B6-hANG2(ANGPT2) Mice

Catalog Number: C001615

Strain Name: C57BL/6JCya-Angpt2tm1(hANGPT2)/Cya

Genetic Background: C57BL/6JCya

Reproduction: Homozygote x Homozygote

 

Strain Description

Angiopoietin-2 (ANG2/ANGPT2), encoded by the ANGPT2 gene, is a secreted glycoprotein of the angiopoietin family predominantly expressed in vascular endothelial cells and stored in Weibel-Palade bodies for rapid release. ANGPT2 regulates vascular biology in a context-dependent manner by binding to the Tie2 tyrosine kinase receptor, playing pivotal roles in angiogenesis and vascular remodeling [1]. Its molecular structure includes a coiled-coil domain facilitating oligomerization and a fibrinogen-like domain critical for receptor binding. Functionally, ANGPT2 acts as a partial Tie2 receptor antagonist to Angiopoietin-1 (ANG1). Through competitive inhibition of Tie2 signaling, ANGPT2 disrupts vascular endothelial homeostasis, inducing increased vascular permeability and structural plasticity. In synergy with vascular endothelial growth factor (VEGF), ANGPT2 drives angiogenic sprouting and pathological neovascularization. Conversely, under conditions of low or absent VEGF, it mediates vascular regression [2-3]. ANGPT2 plays a central pathological role in vascular proliferative diseases such as tumor angiogenesis, diabetic retinopathy, and age-related macular degeneration. Endothelial cell activation and inflammatory responses mediated by ANGPT2 also contribute to the pathogenesis of inflammatory conditions including sepsis and rheumatoid arthritis [4]. Therapeutic strategies targeting ANGPT2 include monoclonal antibodies (e.g., Nesvacumab) and peptide-Fc fusion proteins (e.g., Trebananib), often combined with VEGF inhibitors to enhance anti-angiogenic efficacy [5-6]. Current research efforts are focused on optimizing ANGPT2/VEGF dual-target inhibition strategies and developing biomarkers, aiming to improve clinical outcomes in tumors and ocular vascular diseases and validate its translational value as a therapeutic target in vascular and inflammatory diseases [7-8].

B6-hANG2(ANGPT2) mouse model was generated using gene editing technology to replace the entire sequence of the mouse Angpt2 gene with the human ANGPT2 gene sequence, achieving stable expression of human ANGPT2 protein. This model is suitable for studying tumorigenesis, vascular hyperproliferative diseases (e.g., diabetic retinopathy, age-related macular degeneration), autoimmune disorders, and preclinical evaluation of human ANGPT2-targeted therapeutics.

Strain Strategy

Figure 1. Gene editing strategy of B6-hANG2(ANGPT2) mice. The mouse Angpt2 gene sequence (from the ATG start codon to the TAA stop codon) was fully replaced with the corresponding human ANGPT2 gene sequence.

 

Applications

  • Mechanistic studies of tumorigenesis and cancer progression;
  • Pathogenesis of vascular diseases and autoimmune disorders;
  • Development, screening, and preclinical pharmacodynamic evaluation of human ANGPT2-targeted therapeutics.

 

Validation Data

1. Expression of human ANGPT2 gene and mouse Angpt2 gene

Figure 2. Expression of human ANGPT2 and mouse Angpt2 genes in the heart, kidney, eye, and liver of 5-week-old male homozygous B6-hANG2(ANGPT2) and wild-type (WT) mice. RT-qPCR analysis revealed significant expression of the human ANGPT2 gene and no expression of the mouse Angpt2 gene in homozygous B6-hANG2(ANGPT2) mice. In contrast, wild-type mice expressed only mouse Angpt2 and no human ANGPT2. The relative expression levels of human ANGPT2 across tissues in B6-hANG2 mice largely mirrored the tissue-specific distribution of endogenous mouse Angpt2 (Bars represent mean ± SEM, n=4; ND: Not detected).

 

References
[1]Hu B, Cheng SY. Angiopoietin-2: development of inhibitors for cancer therapy. Curr Oncol Rep. 2009 Mar;11(2):111-6.
[2]Parikh SM. Angiopoietins and Tie2 in vascular inflammation. Curr Opin Hematol. 2017 Sep;24(5):432-438.
[3]Leppänen VM, Saharinen P, Alitalo K. Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization. Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4376-4381.
[4]Sha L, Zhao Y, Li S, Wei D, Tao Y, Wang Y. Insights to Ang/Tie signaling pathway: another rosy dawn for treating retinal and choroidal vascular diseases. J Transl Med. 2024 Oct 4;22(1):898.
[5]Hussain RM, Neiweem AE, Kansara V, Harris A, Ciulla TA. Tie-2/Angiopoietin pathway modulation as a therapeutic strategy for retinal disease. Expert Opin Investig Drugs. 2019 Oct;28(10):861-869.
[6]Gourley C. Trebananib: an alternative anti-angiogenic strategy. Lancet Oncol. 2014 Jul;15(8):776-7.
[7]Chen-Li G, Martinez-Archer R, Coghi A, Roca JA, Rodriguez FJ, Acaba-Berrocal L, Berrocal MH, Wu L. Beyond VEGF: Angiopoietin-Tie Signaling Pathway in Diabetic Retinopathy. J Clin Med. 2024 May 9;13(10):2778.
[8]Liu N, Liu M, Fu S, Wang J, Tang H, Isah AD, Chen D, Wang X. Ang2-Targeted Combination Therapy for Cancer Treatment. Front Immunol. 2022 Jul 8;13:949553.