Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) induces proliferation, migration, and
fenestration in capillary endothelial cells derived from endocrine glands. Its expression is induced by hypoxia and is
restricted to the steroidogenic glands (ovary, testis, adrenal, and placenta). /////////////PROK1 level in the follicular microenvironment: a new non-invasive predictive biomarker of embryo implantation. Alfaidy N et al. (2015) Prokineticin 1 (PROK1), also called EG-VEGF (Endocrine Gland-derived Vascular Endothelial Growth Factor), is a well-established regulator of endometrial receptivity and placental development. However, its clinical usefulness as a non-invasive predictive biomarker of embryo implantation is yet to be validated. The main objective was to determine the relationship between PROK1 levels in the follicular fluid (FF) and fertilization culture media (FCM) and the reproductive outcome in patients who received a first conventional in vitro fertilization-embryo transfer (cIVF-ET). The secondary objective was to characterize the expression of PROK1 and its receptors (PROKR) in the human follicular microenvironment. We conducted a prospective study between January 2013-June 2015 at the University Hospital of Grenoble. 135 infertile IVF patients and 10womenundergoing ovarian tissue cryopreservation were included. PROK1 concentration was measured by ELISA in FF and FCM collected on the day of oocyte retrieval and the day of oocyte denudation step, respectively. Follicular expression of the PROK1/PROKR system was determined by immunohistochemistry, RT-qPCR, and ELISA. Assessment of the clinical pregnancy rates. FF and FCM PROK1 levels were significantly higher in the embryo implantation group (p<0.001) and were predictive of subsequent embryo implantation (AUCROC, 0.91 [0.81-1.00] (p = 0.001) and 0.88 [0.72-1.00] (p = 0.001), respectively). FF and FCM PROK1 levels remain similar irrespective of embryo morphokinetic parameters (p = 0.71 and p = 0.83, respectively). PROK1/ PROKR system is expressed during human folliculogenesis. PROK1 levels in FF and FCM could constitute new predictive non-invasive markers of successful embryo implantation in cIVF-ET.//////////////////
NCBI Summary:
The protein encoded by this gene induces proliferation, migration, and fenestration (the formation of membrane discontinuities) in capillary endothelial cells derived from endocrine glands. It has little or no effect on a variety of other endothelial and non-endothelial cell types. Its expression is restricted to the steroidogenic glands (ovary, testis, adrenal, and placenta), is induced by hypoxia, and often complementary to the expression of vascular endothelial growth factor (VEGF), suggesting that these molecules function in a coordinated manner. [provided by RefSeq, Sep 2011]
General function
Ligand, Growth factor
Comment
Cellular localization
Secreted
Comment
Differential expression of the angiogenic factor genes vascular endothelial growth factor (VEGF) and endocrine gland-derived VEGF in normal and polycystic human ovaries. Ferrara N et al. (2003) 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 gland-derived (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. These findings indicate that both EG-VEGF and VEGF are expressed in PCOS ovaries, but in different cell types at different stages of differentiation, thus suggesting complementary functions for the two factors in angiogenesis and possibly cyst formation.//////////////////
Ovarian function
Luteinization
Comment
Prokineticin ligands and receptors are expressed in the human fetal ovary and regulate germ cell expression of COX2. Eddie SL et al. (2015) Fetal ovarian development and primordial follicle formation underpin future female fertility. Prokineticin (PROK) ligands regulate cell survival, proliferation and angiogenesis in adult reproductive tissues including the ovary. However, their expression and function during fetal ovarian development remains unclear. To investigate expression and localization of the PROK ligands, receptors and their downstream transcriptional targets in the human fetal ovary. This study was conducted at the University of Edinburgh. Ovaries were collected from 37 morphologically normal human fetuses. mRNA and protein expression of PROK ligands and receptors was determined in human fetal ovaries using qRT-PCR, immunoblotting and immunohistochemistry. Functional studies were performed using a human germ tumour cell line (TCam-2) stably transfected with PROKR1. Expression of PROK1 and PROKR1 was significantly higher in mid-gestation ovaries (17-20 weeks) than at earlier gestations (8-11 and 14-16 weeks). PROK2 significantly increased across the gestations examined. PROKR2 expression remained unchanged. PROK ligand and receptor proteins were predominantly localised to germ cells (including oocytes within primordial follicles) and endothelial cells, indicating these cell types to be the targets of PROK signalling in the human fetal ovary. PROK1 treatment of a germ cell line stably-expressing PROKR1 resulted in ERK phosphorylation, and elevated COX2 expression. Developmental changes in expression and regulation of COX2 and pERK by PROK1 suggest that PROK ligands may be novel regulators of germ cell development in the human fetal ovary, interacting within a network of growth and survival factors prior to primordial follicle formation.//////////////////
LeCouter J, et al 2001 reported the identification of an angiogenic mitogen selective for endocrine gland
endothelium.
