The vascular endothelial growth factor/fms-like tyrosine kinase system in human ovary during the menstrual cycle and early pregnancy

In human ovaries, angiogenesis is known to be associated with the developme nt of follicles and the formation of the corpus luteum (CL). A complex vasc ular network is formed within the thecal cell layer during follicular growt h, and rapid neovascularization occurs toward the granulosa cell layer afte r ovulation. Vascular endothelial growth factor (VEGF) is a multifunctional cytokine, stimulating endothelial cell growth and enhancing microvascular permeability. A specific receptor for VEGF, fms-like tyrosine kinase (Flt-1 ), is expressed in vascular endothelial cells that mediates the action of V EGF. We examined the localization and expression of VEGF and Flt-1, using a n immunohistochemical technique and RT-PCR analysis, in human follicles and corpora lutea during the normal menstrual cycle and early pregnancy. We me asured concentrations of VEGF in extracts of human CL using an enzyme-linke d immunosorbent assay during the luteal phase and early pregnancy. Immunost aining for VEGF was observed in granulosa cells from small antral follicles to preovulatory follicles. The staining was detected in thecal cells from medium-sized to preovulatory follicles. The intensity of the staining was g radually increased as a follicle grew. Flt-1 was localized in granulosa and thecal cells of preovulatory follicles as well as in endothelial cells. In the human CL, the intense staining for VEGF was observed in granulosa and thecal lutein cells, especially in the midluteal phase. The immunostaining for Flt-1 was faint in endothelial cells in the CL, whereas it was distinct in granulosa and thecal lutein cells. The concentrations of VEGF in lutein extracts were high in the early and midluteal phases and tended to decreas e toward the late luteal phase. During early pregnancy, a measurable amount of VEGF was detected. RT-PCR analysis demonstrated that messenger ribonucl eic acids encoding VEGF1B1, VEGF 165, and Flt-1 were expressed in the CL. T hese results suggest that VEGF might have an autocrine role in the ovulator y process and luteal function as well as a paracrine role in angiogenesis.