Angiotensin I or II is formed from a precursor angiotensinogen which is produced by the liver and found in the alpha-globulin fraction of plasma. Renin secreted by the kidney cleaves from angiotensinogen a terminal decapeptide, angiotensin I. This is further altered by the enzymatic removal of a dipeptide to form angiotensin II. Ohkubo et al. (1983) determined the sequence of the cloned rat angiotensinogen gene. The human angiotensinogen molecule has a molecular weight of about 50,000 Da. The angiotensin I decapeptide is located in its N-terminal part.
NCBI Summary:
The protein encoded by this gene, pre-angiotensinogen or angiotensinogen precursor, is expressed in the liver and is cleaved by the enzyme renin in response to lowered blood pressure. The resulting product, angiotensin I, is then cleaved by angiotensin converting enzyme (ACE) to generate the physiologically active enzyme angiotensin II. The protein is involved in maintaining blood pressure, body fluid and electrolyte homeostasis, and in the pathogenesis of essential hypertension and preeclampsia. Mutations in this gene are associated with susceptibility to essential hypertension, and can cause renal tubular dysgenesis, a severe disorder of renal tubular development. Defects in this gene have also been associated with non-familial structural atrial fibrillation, and inflammatory bowel disease. [provided by RefSeq, Nov 2019]
General function
Ligand, Hormone, Cell death/survival, Apoptosis
Comment
Mukhopadhyay et al. (1996) proposed that in the presence of healthy granulosa cells, suppression of the ovarian prorenin-renin-angiotensin system (PRAS) by granulosa cell derived factors may prevent a follicle from undergoing atresia, whereas in the presence of atretic granulosa cells, theca cell derived factors may enhance the expression of the PRAS system, resulting in follicular atresia.
Angiotensin-(1-7) in human follicular fluid correlates with oocyte maturation. Cavallo IK et al. (2017) Do angiotensin (Ang)-(1-7) levels in human ovarian follicular fluid (FF) correlate with the number and proportion of mature oocytes obtained for IVF? The present study shows for the first time that Ang-(1-7) levels in human FF correlate with the proportion of mature oocytes collected upon ovarian stimulation for IVF. Ang-(1-7) is an active peptide of the renin-angiotensin system that stimulates oocyte maturation in isolated rabbit and rat ovaries. However, its role in human ovulation remains unexplored. This was a prospective cohort study including 64 participants from a single IVF center. Sample size was calculated to achieve a statistical power of 80% in detecting 20% differences in the proportion of mature oocytes between groups. The participants were enrolled in the study during six consecutive months. Plasma samples were obtained from all subjects at Day 21 of the last menstrual cycle before starting pituitary blockade and controlled ovarian stimulation (COS). Plasma and FF samples were quickly mixed with a protease inhibitor cocktail and stored at -80°C. Ang-(1-7) was quantified in plasma and FF samples by a highly sensitive and specific radioimmunoassay, which was preceded by solid phase extraction, speed vacuum concentration and sample reconstitution in assay buffer. FF Ang-(1-7) levels were stratified into tertiles and the patients of each tertile were compared for COS/IVF outcomes using Kruskal-Wallis ANOVA. Multiple regression analysis was used to adjust correlations for potential confounders. The mRNA encoding for Mas, a receptor for Ang-(1-7), was investigated by real-time PCR in luteinized granulosa cells purified from the FF. There was a four-fold increase in plasma Ang-(1-7) after ovulation induction (median 160.9 vs 41.4 pg/ml, P < 0.0001). FF Ang-(1-7) levels were similar to (169.9 pg/ml) but did not correlate with plasma Ang-(1-7) levels (r = -0.05, P = 0.665). Patients at the highest FF Ang-(1-7) tertile had a higher proportion of mature oocytes compared to patients at the lower FF Ang-(1-7) tertile (median 100% vs 70%, P < 0.01). There was a linear correlation between FF Ang-(1-7) and the proportion of mature oocytes (r = 0.380, P < 0.01), which remained significant after adjustment for age and duration of infertility (r = 0.447, P < 0.001). The luteinized granulosa cells expressed Mas receptor mRNA, which was positively correlated to the number of mature oocytes in women with more than three mature oocytes retrieved (r = 0.42, P < 0.01). This is an observational study, therefore, no causal relationship can be established between Ang-(1-7) and human oocyte maturation. Mas protein expression was not quantified due to limited availability of granulosa cells. Since this peptide promotes oocyte maturation in other species, it deserves further investigation as a potential maturation factor to human oocytes. Research supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG). The authors have nothing to disclose.//////////////////
