Ovarian Angiogenic Factors
As mentioned in the preceding sections, microvascular growth, or angiogenesis, is a critical aspect of normal fol-licular and luteal function. Angiogenesis in these ovarian tissues appears to be regulated ultimately by a suite of angiogenic factors common to many tissues. This suite includes the vascular endothelial growth factor (VEGF) and the fibroblast growth factor (FGF) families. Both ovarian follicles and corpora lutea produce VEGFs and FGFs and also contain receptors for these angiogenic factors. In addition, a relatively large proportion of the angiogenic activity secreted by follicles and corpora lutea can be immunoneu-tralized with antibodies against VEGF and FGF. Recent work by a number of investigators has confirmed that blocking VEGF or its receptors inhibits follicular and luteal growth and function (for example, see Fraser and Wulff, 2001, which is listed under Further Reading).
We also have suggested that the FGFs are involved not only in luteal angiogenesis, which occurs primarily early in the estrous cycle, but also in other aspects of luteal function. For example, we and others have shown that FGF regulates luteal progesterone production. In addition, the FGFs have been shown to inhibit cell death in several cell types. As mentioned previously, many of the larger luteal micro-vessels are maintained during luteal regression, and we observed an increase in FGF receptors in these vessels, which could explain how they selectively avoid cell death while the rest of the luteal tissue is resorbed . We have therefore suggested that FGF may affect not only luteal cell proliferation but also luteal cell function and vascular maintenance.
As mentioned earlier, thecal pericytes invade the granulosa layer within hours after ovulation. These thecal microvascular pericytes are the major source of VEGF in the developing corpus luteum. We also have found that granulosa cells from preovulatory follicles produce a factor that promotes migration of pericytes. Thus, we have suggested that at ovulation the granulosa cells signal the pericytes to invade, and these thecal-derived pericytes may subsequently direct vascularization of the developing corpus luteum via production of VEGF.
We also have recently found that VEGF mRNA expression in cultured ovine luteal cells is increased by only about 30 percent with luteinizing hormone (LH) treatment but by 300 percent under low oxygen (O2) conditions. These studies were based partly on the observation that gonadotropin treatment induces VEGF mRNA expression in preovulatory rat follicles and in cultured bovine luteal cells. If VEGFs were major luteal angiogenic factors, their regulation by LH would make sense because LH is an important luteotropic factor and is critical for normal luteal development and function. However, our work is consistent with the observation that O2 is a potent stimulator of VEGF expression across a number of cell and tissue types and bolsters the concept that metabolic demand is the primary factor regulating vascular development in all tissues, including those of adults.
As mentioned earlier, a variety of pathologies of the female reproductive organs are associated with disturbances of the angiogenic process, including ovarian hyperstimulation syndrome, ovarian carcinoma, and polycystic ovary syndrome. These pathologies also are associated with altered expression of VEGFs and/or FGFs. These pathologies of the female reproductive organs represent major socioeconomic problems. For example, ovarian carcinoma often shows a poor prognosis and low survival rate and therefore is recognized as one of the most dangerous cancers in female patients. In fact, ovarian, uterine, and cervical cancers represent approximately 13 percent of new cases of cancer and 10 percent of cancer deaths in the United States, making these the fourth-leading cause of deaths due to cancer in women. In the near future, angiogenic or antiangio-genic compounds may prove to be effective therapeutic agents for treating these pathologies. In addition, monitoring of angiogenesis or angiogenic factor expression may provide not only a diagnostic tool but also a means of assessing the efficacy of these therapies.
A Model for Follicular/Luteal Angiogenesis
Recent work also has shown that nitric oxide (NO), which is primarily an endothelial product and an important local vasodilator, can stimulate VEGF production and angiogenesis. Similarly VEGF, which as mentioned previously is present in luteal perivascular cells, can stimulate
Figure 4 Working model for the regulation of ovarian follicular and luteal vascular function by VEGF and NO in sheep. This model is based on numerous in vitro and in vivo studies from our laboratories and those of others in which the major angiogenic growth factors have been not only quantified but also localized to specific tissues and cell types. In the model, vascular endothelial growth factor (VEGF) is secreted by follicular/luteal vascular smooth muscle (VSM) cells as well as capillary pericytes. The secreted VEGF acts on the endothelial cells of the follicular/luteal arterioles and capillaries, via VEGF receptor (VEGFR), to stimulate not only angio-genesis but also endothelial nitric oxide synthase (eNOS) and thus nitric oxide (NO) secretion. NO acts on the follicular/luteal VSM and pericytes, via NO receptor (NOR; soluble guanylate cyclase [sol GC]), to stimulate vasodilation and VEGF secretion. This system thereby establishes a positive feedback loop to maximize follicular/luteal angiogenesis and blood flow. Low oxygen tension seems to be the major stimulator of VEGF production, but luteinizing hormone (LH) also has a modest stimulatory effect. The schematic of the arteriole was adapted with permission from Rhodin (Architecture of the vessel wall. In Handbook of Physiology [D. F. Bohr, A. P. Somlyo, and H. V. Sparks, Jr., eds.], Section 2, Vol. II, p. 2. Bethesda, MD: American Physiological Society).
endothelial nitric oxide synthase (eNOS) expression and thus NO production.
