Vascular endothelial growth factor expression in the endometrium during the menstrual cycle, implantation window and early pregnancy

PURPOSE OF REVIEW: The review aims to summarize recent data about vascular endothelial growth factor and its implications in the normal endometrium during the menstrual cycle, implantation window and early pregnancy. RECENT FINDINGS: Angiogenesis is crucial for the development of endometrium as well as for embryo implantation and establishment of pregnancy. A number of cytokines and growth factors including vascular endothelial growth factor are known to modulate angiogenesis in human endometrium in vitro and in vivo. Intrauterine vascular endothelial growth factor expression has been shown to be regulated in a cycle-dependent fashion. Recent studies have demonstrated that female sex steroid hormones and gonadotrophins contribute to the regulation of vascular endothelial growth factor by endometrial glandular epithelial and stromal cells. Vascular endothelial growth factor levels increase around the peri-implantation period and in the late secretory and pre-menstrual phases. Further, the production of this angiogenic growth factor appears to be related to decidualization. SUMMARY: Vascular endothelial growth factor is a key regulator of angiogenesis and vascular function in the human endometrium. Aberrant endometrial angiogenesis may result in menstrual dysfunction, failed implantation and first-trimester miscarriage. The possibility of enhancing or inhibiting angiogenic activity in the endometrium will provide a novel approach to the manipulation of reproductive functions.     

Localization of the VEGF and angiopoietin genes in uterine carcinosarcoma

OBJECTIVE: Carcinosarcoma of the uterus is a highly aggressive tumor. However, the angiogenesis in this tumor remains unclear. This is the first study to examine the characteristics of angiogenesis in this tumor at the molecular level while also comparing the findings with those of high-grade endometrial carcinoma. METHODS: The expression of vascular endothelial growth factors (VEGF) and angiopoietins (Ang) genes were examined in 35 primary uterine carcinosarcomas as well as in 12 high-grade endometrial carcinomas by in situ hybridization. RESULTS: A strong expression of VEGF-A mRNA was significantly seen in carcinosarcomas compared to high-grade endometrial carcinomas. Interestingly, in uterine carcinosarcoma, VEGF-A mRNA was more strongly expressed in the carcinoma cells than in the sarcoma cells. In addition, a decrease in the VEGF-A mRNA expression was found in the transitional areas between carcinomatous and sarcomatous elements in most carcinosarcomas evaluated. Moreover, the Ang-2 mRNA expression was significantly seen in the vasculature adjacent to the periphery of the carcinoma cells in most carcinosarcomas, in comparison to that of endometrial carcinomas. CONCLUSIONS: A high angiogenic activity in uterine carcinosarcoma was shown, in comparison to that of endometrial carcinoma. Tumor angiogenesis in uterine carcinosarcoma might be chiefly influenced by VEGF-A in the carcinoma cells, in cooperation with Ang-2 in the surrounding microvessels, however, this is not fully usually the case in sarcoma cells.     

Role of angiopoietins in reproductive tract angiogenesis

Components of the female reproductive system undergo a number of programmed angiogenic processes coupled with cyclic evolution and decline of ovarian, endometrial, and placental structures. The development of a new vascular network requires a remarkable degree of coordination between different cell types undergoing complex changes. This implies that the expression of the inciting angiogenic factors are hormone dependent. Recently, a second family of vascular endothelial growth factors was identified, the angiopoietins. Angiopoietins are vascular endothelial cell-specific growth factors that play important roles principally during the later stages of angiogenesis, after the induction of new capillaries by vascular endothelial growth factor (VEGF). There are four known angiopoietins, and their specificity for the vascular endothelium results from the restricted expression pattern of their tyrosine kinase receptor, Tie2. In this review, we discuss the molecular characterization and mechanism of action of angiopoietin-1 and angiopoietin-2 in reproductive tract angiogenesis. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader will be able to describe the angiogenic process and specifically explain the role of angiopoietics in reproductive tract angiogenesis and compare the differences between the various proteins that are involved in angiogenesis.     