In vivo imaging reveals an essential role of vasoconstriction in rupture of the ovarian follicle at ovulation. Migone FF et al. (2016) Rupture of the ovarian follicle releases the oocyte at ovulation, a timed event that is critical for fertilization. It is not understood how the protease activity required for rupture is directed with precise timing and localization to the outer surface, or apex, of the follicle. We hypothesized that vasoconstriction at the apex is essential for rupture. The diameter and blood flow of individual vessels and the thickness of the apical follicle wall were examined over time to expected ovulation using intravital multiphoton microscopy. Vasoconstriction of apical vessels occurred within hours preceding follicle rupture in wild-type mice, but vasoconstriction and rupture were absent in Amhr2(cre/+)SmoM2 mice in which follicle vessels lack the normal association with vascular smooth muscle. Vasoconstriction is not simply a response to reduced thickness of the follicle wall; vasoconstriction persisted in wild-type mice when thinning of the follicle wall was prevented by infusion of protease inhibitors into the ovarian bursa. Ovulation was inhibited by preventing the periovulatory rise in the expression of the vasoconstrictor endothelin 2 by follicle cells of wild-type mice. In these mice, infusion of vasoconstrictors (either endothelin 2 or angiotensin 2) into the bursa restored the vasoconstriction of apical vessels and ovulation. Additionally, infusion of endothelin receptor antagonists into the bursa of wild-type mice prevented vasoconstriction and follicle rupture. Processing tissue to allow imaging at increased depth through the follicle and transabdominal ultrasonography in vivo showed that decreased blood flow is restricted to the apex. These results demonstrate that vasoconstriction at the apex of the follicle is essential for ovulation.//////////////////
Role of angiotensin in ovarian follicular development and ovulation in mammals: a review of recent advances. Gonalves PB et al. Angiotensin (Ang) II is widely known for its role in the control of systemic blood vessels. Moreover, Ang II acts on the vascular control of ovarian function, corpus luteum formation, and luteolysis. Over the past 10 years, our research group has been studying the new concept of the renin-angiotensin system (RAS) as autocrine/paracrine factor regulating steroidogenesis and promoting different cellular responses in the ovary, beyond vascular function. We have developed and used different in vivo and in vitro experimental models to study the role of RAS in the ovary, and a brief overview of our findings is presented here. It is widely accepted that there are marked species difference in RAS function in follicle development. Examples of species-specific functions of the RAS in the ovary include the involvement of Ang II in the regulation of follicle atresia in rats versus the requirement of this peptide for the dominant follicle development and ovulation in rabbits and cattle. More recently, Ang-(1-7), its receptor, and enzymes for its synthesis (ACE2, NEP, and PEP) were identified in bovine follicles, implying that Ang-(1-7) has an ovarian function. Other novel RAS components (e.g. (pro)renin receptor, and renin-binding protein) recently identified in the bovine ovary demonstrate that ovarian RAS is poorly understood and more complex than previously thought. In the present review, we have highlighted the progress towards understanding the paracrine and autocrine control of ovarian antral follicle development and ovulation by ovarian tissue RAS, focusing on in vivo studies using cattle as a model.
Angiotensin II Signaling Promotes Follicle Growth and Dominance in Cattle. Ferreira R et al. It is generally understood that angiotensin II (AngII) promotes follicle atresia in rats, although recent data suggested that this may not be true in cattle. In this study, we aimed to determine in vivo whether AngII alters follicle development in cattle, using intrafollicular injection of AngII or antagonist into the growing dominant follicle or the second largest subordinate follicle. Injection of saralasin, an AngII antagonist, into the growing dominant follicle inhibited follicular growth, and this inhibitory effect was overcome by systemic FSH supplementation. Injection of AngII into the dominant follicle did not affect follicular growth, whereas injection of AngII into the second largest follicle prevented the expected atresia of this subordinate follicle, and the treated follicle grew at the same rate as the dominant follicle for the next 24 h. Inhibition of AngII action in the dominant follicle decreased estradiol concentrations in follicular fluid and the abundance of mRNA encoding aromatase, 3?hydroxysteroid dehydrogenase, LH receptor, and cyclinD2 in granulosa cells, with minimal effects on theca cells. The effect of AngII on aromatase mRNA levels was confirmed using an in vitro granulosa cell culture system. In conclusion, these data suggest that AngII signaling promotes follicle growth in cattle and does so by regulating genes involved in estradiol secretion and granulosa cell proliferation and differentiation.