We and others recently have found that eNOS is expressed in endothelial cells of arterioles and capillaries of preovulatory follicles and developing corpora lutea. We also have shown that the follicular and luteal endothelial cells expressing eNOS often are in close physical association with perivascular cells (capillary pericytes and arteriolar smooth muscle) that express VEGF. These observations led us to propose a new model for follicular and luteal vascular function (Figure 4), involving the existence of a paracrine loop whereby endothelial cells release NO, which stimulates perivascular VEGF production, which in turn stimulates endothelial expression of eNOS. This paracrine loop would thereby serve as a feed-forward system to maximize vasodi-lation and angiogenesis during follicular and luteal growth and development.
Corpus luteum: The progesterone-secreting body formed on the ovary from the wall of the ruptured follicle after ovulation; during the non-pregnant (estrous or menstrual) cycle, the corpus luteum secretes progesterone for several days but then regresses at the end of the cycle; during gestation, the corpus luteum remains viable and secretes progesterone throughout most of pregnancy.
Follicle: The ovarian structure composed of an oocyte (or egg), an avascular granulosa cell layer surrounding the oocyte and enclosed by a basement membrane, and a vascular thecal layer; both the granulosa and thecal layers are involved in biosynthesis of estrogens. At ovulation, the wall of the follicle ruptures and the oocyte is released and subsequently "picked up" by the oviduct where it is fertilized; the ruptured wall of the follicle transforms into the corpus luteum (q.v.) over the next few days.
Granulosa (stratum granulosum or granulosa layer): The avascular inner epithelial layer of the ovarian follicle, which surrounds the oocyte, is itself surrounded by a basement membrane, and is involved in biosynthesis of estrogens.
Theca (thecal layer): The outer layer of the growing ovarian follicle, which contains both epithelial and fibroblastic cells and is divided into a theca interna and a theca externa. The theca interna contains a capillary wreath adjacent to the basement membrane surrounding the granulosa layer and also contains a few arterioles and venules; the theca externa contains mostly arterioles and venules and is continuous with the ovarian stroma. The theca interna also is involved in biosynthesis of estrogens.
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Augustin, H. G., Iruela-Arispe, M. L., Rogers, P. A. W., and Smith, S. K. (eds.) (2001). Vascular Morphogenesis in the Female Reproductive System. Cardiovascular Molecular Morphogenesis Series (R. R. Markwald, series ed.). Boston: Birkhauser. See especially the several articles related to the ovary on pp. 107—205.
Ford, S. P. (1982). Control of uterine and ovarian blood flow throughout the estrous cycle and pregnancy of ewes, sows and cows. J Anim. Sci.
55(Suppl. 2), 32-42. This reference provides a review of the regulation of ovarian blood flow. Fraser, H. M., and Wulff, C. (2001). Angiogenesis in the primate ovary.
Reprod. Fertil. Dev. 13, 557-566. Jones, R. E. (ed.) (1978). The Vertebrate Ovary. New York: Plenum Press. See especially the chapters by Ellinwood, Nett, and Niswender (Ovarian vasculature: Structure and function, pp. 583—614), and Jones (Evolution of the vertebrate ovary: An overview, pp. 827—840). Knobil, E., Neill, J. D., Greenwald, G. S., Markert, C. L., and Pfaff, D. W. (eds.) (1994). The Physiology of Reproduction, 2nd ed. New York: Raven Press. See especially the chapters by Byskov andHoyer (Embryology of mammalian gonads and ducts), Greenwald and Roy (Follicu-lar development and its control), and Niswender and Nett (Corpus luteum and its control in infraprimate species). Redmer, D. A., and Reynolds, L. P. (1996). Angiogenesis in the ovary. Rev. Reprod. 1, 182-192. This reference provides a review of vascular growth and development in the ovary. Reynolds, L. P., Grazul-Bilska, A. T., and Redmer, D. A. (2000). Angiogenesis in the corpus luteum. Endocrine 12, 1-9. Reynolds, L. P., Grazul-Bilska, A. T., and Redmer, D. A. (2002). Angio-genesis in the female reproductive system: Pathological implications. Int. J. Exp. Path. 83, 151-164. This reference provides a review of pathologies related to microvascular dysfunction in the ovaries, uterus, and placenta.
Reynolds, L. P., and Redmer, D. A. (1998). Expression of the angiogenic factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), in the ovary. J. Anim. Sci. 76, 1671-1681. Reynolds, L. P., and Redmer, D. A. (1999). Growth and development of the corpus luteum. In Reproduction in Domestic Ruminants IV, Proceedings of the Fifth International Symposium on Reproduction in Domestic Ruminants (W. W. Thatcher, E. K. Inskeep, G. D. Niswender, and C. Doberska, eds.). J. Reprod. Fertil. Suppl. 54, 181-191. This reference provides a review of luteal growth and development.
Dr. Reynolds was trained as a reproductive physiologist and works primarily in the areas of ovarian, uterine, and placental vascular function. His current research interests are the cellular and molecular regulation of fol-licular and luteal angiogenesis as well as uterine and placental angiogene-sis; he also is involved in a collaborative effort to mathematically model development of the ovarian and utero-placental vascular beds. Dr. Reynolds is Director of the Cell Biology Center, and Codirector of the Center for Nutrition and Pregnancy, both at North Dakota State University.
Drs. Grazul-Bilska and Redmer, also at North Dakota State University, have been long-time collaborators in these research efforts.
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