Role of vascular endothelial growth factor in ovarian physiology and pathology

OBJECTIVE: To review the current literature on the role of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in ovarian physiology and pathology. DESIGN: A computerized search was conducted to identify relevant in vitro and in vivo studies published in English. MEDLINE, Current Contents, and the Index Medicus were searched for studies published before January 2000. RESULT(S): VEGF/VPF is an angiogenic factor and a potent mitogen for vascular endothelium. During reproductive life, VEGF/VPF plays a role in the cyclic growth of ovarian follicles and corpus luteum development and maintenance, mediating ovarian angiogenesis. VEGF/VPF expression and secretion are induced by both FSH and LH/hCG receptor-activated pathways. CONCLUSION(S): VEGF/VPF expression and production within the ovary are critical for normal reproductive function. Defects in angiogenesis may contribute to a variety of disorders including anovulation and infertility, pregnancy loss, ovarian hyperstimulation syndrome, and ovarian neoplasms.     

Vascular morphogenesis in the ovary.

Vascular morphogenesis through mechanisms of vasculogenesis, angiogenesis and intussusception is associated primarily with embryonic and fetal development and is down-regulated in the healthy adult. Physiological angiogenesis in the adult is restricted to the female reproductive system where it occurs cyclically in the ovary and the uterus as well as pregnancy-associated in the placenta and in the mammary gland. Of all the different organs, the cyclic corpus luteum of the ovary is the organ site with the strongest physiological angiogenesis. The hormonally regulated cyclic processes in the corpus luteum are characterized by discrete phases of blood vessel growth, vessel maturation and vessel regression. This chapter discusses the morphological changes of the vasculature in the cyclic corpus luteum in relation to the regulating molecular mechanisms. These data establish the dynamic processes in the ovarian corpus luteum as a unique system for studying all steps of the angiogenic cascade, including vessel maturation and vessel regression. Inhibition of angiogenesis impairs the normal ovarian cycle, reflecting that angiogenesis is rate-limiting for ovulation and growth of the corpus luteum and may, thus, be a potential target for therapeutic intervention in the reproductive function.     

Angiogenesis in the female reproductive processes

Angiogenesis or the formation of new vessels out of pre-existing capillaries is a sequence of events that is fundamental to physiology of the female reproductive tract and also pathologic processes such as ovarian hyperstimulation syndrome. Many factors include vascular endothelial growth factor (VEGF), angiopoietins and others involved in the regulation of angiogenesis have been identified. There are some endocrine control mechanisms, which stimulate or inhibit the angiogenesis. The studies indicate that the normal processes of folliculogenesis, ovulation and corpus luteum function in the ovary and the control of menstruation and implantation in the endometrium are profoundly dependent on the angiogenesis. The rapid, controlled and cyclical nature of angiogenesis in the female reproductive tract suggests that interference with this process should provide a novel approach to manipulation of reproductive function.     

Expression of the vascular endothelial growth factors B and C and their receptors in human endometrium during the menstrual cycle

BACKGROUND: Endometrial angiogenesis is important for bleeding control and fertility, and is believed to be regulated by angiogenic growth factors under the influence of ovarian steroids. OBJECTIVE: To document the pattern of expression of the two angiogenic growth factors, vascular endothelial growth factor (VEGF)-B and VEGF-C, and of their receptors, VEGFR-1, VEGFR-2, and VEGFR-3, in order to investigate their possible role in the regulation of angiogenesis in normal cycling human endometrium. MATERIAL AND METHODS: Cryosections of endometrial biopsy specimens obtained from 17 healthy women before laparoscopic sterilization were examined by immunohistochemistry. RESULTS: Vascular endothelial growth factor and VEGF-C and their receptors were all expressed in and around endometrial blood vessels, with no obvious menstrual cycle-dependent changes in expression except for VEGFR-2, which showed stronger expression during the early secretary phase. Stromal blood vessel density did not change significantly during the menstrual cycle. CONCLUSION: The presence and pattern of expression of these angiogenic growth factors and their receptors suggest that they participate in the regulation of normal endometrial angiogenesis.     