Evidence that the effect of angiotensin II on bovine oocyte nuclear maturation is mediated by PGE2 and PGF2{alpha} Barreta M et al. Angiotensin II (AngII) prevents the inhibitory effect of follicular cells on oocyte maturation, but its involvement in LH-induced meiotic resumption remains unknown. The aim of this study was to assess the involvement of AngII in LH-induced meiotic resumption and of prostaglandins in the action of AngII. In the first experiment, seven cows were superovulated, intrafollicularly injected with 10 muM of saralasin (a competitive AngII antagonist) or saline when the follicles reached a diameter larger than 12 mm, and challenged with a GnRH agonist to induce an LH surge. Fifteen hours after GnRH, the animals were ovariectomized and the oocytes were recovered to determine the stage of meiosis. The oocytes from follicles that received saline were in germinal vesicle breakdown (30.8%) or metaphase I (MI; 69.2%) stage while those that received saralasin were in the germinal vesicle stage (GV; 100%; P<0.001) 15 hours after GnRH agonist. In another experiment, oocytes were co-cultured with follicular hemisections for 15 hours to determine whether prostaglandins mediate the effect of AngII on meiotic resumption. Indomethacin (10 muM) inhibited AngII-induced meiotic resumption (13.4% MI vs 77.5% MI without indomethacin; P<0.001). Furthermore, the GV oocytes progressed to MI at a similar rate when PGE2, PGF2alpha or AngII was present in the co-culture system with follicular cells (PGE2 77.4%, PGF2alpha 70.0% and AngII 75.0% of MI). In conclusion, our results provide strong evidence that AngII mediates the resumption of meiosis induced by an LH surge in bovine oocytes and that this event is dependent on PGE2 or PGF2alpha produced by follicular cells.
Nemeth et al. (1994) reviewed the evidence for an intrinsic ovarian renin-angiotensin system (OVRAS), highlighting potential diverse signaling in this system through different bioactive angiotensin peptides, their specific receptors, and second messengers. In addition, sites of action for OVRAS in the regulation of ovarian function in health and disease were reviewed. Ovarian tissues contain all the elements for the production of angiotensin, including prorenin/renin, angiotensinogen, and angiotensin-converting enzyme. In addition, angiotensin II is present in ovarian compartments, and receptors for angiotensin II are demonstrated on specific ovarian cells. Angiotensin II is implicated to play a role in ovulation, steroidogenesis, follicular atresia, and hyperandrogenic syndromes. Kotani et al. (1999) reported that angiotensin II suppressed FSH-caused prevention of DNA fragmentation, increases in luteinizing hormone receptor content, and estrogen production through AT2 in cultured granulosa cells. Moreover, FSH-induced stimulation of extracellular signal-regulated kinase activity, critical for cell survival, was inhibited by angiotensin II.Li YH, et al reported the localization of angiotensin II in pig ovary and its effects on oocyte maturation in vitro.
