Summary and Conclusion

It can fairly be argued that the microvasculature of the endometrium is the essential functional, as opposed to merely supportive, unit of this organ. While it certainly supports the epithelial cells and stromal fibroblasts, it also plays a special and essential role by generating extraordinary amounts of interstitial fluid at specific times—fluid that is absolutely essential for the rapid tissue repair, growth, and differentiation that prepare the endometrium to receive a fertilized egg. Capillaries also are an integral functional component of the endometrial glands, secretions of which nourish and protect the early embryo. Finally, they supply oxygen and nutrients and remove wastes for the invading, growing conceptus in early pregnancy. When they are no longer adequate for this task, the placental cells themselves take over by invading the vessels and forming low-resistance channels that open directly onto the surface of the placenta, bathing it in maternal blood. Rapid progress is being made in understanding the factors that control these complex developmental events, but much remains to be learned. Further research could reveal much about the basic mechanisms that regulate new blood vessel growth, its cessation, and vessel regression in general, knowledge that could be important for understanding and developing new treatments for several uterine pathologies as well as the angiogenesis that plays an essential role in tumor growth and numerous other diseases.


Endometrium: The lining of the uterus that consists of the function-alis layer (lumenal surface epithelium, stroma, and glands) and the basalis layer, which is adjacent to the myometrium (the external muscular layer of the uterus) and from which a new functionalis is regenerated during each menstrual cycle.

Estrogen: The steroid hormone produced cyclically by the ovary that stimulates growth of the uterine endometrium and initiates implantation (in part, via induction of VEGF expression).

Glands: Epithelial cell-lined invaginations that extend from the uterine lumen deep into the functionalis and secrete nutrients and other sub stances essential for the survival, implantation, and early development of the embryo.

Spiral arteries: The major feed arteries that extend from the basalis to near the lumenal surface epithelium of the functionalis layer and give rise to the capillary networks that surround the glands and underlie the lumen; they grow, becoming progressively more convoluted, and regress again during each menstrual cycle.

VEGF: Vascular endothelial growth factor, also known as vascular permeability factor (VPF), is a protein that binds to specific endothelial cell receptors, and through them induces greatly increased microvascular permeability and new blood vessel growth (angiogenesis).


1. Schmidt-Matthiesen, H. (1963). Vascularization. In The Normal Human Endometrium (H. Schmidt-Matthiesen, ed.), pp. 208-226. New York: McGraw-Hill.

2. Blandau, R. J. (1977). The female reproductive system. In: Histology, 4th edition, (L. Weiss, and R. O. Greep, ed.), p 911. McGraw Hill, New York.

3. Williams, M. F. (1948). The vascular architecture of the rat uterus as influenced by estrogen and progesterone. Am. J. Anat. 83, 247308.

4. Nayak, N. R., Critchley, H. O., Slayden, O. D., Menrad, A., Chwalisz, K., Baird, D. T., and Brenner, R. M. (2000). Progesterone withdrawal up-regulates vascular endothelial growth factor receptor type 2 in the superficial zone stroma of the human and macaque endometrium: Potential relevance to menstruation. J. Clin. Endocrinol. Metab. 85(9), 3442-3452.

5. Brasted, M., White, C. A., Kennedy, T. G., and Salamonsen, L. A. (2003). Mimicking the events of menstruation in the murine uterus. Biol. Reprod. 69(4), 1273-1280.

6. Gargett, C. E., and Rogers, P. A. (2001). Human endometrial angiogenesis. Reproduction 121(2), 181-186. This review provides further explanation of the possible modes of endometrial angiogenesis.

7. Cullinan-Bove, K., and Koos, R. D. (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. This paper was the first to demonstrate that estrogen rapidly induces the expression of VEGF in the uterus.

8. Nayak, N. R., and Brenner, R. M. (2002). Vascular proliferation and vascular endothelial growth factor expression in the rhesus macaque endometrium. J. Clin. Endocrinol. Metab. 87(4),1845-1855. This paper is the first to clearly show the spatial and temporal patterns of VEGF expression in the primate uterus throughout the menstrual cycle, thereby providing insight into its roles in the remodeling of the endometrial vasculature.

9. Salamonsen, L. A. (2003). Tissue injury and repair in the female human reproductive tract. Reproduction 125(3), 301-311.

10. Rockwell, L. C., Pillai, S., Olsen, C. E., and Koos, R. D. (2002). Inhibition of vascular endothelial growth factor/vascular permeability factor action blocks estrogen-induced uterine edema and pregnancy in the rodent. Biol. Reprod. 67, 1919-1926. This paper shows that VEGF plays an essential role in both estrogen-induced uterine edema and implantation.

11. Psychoyos, A. (1973). Endocrine control of egg implantation. In Handbook of Physiology (R. O. Greep, E. G. Astwood, and S. R. Geiger, eds.), Section 7, Vol. II, Part 2, pp. 187-215. Washington, DC: American Physiological Society.

12. Noyes, R. W., Hertig, A. T., and Rock, J. (1950). Dating the endometrial biopsy. Fertil. Steril. 1, 3-25.

13. Roberts, W. G., and Palade, G. E. (1995). Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J. Cell Sci. 108(Part 6), 2369-2379.

14. Dvorak, H. F., Brown, L. F., Detmar, M., and Dvoark, A. M. (1995). Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol 146, 1029-1039.

15. Sorger, T., and Soderwall, A. (1981). The aging uterus and the role of edema in endometrial function. Biol. Reprod. 24(5), 1135-1144.

16. Goodger, A. M., and Rogers, P. A. (1993). Uterine endothelial cell proliferation before and after embryo implantation in rats. J. Reprod. Fertil. 99(2), 451-457.

17. Enders, A. C., Welsh, A. O., and Schlafke, S. (1985). Implantation in the Rhesus monkey: Endometrial responses. Am. J. Anat. 173, 147169.

18. Genbacev, O., Zhou, Y., Ludlow, J. W., and Fisher, S. J. (1997). Regulation of human placental development by oxygen tension. Science 277(5332), 1669-1672.

19. Zhou, Y., Genbacev, O., and Fisher, S. J. (2003). The human placenta remodels the uterus by using a combination of molecules that govern vasculogenesis or leukocyte extravasation. Ann. N. Y. Acad. Sci. 995, 73-83. This paper reviews the process by which fetal cells called cytotrophoblasts invade endometrial blood vessels and assume the function of vascular endothelial cells.

20. Unemori, E. N., Erikson, M. E., Rocco, S. E., Sutherland, K. M., Parsell, D. A., Mak, J., and Grove, B. H. (1999). Relaxin stimulates expression of vascular endothelial growth factor in normal human endometrial cells in vitro and is associated with menometrorrhagia in women. Hum. Reprod. 14(3), 800-806.

and the significance of microvascular hyperpermeability in angiogenesis. Curr. Top. Microbiol. Immunol. 237, 97-132. Hastings, J. M., Licence, D. R., Burton, G. J., Charnock-Jones, D. S., and Smith, S. K. (2003). Soluble vascular endothelial growth factor receptor 1 inhibits edema and epithelial proliferation induced by 17beta-estradiol in the mouse uterus. Endocrinology 144(1), 326-334. This recent paper directly links estrogen-induced, VEGF-mediated edema to the subsequent growth of endometrial epithelial cells.

Capsule Biographies

Dr. Koos is a Professor and Graduate Program Director in the Department of Physiology at the University of Maryland School of Medicine. His research, funded by the NICHD and NCI, focuses on the regulation of VEGF expression in the uterus and ovary by estrogen and hypoxia. He has served on numerous NIH review panels, the editorial boards of the journals Endocrinology and Biology of Reproduction, and the FASEB Board of Directors and Public Affairs Executive Committee.

Dr. Rockwell is an Assistant Professor and Director of the Biological Anthropology Research Laboratory at Temple University. Her research includes projects on ovarian function and implantation and is supported by grants from the NIH and Temple University.

Further Reading

Dvorak, H. F., Nagy, J. A., Feng, D., Brown, L. F., and Dvorak, A. M. (1999). Vascular permeability factor/vascular endothelial growth factor

The Vasculature of the Normal Mammary Gland: HIF-1-Independent Expansion and Regression

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