Glucose metabolism and angiogenesis in granulosa cell tumors of the ovary: activation of Akt, expression of M2PK, TKTL1 and VEGF

OBJECTIVES: Very little is known about the biology of granulosa cell tumors of the ovary. A hallmark of granulosa cell tumors of the ovary is extensive growth, distant metastases however, are rarely found. We hypothesise that granulosa cell tumors of the ovary on the one hand need to stimulate vascularisation; on the other hand glucose metabolism has to be altered to ensure the supply of nutrients and metabolites. Increased glycolysis, the main source of energy supply, is considered to be important during malignant transformation. Thus, we focussed on a selection of key factors in angiogenesis and tumor glycolysis to study metabolic characteristics of granulosa cell tumors of the ovary. STUDY DESIGN: We analysed 32 tumor specimens for immunohistochemical expression of vascular endothelial growth factor, phosphorylated Akt, M2 pyruvate kinase isoenzyme, and transketolase-like enzyme 1. As controls, we stained 10 samples of normal ovaries. RESULTS: We found expression of vascular endothelial growth factor in 94%, transketolase-like enzyme 1 in 81%, and phosphorylated Akt as well as M2 pyruvate kinase isoenzyme in 53% of the specimens. There were no significant differences between the expression levels in primary and those in recurrent tumors. Temporal analysis of marker expression in primary tumors and recurrences in the same patients revealed no increase or decrease of marker expression overtime. In contrast to granulosa cell tumors, normal ovaries showed no expression of the markers analysed in granulosa cells. CONCLUSION: Our results show that granulosa cell tumors of the ovary express vascular endothelial growth factor as an important stimulator of tumor angiogenesis as well as several molecular markers for glycolysis. The dependence of granulosa cell tumors of the ovary on the glycolytic pathway may provide a biochemical basis for therapeutic strategies involving glycolytic inhibitors.     

Clinical response, vascular change, and angiogenesis in gonadotropin-releasing hormone analogue-treated women with uterine myomas

OBJECTIVE: Basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) are involved in the pathogenesis of leiomyomas and influence angiogenesis, which is necessary for growth of leiomyomas. Gonadotropin-releasing hormone analogue (GnRH-a) treatment might modify the growth factor expression and the blood supply in myomas. We investigated the effects of GnRH-a treatment on some clinical parameters, on the immunohistochemical expression of bFGF, VEGF, and PDGF, and on the vasculature of leiomyomas. METHODS: Thirty-one women were treated with leuprolide acetate for 3 months; 55 untreated patients formed the control group. Hematologic parameters were assessed at the admission, after GnRH-a treatment, and after surgery. Uterine volume was evaluated by ultrasonography. The immunoexpression of bFGF, VEGF, and PDGF and of the endothelial markers CD34 and CD105, as well as the vascular pattern, were studied in leiomyomas, comparing treated and untreated patients. RESULTS: Hematologic parameters improved and uterine volumes decreased after GnRH-a treatment. The immunoexpression of bFGF, VEGF, and PDGF decreased in treated myomas, together with the total number of vessels and the angiogenetic vessels. CONCLUSION: This study confirms the clinical response of uterine shrinkage after GnRH-a treatment. A pathogenetic role of bFGF, VEGF, and PDGF in myoma growth and vascularization is suggested. Finally, this study indirectly confirms the importance of the vasculature in leiomyoma growth.     

Clinical implications of disturbances of uterine vascular morphology and function

Menstrual disturbances are one of the most common problems presenting to the gynaecologist. In order for the endometrium to bleed, vessels must break down. Disruption in the regulation of endometrial vascular growth and function has been found in association with spontaneous and sex steroid-induced disturbances of menstrual bleeding. Although circulating oestrogens and progestogens influence the endometrial vessels, this effect appears to be indirect, and regulation is primarily via local factors. Deficient vasoconstriction and haemostasis with excessive fibrinolysis is seen in menorrhagia. Breakthrough bleeding in users of progestogen-only contraceptives is associated with increased superficial vascular fragility and disruptions in the supporting basement membrane. Blood vessels in uterine fibroids are abnormal in distribution and appearance. Adenomyosis is also commonly associated with menstrual disturbance, and alterations in vascular distribution suggest altered angiogenesis. Successful human embryo implantation requires endometrial vascular breakdown. Excessive thrombosis associated with the antiphospholipid syndrome may interfere with this re-modelling and compromise implantation. Arteriovenous malformations are a rare but important cause of excessive or irregular vaginal bleeding. Abundant vessels with abnormal morphology, associated with aberrant angiogenesis can be seen, and embolization of these vessels may be an effective conservative treatment. Improved understanding of the regulation of the uterine vasculature is likely to lead to targeted therapies to prevent unscheduled vascular breakdown and to control menstrual disturbance at an endometrial level.     

