.
Koos RD 1995 Increased expression of vascular endothelial growth/permeability factor in the rat ovary following an ovulatory gonadotropin stimulus: Potential roles in follicle rupture. Biology of Reproduction 52:1426-1435.
Forsythe JA, Jiang B-H, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL 1996 Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Molecular and Cellular Biology 16:4604-4613.
