Differential Expression of the Angiogenic Factor Genes Vascular Endothelial Growth Factor (VEGF) and Endocrine Gland-Derived VEGF in Normal and Polycystic Human Ovaries

Abstract

Angiogenesis is a key aspect of the dynamic changes occurring during the normal ovarian cycle. Hyperplasia and hypervascularity of the ovarian theca interna and stroma are also prominent features of the polycystic ovary syndrome (PCOS), a leading cause of infertility. Compelling evidence indicated that vascular endothelial growth factor (VEGF) is a key mediator of the cyclical corpus luteum angiogenesis. However, the nature of the factor(s) that mediate angiogenesis in PCOS is less clearly understood. Endocrine glandderived (EG)-VEGF has been recently identified as an endothelial cell mitogen with selectivity for the endothelium of steroidogenic glands and is expressed in normal human ovaries. In the present study, we compared the expression of EG-VEGF and VEGF mRNA in a series of 13 human PCOS and 13 normal ovary specimens by in situ hybridization. EG-VEGF expression in normal ovaries is dynamic and generally complementary to VEGF expression in both follicles and corpora lutea. A particularly high expression of EG-VEGF was detected in the Leydig-like hilus cells found in the highly vascularized ovarian hilus. In PCOS ovaries, we found strong expression of EG-VEGF mRNA in theca interna and stroma in most of the specimens examined, thus spatially related to the new blood vessels. In contrast, VEGF mRNA expression was most consistently associated with the granulosa cell layer and sometimes the theca, but rarely with the stroma. Angiogenesis is a key aspect of normal cyclical ovarian function. Follicular growth and the development of the corpus luteum (CL) are dependent on the proliferation of new capillary vessels.

The VEGF +405 G>C 5' untranslated region polymorphism and risk of PCOS: a study in the South Indian Women

“…Therefore, the -460T/+405G haplotype carriers may have a higher levels of VEGF which can lead to increased vascularity and accentuated stromal growth in the ovary with subsequent hyperplasia of the theca interna and excessive production of androgens. This hypothesis is supported by demonstration of a strong immunohistochemical staining of VEGF in the ovarian stroma of patients with PCOS [10]. VEGF can induce connective stromal growth by increasing microvascular permeability, which leads to extravasation of plasma proteins in the polycystic ovarian syndrome [27].…”

“…VEGF can induce connective stromal growth by increasing microvascular permeability, which leads to extravasation of plasma proteins in the polycystic ovarian syndrome [27]. The extravascular matrix thus formed favours the growth of new blood vessels and fibroblasts, which in turn organize the avascular provisional fibrin matrix into a mature, vascularized connective tissue stroma [10].…”

“…Increased secretion of VEGF in the serum of patients may induce an increased number of active granulosa lutein cells which have both increased secretory capacity as well as up-regulated gene expression level [8,9]. Furthermore, increased VEGF levels have also been reported in the hyperthecotic stroma of PCOS which can induce connective stromal growth by promoting microvascular permeability [10]. High vascularisation may lead to the abnormal growth of the thecal interna, which is a major site for androgen steroidogenesis.…”

Prokinéticines

“…L'expression de PROK1 fluctuerait selon le cycle ovarien, avec une présence importante des transcrits dans les cellules de la granulosa des follicules primordiaux, primaire et secondaire, suivie d'une baisse dans le follicule tertiaire [18]. Après l'ovulation, les ARNm de PROK1 sont de nouveau abondants dans le corps jaune et les follicules atrétiques [18,20]. La présence des transcrits de PROK1 est intense dans les cellules lutéales de la thèque dès 8 jours après l'ovulation et jusqu'à la fin de la phase lutéale.…”

“…L'injection de PROK1 dans l'ovaire a un effet angiogène intense chez le rat [1]. Une expression anormale du gène PROK1 est associée à plusieurs maladies ovariennes, comme le syndrome des ovaires polykystiques [20] et le syndrome d'hyperstimulation ovarienne [21]. Le syndrome des ovaires polykystiques, caractérisé par une accumulation de follicules qui n'arrivent pas à maturité, est associé à une augmentation des transcrits de PROK1 [20].…”