Radiation damage to the uterus — Review of the effects of treatment of childhood cancer

At the present time approximately 1 in 1000 young people aged between 16 and 35 years will have been cured of cancer in childhood and some of the treatment regimens used will have predictable effects on their future fertility prospects. In young women who have been exposed to radiotherapy below the diaphragm, the reproductive problems include the risk of ovarian failure and significantly impaired development of the uterus. The magnitude of the risk is related to the radiation field, total dose and fractionation schedule. Premature labour and low birth weight infants have been reported after flank abdominal radiotherapy. Female long-term survivors treated with total body irradiation and marrow transplantation are also at risk of ovarian follicular depletion and impaired uterine growth and blood flow, and of early pregnancy loss and premature labour if pregnancy is achieved. Despite standard oestrogen replacement, the uterus of these young girls is often reduced to 40% of normal adult size. Uterine volume correlates with the age at which radiation was received. Regrettably, it is likely that radiation damage to the uterine musculature and vasculature adversely affects prospects for pregnancy in these women. It has been demonstrated that, in women treated with total body irradiation, sex steroid replacement in physiological doses significantly increases uterine volume and endometrial thickness, as well as re-establishing uterine blood flow. However, it is not known whether standard regimens of oestrogen replacement therapy are sufficient to facilitate uterine growth in adolescent women treated with total body irradiation in childhood. Even if the uterus is able to respond to exogenous sex steroid stimulation, and appropriate assisted reproductive technologies are available, a successful pregnancy outcome is by no means ensured. The uterine factor remains a concern and women who are survivors of childhood cancer and their carers must recognize that these pregnancies will be at high risk.     

Radiation damage to the uterus -- review of the effects of treatment of childhood cancer

At the present time approximately 1 in 1000 young people aged between 16 and 35 years will have been cured of cancer in childhood and some of the treatment regimens used will have predictable effects on their future fertility prospects. In young women who have been exposed to radiotherapy below the diaphragm, the reproductive problems include the risk of ovarian failure and significantly impaired development of the uterus. The magnitude of the risk is related to the radiation field, total dose and fractionation schedule. Premature labour and low birth weight infants have been reported after flank abdominal radiotherapy. Female long-term survivors treated with total body irradiation and marrow transplantation are also at risk of ovarian follicular depletion and impaired uterine growth and blood flow, and of early pregnancy loss and premature labour if pregnancy is achieved. Despite standard oestrogen replacement, the uterus of these young girls is often reduced to 40% of normal adult size. Uterine volume correlates with the age at which radiation was received. Regrettably, it is likely that radiation damage to the uterine musculature and vasculature adversely affects prospects for pregnancy in these women. It has been demonstrated that, in women treated with total body irradiation, sex steroid replacement in physiological doses significantly increases uterine volume and endometrial thickness, as well as re-establishing uterine blood flow. However, it is not known whether standard regimens of oestrogen replacement therapy are sufficient to facilitate uterine growth in adolescent women treated with total body irradiation in childhood. Even if the uterus is able to respond to exogenous sex steroid stimulation, and appropriate assisted reproductive technologies are available, a successful pregnancy outcome is by no means ensured. The uterine factor remains a concern and women who are survivors of childhood cancer and their carers must recognize that these pregnancies will be at high risk.     

The effect of uterine fibroids on embryo implantation

Uterine fibroids are common but their role in infertility and effect on embryo implantation is unclear. There is evidence that submucosal fibroids are associated with poor reproductive outcome and that treatment with myomectomy is associated with an improvement in pregnancy rates. Various theories have been proposed to explain this relationship. Fibroids cause a mechanical distortion of the endometrial cavity-their presence may alter gamete and embryo transport (due to blockage of the tubal ostia or by altering uterine contractility and peristalsis) and subsequent embryo implantation (due to compression of the endometrium). They may lead to disruption of the junctional zone within the myometrial layer, affecting general uterine function in the initial stages of embryo invasion and later placentation. Altered vasculature due to the abnormal expression of angiogenic factors by uterine fibroids (such as basic fibroblast growth factor and platelet-derived growth factor) could play a role in a reduced implantation rate in patients with fibroids. Similarly, changes in the endometrium mediated by inflammation and factors involved in the process of fibrosis (such as transforming growth factor) could also have a detrimental effect. In addition, fibroids may affect gene expression pattern in the endometrium (such as HOXA10), disrupting the window of implantation. The supporting evidence for these theories is discussed in this review.     