The renin-angiotensin system (RAS) has been found in mammalian ovarian tissue; however, its physiological role is unclear. This study examined the content of angiotensin II (Ang II) in porcine follicular fluid (pFF), Ang II localization and its receptors in ovary, and the effects of Ang II on porcine oocyte maturation. The concentrations of Ang II were 6951.82+/-1295.83, 3502.99+/-679.10, 3147.89+/-690.60, and 2545.92+/-407.01pg/ml in pFF from small, medium, large, and extra-large follicles, respectively. In addition, Ang II was found on zona pellucidae (ZP) and granulosa cells by immunoreactive staining. The distribution of AT(1), an Ang II receptor subtype, was in accordance with that of Ang II. However, AT(2), another Ang II receptor, was mainly distributed in the stroma and thecal layers of follicles. When oocytes were cultured in media containing various concentrations of Ang II, a higher (P<0.05) proportion of oocytes reached metaphase II (MII) in the medium with 100ng/ml (87.0%) than without Ang II (61%). When oocytes from different sizes of follicles were separately cultured in media containing 100ng/ml Ang II, maturation rates were significantly higher in oocytes from small (61.5%) and medium (85.1%) follicles than that of their controls (45.1 and 72.6%, respectively). However, addition of Ang II inhibited nuclear maturation in oocytes from large follicles (77.8% versus 87.3%). Fertilization and male pronuclear (MPN) formation rates of oocytes matured in medium containing 100 or 1000ng/ml of Ang II were higher (P<0.05) than that of oocytes matured in medium containing 0 or 10ng/ml Ang II. Glutathione content in oocytes cultured for 44h in medium containing 100 or 1000ng/ml of Ang II was also higher (P<0.01) than that of oocytes cultured in medium containing 0 or 10ng/ml Ang II. In conclusion, Ang II was present in porcine ovaries and may regulate follicle growth and oocyte maturation.
Localized Accumulation of Angiotensin II and Production of Angiotensin-(1-7) in Rat Luteal Cells, and Effects on Steroidogenesis. Pepperell JR et al. These studies aim to investigate subcellular distribution of angiotensin II (Ang II) in rat luteal cells, identify other bioactive angiotensin peptides, and investigate a role for angiotensin peptides in luteal steroidogenesis. Confocal microscopy showed Ang II distributed within the cytoplasm, and nuclei of luteal cells. HPLC analysis showed peaks that eluted with the same retention times as Ang-(1-7), Ang II and Ang III. Their relative concentrations were: Ang II >/= Ang-(1-7) >> Ang III, and accumulation was modulated by quinapril, an inhibitor of the angiotensin converting enzyme (ACE), Z-proprolinal (ZPP) an inhibitor of prolyl endopeptidase (PEP), and parachloromercurylsulfonic acid (PCMS) a sulfhydryl protease inhibitor. Phenylmethylsulfonyl fluoride (PMSF) a serine protease inhibitor did not affect peptide accumulation. Quinapril, ZPP, PCMS, PMSF, losartan, the angiotensin receptor type 1 (AT1), and PD123319, the AT2, receptor antagonists were used in progesterone production studies. ZPP significantly reduced LH-dependent progesterone production (p < 0.05). Quinapril plus ZPP had a greater inhibitory effect on LH-stimulated progesterone than either inhibitor alone, but this was not reversed by exogenous Ang II or Ang-(1-7). Both PCMS and PMSF acutely blocked LH-stimulated progesterone, and PCMS blocked LH-sensitive cyclic AMP accumulation. Losartan inhibited progesterone production in permeabilized, but not intact luteal cells that was reversed by Ang II. PD123319 had no significant effect on luteal progesterone production in either intact or permeabilized cells. These data suggest that steroidogenesis may be modulated by angiotensin peptides that act in part through intracellular AT1 receptors.
Expression regulated by
Comment
Amilton P. R. Costa et al reported the presence of angiotensin-(1?7) as A Novel Peptide in the Ovary.
The present study was undertaken to investigate the presence of angiotensin-(1?7) [Ang-(1?7)] in the ovary and a possible role for it. Cycling female rats were killed in each phase of the estrous cycle, and ovarian Ang II and Ang-(1?7) were separated by HPLC and measured by RIA. The mean levels of Ang-(1?7) in proestrus and estrus were significantly higher than those in metestrus and diestrus (P < 0.05). Ang-(1?7) was also significantly higher in equine chorionic gonadotropin (eCG)-treated immature rats. Ang-(1?7) induced a significant increase in estradiol and progesterone production (P < 0.05) in the ovary of immature rats (24?25 d old) pretreated with eCG and perfused in a closed circuit system. This effect was blocked by A-779, a specific Ang-(1?7) antagonist (P < 0.05). The present data demonstrate the presence and physiological role of a novel renin-Ang system peptide in the ovary. The higher level of Ang-(1?7) in proestrus and estrus as well as in eCG-treated rats suggests the involvement of this renin-Ang system peptide in pre- and postovulatory events.