The known endothelial mitogens stimulate growth of vascular endothelial cells without regard to their tissue of origin. Here
we report a growth factor that is expressed largely in one type of tissue and acts selectively on one type of endothelium.
This molecule, called endocrine-gland-derived vascular endothelial growth factor (EG-VEGF), induced proliferation,
migration and fenestration (the formation of membrane discontinuities) in capillary endothelial cells derived from endocrine
glands. However, EG-VEGF had little or no effect on a variety of other endothelial and non-endothelial cell types tested.
Similar to VEGF, EG-VEGF possesses a HIF-1 binding site, and its expression is induced by hypoxia. Both EG-VEGF and
VEGF resulted in extensive angiogenesis and cyst formation when delivered in the ovary. However, unlike VEGF,
EG-VEGF failed to promote angiogenesis in the cornea or skeletal muscle. Expression of human EG-VEGF messenger RNA
is restricted to the steroidogenic glands, ovary, testis, adrenal and placenta and is often complementary to the expression of
VEGF, suggesting that these molecules function in a coordinated manner. EG-VEGF is an example of a class of highly
specific mitogens that act to regulate proliferation and differentiation of the vascular endothelium in a tissue-specific
manner.
Expression regulated by
mir28
Comment
miR‑28‑5p suppresses cell proliferation and weakens the progression of polycystic ovary syndrome by targeting prokineticin‑1. Meng L et al. (2019) Prokineticin‑1 (PROK1) serves important roles in the pathogenesis of polycystic ovary syndrome (PCOS); however, the association between microRNA (miR)‑28‑5p and PROK1 remains unclear. In the present study, the roles of miR‑28‑5p and PROK1, and their interaction in PCOS were investigated. Rat ovary granule cells were transfected with miR‑28‑5p mimics, and PROK1 expression levels were measured by reverse transcription‑quantitative PCR and western blotting. A dual‑luciferase reporter assay was performed to determine the association between miR‑28‑5p and PROK1. Additionally, pcDNA‑PROK1 was co‑transfected into rat ovary granule cells with miR‑28‑5p mimics. Cell proliferation, apoptosis, cell cycle and the expression of signaling proteins were investigated using Cell Counting Kit‑8 assays, 5‑ethynyl‑2'‑deoxyuridine staining, flow cytometry and western blotting, respectively. PROK1 expression was suppressed in rat ovary granule cells by miR‑28‑5p mimics, but upregulated following transfection with miR‑28‑5p inhibitors. The dual‑luciferase reporter assay revealed that miR‑28‑5p binds to the 3'‑untranslated region of PROK1. Proliferation activity was increased in PROK1‑overexpressing cells; this effect was eliminated by co‑transfection with miR‑28‑5p mimics. PROK1‑overexpressing rat ovary granule cells exhibited significantly suppressed cell apoptosis and a decreased number of cells in G1; miR‑28‑5p mimics reversed these effects. Western blotting revealed that the PI3K/AKT/mTOR signaling pathway was activated by PROK1. The present results suggested that miR‑28‑5p attenuated the progression of PCOS by targeting PROK1, which may promote the pathogenesis of PCOS via the PI3K/AKT/mTOR pathway, indicating that the miR‑28‑5p/PROK1 axis may be a potential therapeutic target for patients with PCOS.//////////////////
Localization and Quantification of Cyclic Changes in the Expression of Endocrine Gland Vascular Endothelial Growth Factor in the Human Corpus Luteum Fraser HM,et al .