富半胱氨酸61与妇科肿瘤

富半胱氨酸61（Cyr61）是结缔组织生长因子（CCN）家族中具有代表性的成员,其富含半胱氨酸残基的分泌性肝素连接蛋白具有多模组结构。具有诱导血管生成,促进细胞黏附、转移及诱导多药耐药形成等效用,在子宫内膜癌、宫颈癌、卵巢癌、子宫肌瘤及子宫内膜异位症的发生发展中起重要作用。     

The role of prostaglandin E2 in endometriosis

Endometriosis is a leading cause of infertility in women of reproductive age. It involves the occurrence of endometrial tissue outside the uterine endometrium, mainly in the peritoneal cavity. Prostaglandin E(2) is up regulated in the peritoneal cavity in endometriosis and is produced by macrophages and ectopic endometrial cells. This prostaglandin is involved in the pathophysiology of the disease and elicits cell signals via four receptor types. Prostaglandin E(2) increases estrogen synthesis by up regulating steroidogenic acute regulatory protein (StAR) and aromatase. It inhibits apoptosis and up regulates fibroblast growth factor-9 (FGF-9) promoting cell proliferation. Prostaglandin E(2) affects leukocyte populations and promotes angiogenesis through its effect on estrogen and up regulation of vascular endothelial growth factor (VEGF). Dienogest is a synthetic progestin targeting expression of genes involved in prostaglandin synthesis.     

经宫颈子宫内膜电切术后微血管密度、血管内皮因子及其受体表达变化的研究

目的 研究微血管密度(microvessel density,MVD)、血管内皮生长因子(vascular endothelial growth factor,VEGF)及其受体(vascular endothelial growth factor receptor,KDR)在单纯增生、腺肌病患者经宫颈子宫内膜电切手术(transcervical resection of endometrium,TCRE)前后表达的变化，探讨子宫内膜电切手术治疗子宫异常出血的分子学机制。方法 功能失调性子宫出血患者诊刮病理为单纯增生内膜，于刮宫后12～15d行电切手术，取电切内膜标本10例、子宫腺肌病增殖中晚期的患者电切子宫内膜10例为术前实验组；功血患者于TCRE术后6～18个月取内膜8例、子宫腺肌病患者于TCRE术后6～18个月取内膜7例为术后实验组；正常对照选取增殖中晚期子宫内膜8例为对照组。采用免疫组织化学LSAB法检测组织中MVD、VEGF及其受体KDR的表达，并抗第八因子相关抗原抗体标记间质微血管并进行微血管计数、以计算机图像分析获得VEGF、KDR值。结果 单纯增生及腺肌病之子宫内膜其MVD、VEGF及KDR的表达在TCRE术前与正常对照组和术后的表达比较差异均有显著性；单纯增生和腺肌病TCRE术后的子宫内膜MVD、VEGF及KDR的表达与正常对照组比较差异无显著性。单纯增生与腺肌病之子宫内膜MVD、VEGF及KDR表达比较无明显统计学意义，但腺肌病子宫内膜MVD、VEGF及KDR的均值比单纯增生高。结论 子宫内膜电切术对子宫内膜MVD、VEGF及KDR的表达起降调节，为子宫内膜电切术治疗子宫异常出血提供理论依据。对于腺肌症患者术后辅以抗血管药物可能有助于抑制复发。     

VEGF concentration in peritoneal fluid of patients with endometriosis

The theory of Sampson that endometrial cells and fragments desquamated during the menstrual period are transported through fallopian tubes into the peritoneal cavity where they implant, proliferate and develop into endometriotic lesions is generally accepted. There is increasing evidence that immunological mechanisms play a role in the pathogenesis and pathophysiology of endometriosis. Excessive endometrial angiogenesis is proposed as an important mechanism in the pathogenesis of endometriosis. Evidence is reviewed for the hypothesis that the endometrium of women with endometriosis has an increased capacity to proliferate, implant and grow in the peritoneal cavity. From the known angiogenic factors, vascular endothelial growth factor (VEGF) has emerged as a pivotally important regulator of normal angiogenesis and pathological neovascularization. In present study we evaluated the concentrations of VEGF in peritoneal fluid of patients with endometriosis and showed no correlation between AFS score and VEGF concentration in peritoneal and in ovarian endometriosis. Above results do not confirm former observations indicating the role of VEGF in endometriosis pathogenesis.     

