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Angiopoietin 2 OKDB#: 363
 Symbols: ANGPT2 Species: human
 Synonyms: ANG2  Locus: 8p23 in Homo sapiens


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General Comment Angiogenesis is thought to depend on a precise balance of positive and negative regulation. Angiopoietin-1 is an angiogenic factor that signals through the endothelial cell-specific TIE2 receptor tyrosine kinase (TIE2). Like vascular endothelial growth factor (VEGF), ANGPT1 is essential for normal vascular development in the mouse. By homology screening, Maisonpierre et al. (1997) identified a relative of ANGPT1, termed angiopoietin-2 (ANG2), and showed that it is a naturally occurring antagonist for both ANGPT1 and TIE2.Angiopoietin-2 (ANGPT2) is a naturally occurring antagonist of angiopoietin-1 (ANGPT1; 601667) that competes for binding to the TIE2 receptor (600221) and blocks ANGPT1-induced TIE2 autophosphorylation during vasculogenesis (Kim et al., 2000).

NCBI Summary: Naturally occurring antagonist for both ANGPT1 and TIE2; expressed only at the sites of vascular remodeling; similar to angiopoietin-1
General function Ligand, Growth factor
Comment Angiopoietin-2 (ANG2)is a naturally occurring antagonist for both the TIE2 receptor. Xu F, et al reported that local Delivery of Angiopoietin-2 into the Preovulatory Follicle Terminates the Menstrual Cycle in Rhesus Monkeys. The angiopoietin (ANGPT)-receptor (TEK) system plays a crucial role in blood vessel formation and stability. Since the endogenous agonist ANGPT1, antagonist ANGPT2 and TEK are expressed in the primate ovary, experiments were designed to investigate their role at a critical time during tissue remodeling/angiogenesis in the menstrual cycle, i.e. at midcycle during maturation, ovulation and luteinization of the dominant follicle. Either vehicle, 20 microg of ANGPT1, 2 microg ANGPT2 (low-dose), or 20 microg ANGPT2 (high-dose) was injected directly into the preovulatory follicle of monkeys around the day (-1 to 0) of the midcycle estradiol (E)/LH peak. Ovaries were evaluated on day 3 post-injection for follicle rupture, and serum samples were analyzed for E and progesterone (P) levels. Similar to controls, ANGPT1 treatment was followed by ovulation, and elevated P levels during a luteal phase. In contrast, high-dose ANGPT2 treatment prevented follicle rupture, and P levels never rose above baseline in the subsequent 12 days. However, an E peak typically occurred 12 days post-injection. Laparoscopy detected a preovulatory follicle on the contralateral (non-injected) ovary. P levels subsequently increased above baseline in these animals. Thus, exogenous ANGPT2 disrupted maturation of the preovulatory follicle, preventing its ovulation and conversion into the corpus luteum. ANGPT antagonism eliminated the dominant structure, thereby resetting the ovarian cycle, with selection and maturation of the next preovulatory follicle occurring in a timely manner. The data are consistent with a critical role of the ANGPT-TIE1/TEK system in the ovary, notably at the late stages of follicle maturation during the menstrual cycle.
Cellular localization Secreted
Comment
Ovarian function Luteinization
Comment Angiopoietin-1 and angiopoietin-2 are altered in polycystic ovarian syndrome (PCOS) during controlled ovarian stimulation. Tal R 2013 et al. Polycystic ovarian syndrome (PCOS) ovaries are characterized by increased angiogenesis and hypervascularity. While angiopoietin-1 (Ang-1) and its antagonist, angiopoietin-2 (Ang-2), are essential for ovarian function and angiogenesis, the levels of Ang-1 and Ang-2 in PCOS are unknown. This was a prospective cohort study of 14 PCOS women and 14 matched controls undergoing controlled ovarian stimulation (COS). Serum was collected on day 3, hCG and retrieval days. Follicular fluid (FF) was collected on retrieval day. Serum Ang-1 and Ang-2 levels were constant throughout COS, but serum Ang-1 levels were increased at all time points in PCOS women compared with controls (p<0.05). No differences between groups were found in serum Ang-2 levels or FF Ang-1 levels. However, FF Ang-2 levels were increased almost 2-fold in PCOS women compared with controls (p<0.01), and correlated positively with number of oocytes retrieved (r = 0.65, p < 0.0001). This study is the first to provide evidence of an alteration in the Ang-1/Ang-2 system in PCOS women. The biological role of Ang-2 in promoting capillary leakage, the increased Ang-2 FF level in PCOS, and its correlation with number of oocytes suggest that Ang-2 may play an important role in the increased risk of ovarian hyperstimulation in PCOS. ///////////////////////// The role of endothelial cell-specific growth factors in the vascularization of the primate peri-ovulatory follicle was examined by Hazzard et al . Experiments were designed firstly to detect expression of vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) in granulosa cells and secondly, to determine whether gonadotrophins and/or steroids regulate their expression during the peri-ovulatory interval. VEGF, Ang-1 and Ang-2 mRNA were all detected prior to the ovulatory stimulus in punctured granulosa cells. Whereas follicular fluid VEGF concentrations increased 6-fold between 0 and 12 h after hCG treatment, VEGF mRNA values were unchanged and were unaffected by steroid ablation. Ang-1 mRNA decreased from 0 to 12 h, followed by a 30-fold increase at 36 h, while Ang-2 mRNA values were unchanged between 0, 12 and 36 h.
Expression regulated by FSH, LH, Steroids
Comment Steroid ablation decreased Ang-1 mRNA at 36 h, and Ang-2 mRNA at 12 h after hCg treatment, while only Ang-1 was restored by progestin replacement Hazzard et al . Pietrowski D, Keck C reported the differential Regulation of ANG2 and VEGF-A in Human Granulosa Lutein Cells by Choriogonadotropin. Circulating levels of total angiopoietin-2 and the soluble Tie-2 receptor in women during ovarian stimulation and early gestation. Molskness TA et al. Circulating levels of Ang-2 and sTie-2 receptor were detectable but invariant in women during COS cycles. During the postimplantation period, the rise in Ang-2 (but not sTie-2) levels probably reflects placental rather than luteal production.
Ovarian localization Granulosa, Luteal cells
Comment Expression and regulation of Ang-2 in murine ovaries during sexual maturation and development of corpus luteum. Guo B et al. The aim of this study was to examine the expression and regulation of angiopoietin-2 (Ang-2) in murine ovaries during sexual maturation, gonadotropin treatment and luteal development by in situ hybridization and RT-PCR. By in situ hybridization Ang-2 mRNA was mainly localized in granulosa cells, thecal cells and corpus luteum, otherwise in oocytes. Moreover, Ang-2 mRNA was highly expressed in corpus luteum and granulosa cells of atretic follicles. According to RT-PCR data, Ang-2 mRNA was lowly expressed on day 10 after birth, then expression levels gradually increased and reached their highest values on day 25 after birth. In the superovulated model of immature mice, Ang-2 expression was strongly induced by equine chorionic gonadotropin (eCG) 48 h post the eCG injection, and was high from 0.5 to 13 h after hCG treatment. In situ hybridization showed that Ang-2 mRNA was highly expressed in corpus luteum from day 2 to 9 post the hCG injection, then the expression levels gradually declined on days 11 and 13 after hCG treatment. According to RT-PCR data, the levels of Ang-2 mRNA expression showed a decline after the hCG injection, with a nadir on day 3, followed by an increase, reaching the highest level on day 9 post-hCG injection. Then again Ang-2 expression gradually declined from day 11 to 15 after hCG injection. These results suggest that Ang-2 may be involved in follicular development, atresia, ovulation, and corpus luteum formation and regression. Hazzard, et al 2000 reported changes in expression of vascular endothelial growth factor and angiopoietin-1 and -2 in the macaque corpus luteum during the menstrual cycle. Messenger ribonucleic Acid expressions of hepatocyte growth factor, angiopoietins and their receptors during follicular development in gilts Shimizu T, et al . Angiogenic factors are associated with angiogenesis during follicular development in the mammalian ovary. The aim of the present study was to determine the relationships between the vascular network and mRNA expressions of angiopoietins (Ang)-1, Ang-2 and hepatocyte growth factor (HGF), and their receptors in follicles at different developmental stages during follicular development. Ovaries in gilts were collected 72 h after equine chorionic gonadotropin (eCG, 1250 IU) treatment for histological observation of the capillary network. Granulosa cells and thecal tissues in small (<4 mm), medium (4-5 mm) or large (>5 mm) individual follicles were collected for detection of mRNA expression of HGF, Ang-1 and Ang-2 in granulosa cells, and HGF receptor (HGF-R) and Tie-2 in the theca cells by semi-quantitative RT-PCR. The number of capillaries in the thecal cell layer increased significantly in healthy follicles at all developmental stages in the eCG group compared with those in controls. The expression of Ang-1 mRNA declined in granulosa cells of medium and large follicles and the level of Ang-2 mRNA increased in granulosa cells of small follicles after eCG treatment. The ratio of Ang-2/Ang-1 increased in small, medium and large follicles from ovaries after eCG treatment, but Tie-2 mRNA expression in the theca cells did not change. The level of HGF mRNA increased in granulosa cells of small follicles after eCG treatment but HGF-R in theca cells was not increased by eCG. These data suggested that the angiopoietins might be associated with thecal angiogenesis during follicular development in eCG-treated gilts. L.K. Christenson3 and R.L. Stouffer1,2,4 Ang-1 and Ang-2 mRNA expression was low in the early to mid-luteal phase but increased (P < 0.05) at late luteal phase before declining at menstruation. These data suggest transcriptional control of VEGF, Ang-1 and Ang-2, as well as post-transcriptional control of VEGF, in macaque corpus luteum. Dynamic expression of angiogenic/angiostatic factors appears critical for development, maintenance and regression of the luteal microvasculature during the menstrual cycle.
