Research Progress of Angiogenin in Reproduction Review Article

ISSN: 2637-4617

Review Article Current Opinion in Gynecology and Obstetrics Research Progress of Angiogenin in Reproduction

Xiaotao H1, Yunxia W2,*

1Department of Integrative Traditional Chinese Medicine and Western Medicine, Affiliated Women and Children’s Hospital of Hubei Province, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China 2Department of Pharmacology, Pharmacy School of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China

*Correspondence: Wu Yunxia, Department of Pharmacology, Pharmacy School of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China, E-mail: [email protected]

Received: November 16, 2018; Accepted: January 31, 2019; Published: February 05, 2019

Abstract

Angiogenin (ANG) was previously proved one of the potent proangiogenic factors in the process of formation, remodeling and maturation of new blood vessel, then was found playing a dual role in tumor growth by promoting both tumor angiogenesis and cancerous cell proliferation and promoting neuron neurite growth, recently it has been proved an important regulator in stem cell regeneration and stemness maintenance by affecting nucleic acid hydrolysis and protein synthesis. Here we review the related research about ANG in reproduction. ANG was detected in different levels of follicle except in primordial stage in bovine and human and reveals that it may play role in follicle development and mature. During pregnancy, large amount of ANG dramatically expressed in maternal, amniotic fluid or fetal placenta, it may play a role in embryo implantation, the growth and development of fetus. The occurrence of reproduction related diseases such as infertility, endometriosis, ovarian hyperstimulation syndrome, gestational hypertension, fetal growth retardation and etc seems related with ANG. However, detailed research on the mechanism of ANG in related diseases is lack. Therefore, the further study about the role of ANG is of great significance for the understanding ANG function and may bring promising treatment of fertility, reproduction related diseases.