Paracrine/autocrine control of female reproduction.

Neuropeptides, growth factors and cytokines are expressed in reproductive organs and tissues, where they interact with afferent endocrine messages to modulate cell proliferation and differentiation, local hormone secretion and vascular function. These events regulate complex processes such as gonadotropin pulsatility, ovulation, implantation and parturition. During reproductive life, a number of neuropeptides produced within the hypothalamus play a modulatory role in the control of gonadotropin-releasing hormone (GnRH) release, hence characterizing a hypothalamic paracrine system. The pituitary gland is a source and target of inhibin-related proteins, and these typical 'gonadal' products, once secreted by the pituitary cells, acquire the function of paracrine modulators of follicle-stimulating hormone (FSH) secretion. In the ovary, the effect of gonadotropins is locally modulated by growth factors acting in an autocrine/paracrine manner, although their precise role in folliculogenesis remains uncertain. Numerous local factors are involved in the control of endometrial growth, differentiation, receptivity and menstruation. Alterations in the paracrine endometrial system may underlie pathological processes such as infertility or endometrial neoplasia. The human placenta and its related membranes produce cytokines, hormones and growth factors that participate in the control of gestational development as well as in the maternal-fetal adaptation to gestational diseases. There is increasing evidence that paracrine signaling plays a fundamental role in all spheres of female reproductive function, and future research will concentrate on clarifying which of these local mechanisms play a decisive role in both physiology and disease, thus giving rise to new therapeutic strategies.     

Localization of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2 in bovine placentomes from implantation until term

Interactions of vascular endothelial growth factor (VEGF) with its receptors VEGFR-1 and VEGFR-2 promoting angiogenesis have been described in placentation of human, mink and pig. The bovine placenta is multiplex, villous and synepitheliochorial due to migratory trophoblast giant cells (TGC). To determine the role of VEGF in bovine implantation and placentation, placentomes and interplacentomal areas from 33 cows from early implantation until near term were evaluated by immunohistochemistry. VEGF immunoreactivity was detected in fetal and maternal blood vessel tissues during implantation and throughout gestation, and in preimplantatory trophoblast cells and uterine epithelium. After implantation the immunoreaction was confined to TGC and uterine epithelium. An antibody against bovine VEGF revealed a strong reactivity in the stroma of maternal caruncular septa in early and mid-gestation, which distinctly decreased near term. In interplacentomal areas, VEGF was found in luminal and glandular epithelia as well as in trophoblast, with distinctly higher reactivity in giant cells. VEGFR-1 was observed in trophoblast and uterine epithelium around implantation. Later, in definite placentomes, VEGFR-1 was localized in TGC near the chorionic plate and in maternal endothelial cells in the center of the placentome. VEGFR-1 and VEGFR-2 were co-localized in uterine epithelium and trophoblast as well as in blood vessel tissue and uterine glands. The presence of VEGF, VEGFR-1 and VEGFR-2 at the feto-maternal interface and in vasculature indicates that in the bovine VEGF may have (1) classic functions in angiogenesis and vascular permeability, (2) growth factor properties, facilitating feto-maternal exchange via paracrine action, (3) chemotactic activity on capillary endothelium, and (4) an autocrine influence on TGC migratory activity.     

Angiogenesis in ovarian follicular and luteal development

Angiogenesis is the process of new capillary formation from previously existing mature vessels. The adult ovary exhibits dramatic growth and regression of capillary networks on a cyclic basis. Ovarian follicles and the corpus luteum contain and produce endothelial cell-specific factors, which may act alone or in concert to regulate the process of angiogenesis. These factors are ultimately controlled by endocrine, paracrine and autocrine regulation, as well as by metabolic cellular signals such as intracellular oxygen content and ageing. Aberrant production of these angiogenic factors may be the cause of vascular dysfunction and the development of ovarian disorders. Recent technological advances for monitoring blood flow and measuring angiogenic factors could assist in accurately diagnosing ovarian disorders. Further elucidation of specific physiological role(s) of factors involved in angiogenesis of the pre-ovulatory follicle and developing corpus luteum may be useful in addressing issues of infertility in women.