Angiotensin-(1-7), its receptor Mas, and the angiotensin-converting enzyme type 2 are expressed in the human ovary. Reis FM et al. OBJECTIVE: To investigate whether angiotensin (Ang)-(1-7), its receptor Mas, and angiotensin-converting enzyme type 2 (ACE2) are present in human ovary. DESIGN: Cross-sectional study. SETTING: Academic hospital. PATIENT(S): Twelve reproductive-age women and five postmenopausal women undergoing oophorectomy for nonovarian diseases and seven women having controlled ovarian hyperstimulation for IVF. INTERVENTION(S): Ovarian tissue was obtained from the reproductive-age women and postmenopausal women undergoing oophorectomy for nonovarian diseases. Follicular fluid (FF) samples were obtained from the women having controlled ovarian hyperstimulation for IVF. MAIN OUTCOME MEASURE(S): Localization of Ang-(1-7) and Mas by immunohistochemistry; measurement of Ang-(1-7) in ovarian FF by RIA; detection of messenger RNAs encoding Mas and ACE2 with use of real-time polymerase chain reaction; assessment of (125)I-labeled Ang-(1-7) binding to ovarian sections with use of autoradiographic binding assay. RESULT(S): Angiotensin-(1-7) and the receptor Mas were localized to primordial, primary, secondary, and antral follicles, stroma, and corpora lutea of reproductive-age ovaries. Postmenopausal women expressed both the peptide and its receptor in the ovarian stroma. Angiotensin-(1-7) was detectable in FF (mean +/- SE: 191 +/- 54 pg/mL). Both Mas and ACE2 messenger RNAs were expressed in ovarian tissue, as revealed by real-time polymerase chain reaction, and ovarian binding sites for (125)I-labeled Ang-(1-7) were identified by autoradiography. CONCLUSION(S): Angiotensin-(1-7), its receptor Mas, and ACE2 are expressed in the human ovary. The peptide is present in several ovarian compartments and can be quantified in FF.
Thomas and Sernia (1990) examined the presence and cellular distribution of angiotensinogen, the precursor to the angiotensin peptides, in the ovary of the normal cycling rat by immunocytochemistry. Angiotensinogen staining was present in the granulosa cells of maturing follicles and to a lesser extent in those undergoing atresia. Staining was not seen in the granulosa cells of primordial or early primary follicles. In maturing follicles intense staining for angiotensinogen was confined to the antral cell layers, cells of the cumulus oophorus and in the follicular fluid. Strong immunostaining was also seen in the germinal epithelium covering the ovary. Lighter angiotensinogen staining was observed in some parts of the cortical and medullary stroma and occasionally in corpora lutea. No variation in the intensity or pattern of angiotensinogen staining was observed throughout the estrous cycle.
Follicle stages
Secondary, Antral, Preovulatory, Corpus luteum
Comment
Angiotensin II reverses the inhibitory action produced by theca cells on bovine oocyte nuclear maturation Giometti IC, et al .
The presence of prorenin, renin, angiotensinogen, angiotensin-converting enzyme, angiotensin II (Ang II) and Ang II receptors in the ovary is suggestive of a functional ovarian renin-angiotensin system (RAS). In cattle, the expression of Ang II is greatest in large follicles, suggesting that it is important during follicular growth and maturation. The present study was designed to investigate the role of Ang II in bovine oocyte nuclear maturation. Bovine cumulus-oocyte complexes (COCs) were cultured with or without follicular cells and Ang II or saralasin (Ang II antagonist). In the absence of follicular cells, Ang II at 0, 10(-11), 10(-9) and 10(-7)M did not affect the percentage of oocytes reaching the germinal vesicle breakdown (GVBD), metaphase I (MI) and metaphase II (MII) stage after 7-h (41.3 +/- 4.3, 35.3 +/- 4.0, 31.3 +/- 9.7, 38.7 +/- 8.6), 12-h (31.6 +/- 7.0, 34.7 +/- 6.1, 31.7 +/- 5.3, 28.9 +/- 9.1; mean +/- S.E.M.) and 18-h (44.9 +/- 7.3, 58.4 +/- 8.4, 53.1 +/- 7.4, 44.9 +/- 7.3) of culture, respectively. Similarly, saralasin at 0, 10(-11), 10(-9) and 10(-7)M did not affect the percentage of oocytes reaching MII stage after 18-h of culture (37.6 +/- 7.4, 34.4 +/- 7.7, 30.0 +/- 10.8 and 31.2 +/- 5.1, respectively). The theca cells (MII = 22.9%) or medium conditioned with follicular cells (GV = 65.5%, MI = 23.6%) inhibited oocyte maturation; however, theca cells (MII = 35.5 +/- 4.9; P < 0.05) or medium conditioned with follicular cells (GV = 34.6%, MI = 52.7%; P < 0.01) were not able to inhibit nuclear maturation when Ang II (10(-11)M) was present in the culture system. Theca cells remained viable during the culture period when Ang II was present. Therefore, results supported the idea of a role of Ang II in blocking the inhibitory effect of theca cells on nuclear maturation of bovine oocytes.
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
3 mutations
Species: mouse
Mutation name: None
type: targeted overexpression fertility: fertile Comment:Yang et al. (1994) generated transgenic mice with a human angiotensinogen genomic clone to develop an animal model to examine tissue- and cell-specific expression of the gene and to determine if overexpression of angiotensinogen results in hypertension. Human angiotensinogen mRNA was expressed in transgenic mouse liver, kidney, heart, adrenal gland, ovary, brain, and white and brown adipose tissue and, in kidney, was exclusively localized to epithelial cells of the proximal convoluted tubules. Plasma levels of human angiotensinogen were approximately 150-fold higher in transgenic mice than that found normally in human plasma. The blood pressure of mice bearing the human angiotensinogen gene was normal but infusion of a single bolus dose of purified human renin resulted in a transient increase in blood pressure of approximately 30 mm Hg within 2 min. These results suggest that abnormalities in the angiotensinogen gene resulting in increased circulating levels of angiotensinogen could potentially contribute in part to the pathogenesis of essential hypertension.
Species: human
Mutation name: type: naturally occurring fertility: subfertile Comment: The M235T polymorphism of the angiotensinogen gene in women with polycystic ovary syndrome. Zulian E et al. (2005) To explore the relationship between variation in AGT M235T gene and the development of the polycystic ovary syndrome (PCOS) and its sequelae, in the present study we evaluated AGT polymorphism M235T in women with PCOS and in a control group. Moreover, to detect any relationship between AGT M235T variation and intermediate and quantitative traits relevant to the pathogenesis of cardiovascular disease and PCOS, we looked for genotype-dependent differences within the subjects with PCOS.//////////////////
Species: human
Mutation name: type: None fertility: None Comment: ////Role of Angiotensin II in the Periovulatory Epidermal Growth Factor-Like Cascade in Bovine Granulosa Cells In Vitro. Portela VM et al. Angiotensin II (AGT-2) induces follicular prostaglandin release in a number of species, and induces ovulation in rabbits. Conversely, AGT-2 antagonists block ovulation in cattle. To determine the mechanism of action of AGT-2, we used a bovine granulosa cell model in which LH increased the expression of genes essential for ovulation in a time- and dose-dependent manner. The addition of AGT-2 to LH-stimulated cells significantly increased abundance of prostaglandin synthase 2 (PTGS2) mRNA and protein, whereas AGT-2 alone had no effect. Upstream of PTGS2, AGT-2 increased abundance of mRNA encoding the EGF-like ligands amphiregulin (AREG) and epiregulin (EREG) at 6 h post treatment, and of a disintegrin and metalloprotease 17 (ADAM17), a sheddase, within 3 h of treatment. Inhibiting sheddase activity abolished the stimulatory effect of AGT-2 on AREG, EREG and PTGS2 mRNA. The addition of selective AGT-2 antagonists to cells stimulated with LH plus AGT-2 demonstrated that AGT-2 does not act through the type 1 receptor, and did not increase MAPK3/1 phosphorylation. Combined with previous data from studies in vitro, we conclude that AGT-2 is an essential cofactor for LH in the early increase of ADAM expression/activity that induces the cascade of events leading to ovulation.