Keywords: Angiogenin, Reproduction Introduction in specific time and space, suggesting ANG may involve in follicle development, menstruation, embryo Angiogenin (ANG) is one of the most potent angiogenic implantation, placental development and fetal growth proteins, and also belongs to the ribonuclease family and and development. Women with reproduction related named as RNAse 5, it was firstly found playing a central diseases were found abnormal expression of ANG in role in the formation, reshape and mature of new blood serum or plasma comparing with normal healthy women, vessels [1], then found closely related to the formation, but all the mechanisms are not clear yet. Here we review development and metastasis of tumor, neuro growth the progress of ANG in reproduction. and development and most recently ANG was found also a stem cell regulator in promoting hematopoietic Molecular biology characteristics of ANG regeneration by dichotomously regulating quiescence ANG, one of the most potent protein with strongly of stem and progenitor cells. ANG participates in a promoting angiogenesis activity was firstly isolated from variety of physiological and pathological process [2,3]. colonic carcinoma medium in Harvard medical school It has been reported the expression of ANG in follicle, by Vallee BL in 1985 [1]. ANG, composed of 123 amino endometrial matrix, amniotic fluid and fetal placenta acid residues, a single alkaline secreted protein, also Cur Op Gyn Obs, 2(1): 161-166 (2019) 167 belongs to ribonuclease (RNase) family, named RNase5, and after mature oocytes fertilization. Therefore ANG its genes located on chromosome 14 and shared same may has no direct relation with the oocyte fertilization promoter with RNase4, its stability is very good. Although but related with follicle development and mature [20]. has lower RNase activity, but its nucleic acid hydrolase activity is necessary for its promoting angiogenesis ANG in menstrual cycle: In the female menstrual activity. Structure analysis found that ANG protein crystal physiological cycles, the growth of blood vessels is has three main structure domains: cell surface receptor necessary for endometrium thickening [21]. It was binding sites, RNase activity centre, nuclear sequence of found that the concentration of serum ANG increased regulating the ribosomal RNA synthesis [4-10]. ANG plays significantly 2-3 days after the peak luteinizing hormone dual role in the development of the cancer, it can both secretion in women with normal menstrual cycle [22], promote tumor angiogenesis and promote cancer cells therefore ANG may play a role in the later stage of proliferation [11-13]. ANG also exists in normal human menstrual cycle after ovulation. Keiji [23] found that the tissues and body fluids, such as serum, amniotic fluid, levels of serum ANG was not significantly different in follicle fluid and etc. Accumulated 30 years of research, the normal menstrual cycle of unfertilized female with people gradually realize ANG plays very important role normal blood pressure. Therefore, whether or not ANG in many physiological and pathology conditions such as changes in various stages during the menstrual cycle wound healing, menstrual period, pregnancy, follicle and needs further examination in more samples. embryonic development, nerve cells survive and growth, immunology, stress, defensive even stem cell regulating ANG in embryo implantation, placenta aspects and etc. [14-18]. formation and embryonic development: ANG was expressed in endometrial cavity or glandular epithelium ANG in physiology of reproduction and mesenchymal cells, and time-space expressed in ANG in follicle: Follicle dysplasia or ovulation different trophoblast cells in decidual tissue during dysfunction will affect menstruation and pregnancy, and implantation. ANG expression increased significantly in then lead to infertility. Follicle development is related decidua in the endometrium at middle-late secretion, to angiogenesis and many vascular growth factors. and ANG can stimulate the proliferation of endothelial ANG strongly promotes the angiogenesis, therefore, it cells and vascular smooth muscle from decidua, so ANG might involve in the development of follicles. Heungshik may involve in embryo implantation, placenta formation [19] found ANG mRNA expression existed in bovine and embryonic development [24-27]. In addition, Hayashi ovaries, not in the primordial follicle but in primary [28] found that during 7 to 15 weeks of pregnancy, the follicles, secondary, tertiary and Musharraf’s follicles; levels of serum ANG kept decreasing, but after 15 weeks, Mature follicles and granular layer cells expressed ANG the levels of serum ANG kept rising, so ANG may relate very strongly; but atresic follicles had only weak ANG to the whole process of pregnancy including embryo expression in follicle epithelial cells, not inside or outside implantation, placenta formation and embryonic of the follicle membranes; also ANG expression changed development. in different levels of the follicle development. Kaori Kago ANG in pathology of reproduction [15] firstly found ANG expressed in ovariesin women undergoing in vitro fertilization (IVF), Protein Imprinting ANG and infertility: The incidence of infertility and RT-PCR technology were used in detection of ANG, is increasing in recent years, the etiology is complex, ANG was found in follicle fluid, granulosa cells and including follicle developing and ovulation, fallopian tubal granular cell culture media, and ANG concentration was and endometrial factors, etc. ANG was found expressed affected by human chorionic gonadotropin (HCG), cycline in the endometrium and might play important role in adenosine phosphate and low oxygen environment promoting the growth and development of endometrium, regulation. Women undergoing IVF, ANG concentration and ANG was also found expressed in ovary and in follicle fluid in mature follicles was significantly higher might regulate follicle developing and maturing, ANG than that in immature follicles, but vascular endothelial secretion abnormal will affect all these progress and growth factor (VEGF) and basic fibroblast growth factor cause infertility [20]. Studies confirmed that the serum (bFGF) did not show significant difference. In addition, angiogenin mRNA level in endometrial proliferation they found that ANG was unique angiogenesis factor phase of infertility patients with endometriosis increased with positively related to the maturity of follicles, ANG significantly compared with healthy women [29]. ANG not concentration was not found significant change before only existed in woman genital duct but also distributed in

Cur Op Gyn Obs, 2(1): 161-166 (2019) 168 mens’ testicles, it had been confirmed ANG distributed important regulatory factors. It was found that ANG levels in peritubular myoid cells by using immunohistochemical in serum of pregnant women with preeclampsia changed and in situ hybridization technology, ANG may play an significantly, ANG levels of mild and severe preeclampsia important role in male reproductive cells by regulating patients are significantly higher than normal pregnant the formation and transportation of sperm cells [30]. women, at last, increased ANG expression in placenta may also lead to low birth weight. Although still unclear ANG and OHSS: Original aim of ovarian stimulation is increased maternal serum ANG is a cause or a result to use hormone to promote ovulation, but due to the high of maternal blood pressure increasing, but inhibition ovarian response, it usually will produce a large number maternal serum ANG may be a way for the treatment of of vascular active substances and steroid hormone, pregnancy-induced hypertension [36-39]. increase the permeability of blood vessel walls, triggering a series symptoms such as edma and pleuroperitoneal ANG and fetal growth restriction (FGR): FGR fluids of harmful, serious and sometimes can be life- is also called the intrauterine growth restriction (IUGR), threatening, that is ovarian hyperstimulation syndrome refers to the abnormal fetal size in the uterine not (OHSS). The exact pathogenesis is not clear at present. reaching their genetic growth potential. The clinical But it was found that the ANG levels in serum and ascites diagnosis is difficult due to the complexity of etiology, of patients with OHSS significantly higher than that in it is not only a threat to the health of the fetus during normal healthy women, and high concentration of ANG pregnancy, also increases the incidence of various strongly related with increased vascular permeability diseases after childbirth. In most cases, the main reason is [31]. Miro also speculated ANG might be the key factor abnormal placentation development, lacking of nutrients of OHSS, it likely promoted the development of OHSS and oxygen supply, leading to fetal growth slowdown. combining with other angiogenic factors [32,33], but the It was showed ANG levels in placenta of patients with mechanism of ANG in the pathogenesis of OHSS is still IUGR increased significantly, almost 2 folds higherthan not very clear, needs further research. in normal placenta [40,41]. Therefore, ANG might relate with FGR. ANG and endometriosis: Incidence of endometriosis in women of childbearing age to be as high as 10% ~ 15%, ANG and preterm birth: The organ development the main symptoms is pain and infertility. Endometriosis of premature newborns is generally imperfect, so has seriously impact on women’s health because it is the survival rate is low, and is one of the causes of difficult to heal and easy to relapse. It was found that neonatal death. Now it is not clear for the etiology and ANG levels in serum of patients with endometriosis pathogenesis of preterm birth, may relate with gestational were significantly higher than that of healthy people in hypertension disease, twin pregnancy, placental injury. the follicle phase, but in the luteal phase had no obvious Studies have shown that ANG levels in amniotic fluid of differences [34]. Nobuhiro also found ANG concentration patients with preterm birth increased significantly in the in peritoneal fluidin patients with endometriosis on middle of a pregnancy, so it was suggested according to proliferation and secretion increased compared with that ANG levels in the amniotic fluid in mid gestationto predict of healthy people, but no obvious difference between the the occurrence of premature birth, and found 31 ng/ml secretion and proliferation, however, as the illness grew is the best ANG critical value to predict pretern birth [42- worse, ANG level in the peritoneal fluid increased more 44]. But Dongdong Yu suggests ANG has the potential of [35]. being a serum biomarker for cancers and cardiovascular diseases, not in other diseases [45]. ANG and gestational hypertension: Gestational hypertension is related with pregnancy, including Conclusion gestational hypertension, preeclampsia and eclampsia. To sum up, in physiological condition, ANG may play They affect maternal and child health seriously.The role in follicle development and menstrual cycle, and occurrence may be related to over erosion, placental may also play important role in embryo implantation, trophoblastic cells ischemia hypoxia, cell apoptosis, the growth and development of fetus during pregnancy metabolic or angiogenesis disorder and so on. Of them, because large of ANG dramaticly expresses in maternal, angiogenesis regulation disorder is one of the important amniotic fluid or fetal placenta. In pathological condition, mechanisms of the disease, many factors involved in the occurrence of reproduction related diseases such as regulating angiogenesis, but ANG may be one of the most infertility, endometriosis, OHSS, gestational hypertension, Cur Op Gyn Obs, 2(1): 161-166 (2019) 169 FGR and etc seems closely related with ANG. However, 9. Shapiro R, Vallee BL. 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