Angiogenesis is essential for normal growth and function of the corpus luteum. The roles of various angiogenic factors in these events are being elucidated. Endocrine gland vascular endothelial growth factor (EG-VEGF) has recently been described in the human ovary. To define the localization of EG-VEGF mRNA in the corpus luteum and determine changes in its expression, dated human corpora lutea were studied at the early, mid- and late luteal phase. Quantitative RT-PCR was employed to determine changes in EG-VEGF mRNA and compare expression to its related factor Prokineticin-2 (PK-2) and the established angiogenic factor, VEGF. In situ hybridization was used to localize sites of production of EG-VEGF. To investigate whether expression of EG-VEGF was under the influence of LH or progesterone, luteinised granulosa cells were stimulated with hCG +/- a progesterone synthesis inhibitor. EG-VEGF mRNA increased throughout the luteal phase while there was no change in VEGF mRNA. The relative abundance of RNAs based upon PCR signal intensity showed that VEGF and EG-VEGF were highly expressed while expression of PK-2 was low. EG-VEGF mRNA was localized predominantly to granulosa-derived cells of the corpus luteum. HCG stimulated both VEGF and EG-VEGF mRNA in vitro but the level of expression was not influenced by progesterone. These results establish that in the human corpus luteum EG-VEGF is principally derived from granulosa lutein cells and that its synthesis is highest during the mid to late luteal phase.
Ferrara N, et al reported the differential expression of the angiogenic factor genes vascular endothelial growth factor (VEGF) and endocrine gland-derived VEGF in normal and polycystic human ovaries.
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 gland-derived (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, the authors 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, strong expression of EG-VEGF mRNA was 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. These findings indicate that both EG-VEGF and VEGF are expressed in PCOS ovaries, but in different cell types at different stages of differentiation, thus suggesting complementary functions for the two factors in angiogenesis and possibly cyst formation.
Expression Pattern of Prokineticin 1 and Its Receptors in Bovine Ovaries During the Estrous Cycle: Involvement in Corpus Luteum Regression and Follicular Atresia. Kisliouk T et al. Prokineticin (PROK) 1, also termed endocrine gland-VEGF, is a newly identified protein assigned with diverse biological functions. It binds two homologous G protein-coupled receptors, PROKR1 and PROKR2. To better understand the roles of PROK1 and its receptors in ovarian function, their expression was determined in follicles and corpora lutea (CL) at different developmental stages. PROK1 mRNA levels were low at early and mid luteal stages, but increased sharply during natural or induced luteolysis. High PROK1 mRNA levels were also found in atretic follicles. This profile of PROK1 expression was opposite to that of the well-established angiogenic factor, VEGF. Of the two receptor types expression PROKR1 but not PROKR2, was positively correlated with its ligand. Immunohistochemical staining revealed that PROK1 was mainly located within the muscular layer of arterioles, and during regression it was also localized to macrophages and steroidogenic cells. The expression pattern of ITGB2 mRNA, a leukocyte cell marker, overlapped that of PROK1, thus suggesting that leukocyte infiltration may explain the elevated expression of PROK1 in atretic follicles and regressing CL. Indeed, flow cytometry analyses showed that nearly all ITGB2-positive cells were also stained with anti-PROK1 and that significantly more ITGB2/PROK1 double-stained cells were present in degenerating follicles and CL. Furthermore, when challenged in-vitro with PROK1, adherent, mononuclear cell numbers and TNF levels were elevated, indicating that PROK1 triggers monocyte activation. Together, these data suggest that PROK1, acting via PROKR1, may be involved in the recruitment of monocytes to regressing CL and atretic follicles and their consequent activation therein.