TIE2 is a receptor-like tyrosine kinase expressed almost exclusively in endothelial cells and early hematopoietic cells and required for the normal development of vascular structures during embryogenesis. Davis et al.(1996) identified a secreted ligand for TIE2, termed angiopoietin-1. The human gene encodes a 498-amino acid polypeptide with predicted coiled-coil and fibrinogen-like domains. The structure of angiopoietin-1 differs from that of known angiogenic factors or other ligands for receptor tyrosine kinases. Although angiopoietin-1 bound and induced the tyrosine phosphorylation of TIE2, it did not directly promote the growth of cultured endothelial cells.
NCBI Summary:
This gene encodes a secreted glycoprotein that belongs to the angiopoietin family. Members of this family play important roles in vascular development and angiogenesis. All angiopoietins bind with similar affinity to an endothelial cell-specific tyrosine-protein kinase receptor. The protein encoded by this gene is a secreted glycoprotein that activates the receptor by inducing its tyrosine phosphorylation. It plays a critical role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme and inhibits endothelial permeability. The protein also contributes to blood vessel maturation and stability, and may be involved in early development of the heart. Mutations in this gene are associated with hereditary angioedema. [provided by RefSeq, Aug 2020]
General function
Ligand, Growth factor
Comment
Holash et al. (1999) noted that angiopoietin-1 was antiapoptotic for cultured endothelial cells and expression of its antagonist angiopoietin-2 was induced in the endothelium of co-opted tumor vessels before their
regression. Thurston et al. (1999) compared transgenic mice overexpressing either Vegf or Ang1 in the skin. Vegf-induced blood vessels were leaky, whereas those induced by Ang1 were not. Moreover, vessels in Ang1-overexpressing mice were resistant to leaks caused by inflammatory agents. Coexpression of Ang1 and Vegf had an additive effect on angiogenesis but resulted in leakage-resistant vessels typical of Ang1. They concluded that ANG1, therefore, may be useful for reducing microvascular leakage in diseases in which the leakage results from chronic inflammation or elevated VEFG and, in combination with VEGF, for promoting growth of nonleaky vessels.
Cellular localization
Secreted
Comment
Aberrant expression of angiopoietin-like proteins 1 and 2 in cumulus cells is potentially associated with impaired oocyte developmental competence in polycystic ovary syndrome. Liu Z et al. (2016) Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder associated with obesity, insulin resistance, hyperandrogenism, alterations in ovarian angiogenesis and impaired oocyte competence. Emerging evidence demonstrates that angiopoietin-like protein 1 (ANGPTL1) and angiopoietin-like protein 2 (ANGPTL2) have an important influence on angiogenesis, androgen biosynthesis, insulin resistance and adipocytes function. In this study, we set out to determine the potential relationship between ANGPTL1, ANGPTL2 and oocyte competence in PCOS through analyzing the expression levels and dynamic pattern of the two genes in cumulus cells (CCs) during different phases of nuclear maturation of PCOS patients and control groups undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization and embryo transfer. We found that the relative abundance of ANGPTL1 and ANGPTL2 transcripts in CCs from patients with PCOS showed dynamic changes during oocyte maturation. Specifically, their expressions were increased significantly at the Metaphase II stage. In summary, the present novel evidence indicates that the expression patterns of ANGPTL1 and ANGPTL2 mRNAs are disordered during oocyte maturation in PCOS, which were potentially related to aberrant oocyte quality and developmental potency, at least in part, via pathological angiogenesis and metabolism.//////////////////
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.