Follicle stages Antral, Preovulatory, Corpus luteum
Comment Local Delivery of Angiopoietin-2 into the Preovulatory Follicle Terminates the Menstrual Cycle in Rhesus Monkeys Xu F, Stouffer . The angiopoietin (ANGPT)-receptor (TEK) system plays a crucial role in blood vessel formation and stability. Since the endogenous agonist ANGPT1, antagonist ANGPT2 and TEK are expressed in the primate ovary, experiments were designed to investigate their role at a critical time during tissue remodeling/angiogenesis in the menstrual cycle, i.e. at midcycle during maturation, ovulation and luteinization of the dominant follicle. Either vehicle, 20 microg of ANGPT1, 2 microg ANGPT2 (low-dose), or 20 microg ANGPT2 (high-dose) was injected directly into the preovulatory follicle of monkeys around the day (-1 to 0) of the midcycle estradiol (E)/LH peak. Ovaries were evaluated on day 3 post-injection for follicle rupture, and serum samples were analyzed for E and progesterone (P) levels. Similar to controls, ANGPT1 treatment was followed by ovulation, and elevated P levels during a luteal phase. In contrast, high-dose ANGPT2 treatment prevented follicle rupture, and P levels never rose above baseline in the subsequent 12 days. However, an E peak typically occurred 12 days post-injection. Laparoscopy detected a preovulatory follicle on the contralateral (non-injected) ovary. P levels subsequently increased above baseline in these animals. Thus, exogenous ANGPT2 disrupted maturation of the preovulatory follicle, preventing its ovulation and conversion into the corpus luteum. ANGPT antagonism eliminated the dominant structure, thereby resetting the ovarian cycle, with selection and maturation of the next preovulatory follicle occurring in a timely manner. The data are consistent with a critical role of the ANGPT-TIE1/TEK system in the ovary, notably at the late stages of follicle maturation during the menstrual cycle. Angiogenesis in the human corpus luteum: Changes in expression of angiopoietins in the corpus luteum throughout the menstrual cycle and in early pregnancy Sugino N, et al . Context: Blood vessel stabilization is regulated by angiopoietins and important for angiogenesis in the corpus luteum (CL). Objective: To study angiogenesis and blood vessel stabilization in the human CL, changes in expression of angiopoietin-1 (Ang-1), Ang-2 and their specific receptor, Tie-2 together with the number of blood vessels and pericytes were examined in the CL throughout the menstrual cycle and in early pregnancy. Design: The number of blood vessels and pericytes was determined by immunohistochemistry for CD34 and alpha-smooth muscle actin, respectively. Ang and Tie-2 expression were examined by immunohistochemistry or RT-PCR. Results: The number of blood vessels increased during the early luteal phase whereas the number of pericytes was small in the early luteal phase and increased in the mid-luteal phase, suggesting that angiogenesis is undergoing during the early luteal phase and blood vessels are stabilized in the mid-luteal phase. Blood vessels and pericytes decreased in number during the late luteal phase. The increased number of both blood vessels and pericytes in early pregnancy suggests that angiogenesis is undergoing accompanied by blood vessel stabilization. Ang-2 expression with low Ang-1 expression was found during the early luteal phase. Thereafter, increasing Ang-1 expression during the mid-luteal phase, declining Ang-1 expression with continued Ang-2 expression during the late luteal phase, and relatively high Ang-1 expression in early pregnancy were observed. Conclusions: The change in Ang expression is closely associated with angiogenesis, blood vessel stabilization and blood vessel regression during the divergent phases of luteal formation, luteal regression, and luteal rescue by pregnancy.
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created: Jan. 5, 2000, midnight by: hsueh   email:
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last update: Oct. 29, 2013, 2:54 p.m. by: hsueh    email:



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