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Involvement of the ANGPTs/Tie-2 system in ovarian hyperstimulation syndrome (OHSS). Scotti L et al. Ovarian hyperstimulation syndrome (OHSS) is a disorder associated with ovarian stimulation. OHSS features are ovarian enlargement with fluid shifting to the third space. Disturbances in the vasculature are considered the main changes that lead to OHSS. Our aim was to analyze the levels of angiopoietins 1 and 2 (ANGPT1 and 2) and their soluble and membrane receptors (s/mTie-2) in follicular fluid (FF) and in granulosa-lutein cells culture (GLCs) from women at risk of developing OHSS. We also evaluated the effect of ANGPT1 on endothelial cell migration. In ovaries from an OHSS rat model, we analyzed the protein concentration of ANGPTs, their mTie-2 receptor, and platelet-derived growth factor PDGF-B, -D and PDGFR-? ANGPT1 levels were increased in both FF and GLCs from women at risk of OHSS. Incubation of these FF with an ANGPT1 neutralizing antibody decreased endothelial cell migration. In the ovaries of OHSS rat model, mTie-2 protein levels increased and PDGF-B and -D decreased. In summary, these results suggest that ANGPT1 could be another mediator in the development of OHSS.
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.
Intrabursal Administration of the Antiangiopoietin 1 Antibody Produces a Delay in Rat Follicular Development Associated with an Increase in Ovarian Apoptosis Mediated by Changes in the Expression of BCL2 Related Genes. Parborell F et al. The angiopoietin (ANGPT)-receptor (TEK) system plays a crucial role in blood vessel development and regression. To date, no reports have addressed the actions of the anti-ANGPT1 antibody on gonadotropin-stimulated follicular development and atresia in the ovary. Therefore, in this study, we specifically investigated whether ANGPT1 plays a critical intraovarian survival role for gonadotropin-dependent folliculogenesis. In particular, we examined the effect of local administration of anti-ANGPT1 antibody on follicular development, apoptosis and expression of BCL2 protein family members (BAX, BCL2 and BCL2L1), TNFRSF6 and FASLG in ovarian follicles from prepubertal eCG-treated rats. The inhibition of ANGPT1 caused an increase in the number of atretic follicles and a decrease in the number of both antral follicles (AF) and preovulatory follicles (POF) in gonadotropin-treated rat ovaries. Taking into account that follicular atresia is mediated by apoptosis, we analyzed the effect of the antibody against ANGPT1 on programmed cell death. The inhibition of the action of ANGPT1 caused an increase both in the number of apoptotic granulosa cells in AF and in the spontaneous DNA fragmentation of AF cultured in serum-free medium. Besides, AF obtained from rats treated with intraovarian antibodies against ANGPT1 showed both a decrease in BCL2 and an increase in BAX protein levels. Moreover, a reduction in the BCL2L1L:BCL2L1S ratio was observed in this group, with a reduction of BCL2L1L greater than that of BCL2L1S, thus showing that the expression of these antiapoptotic proteins is lower in follicles from treated rats than in those from untreated ones. Our findings suggest that the inhibition of ANGPT1 activity causes an increase in the number of atretic follicles mediated by ovarian apoptosis through an imbalance in the ratio of antiapoptotic:proapoptotic proteins. This could take place through a paracrine effect on granulosa cells mediated by the TEK receptor in theca cells. Therefore, these data clearly indicate that ANGPT1 is necessary for follicular development induced by gonadotropins.
Expression regulated by
FSH, LH, Steroids
Comment
Steroid ablation decreased Ang-1 mRNA at 36 h, and Ang-2 mRNA at 12 h, while only Ang-1 was restored by progestin replacement Hazzard et al .
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.
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: embryonic lethal Comment:Suri et al. (1996) showed that mice engineered to lack angiopoietin-1 display angiogenic defects reminiscent of those previously seen in mice lacking Tie2. Mouse embryos homozygous for a disrupted Tie2 allele die by day 10.5 of embryogenesis due to endocardial defects, hemorrhaging, and impaired vascular network formation Sato et al . These data demonstrate that angiopoietin-1 is a primary physiologic ligand for Tie2 and that it has critical in vivo angiogenic actions that are distinct from vascular endothelial growth factor and that are not reflected in the classic in vitro assays used to characterize VEGF. They concluded that angiopoietin-1 appears to play a crucial role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme.