B6-hVEGFA/hANGPT2 Mice

Catalog Number: C001691

Strain Name: C57BL/6JCya-Vegfatm1(hVEGFA)Angpt2tm1(hANGPT2)/Cya

Genetic Background: C57BL/6JCya

Reproduction: Homozygote B6-hVEGFA mice x Homozygote B6-hANG2(ANGPT2) mice

 

Strain Description

The Vascular Endothelial Growth Factor (VEGF) family is a group of particular endothelial growth factors intimately associated with angiogenesis. These factors promote increased vascular permeability, extracellular matrix degeneration, vascular endothelial cell migration and proliferation, and are capable of stimulating angiogenesis and increasing the permeability of existing vessels. As such, they play a pivotal role in normal vascular development and wound healing. The VEGF family comprises VEGFA, VEGFB, VEGFC, VEGFD, VEGFE, and PLGF [1]. Of these, VEGFA is the most commonly targeted in research related to neovascular ophthalmic diseases due to its crucial role in the proliferation, migration, and formation of endothelial cell microvessels [2]. Overexpression of VEGFA in the eye can result in abnormal vascular growth and leakage, leading to various ophthalmic diseases such as Age-Related Macular Degeneration (AMD), Diabetic Retinopathy (DR), and corneal neovascularization [2-3]. The progression of solid tumors depends on vascularization and angiogenesis within malignant tissues, with VEGFA playing a crucial role among various pro-angiogenic factors. The VEGFA gene is upregulated in many known tumors, correlating with tumor staging and progression. Blocking VEGFA may lead to vascular network regression, thereby inhibiting tumor growth. Thus, VEGFA is an important target for anti-angiogenic cancer therapies.

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 [5]. 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 [6-7]. 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 [8]. 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 [9-10]. 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 [11-12].

B6-hVEGFA/hANGPT2 mice are VEGFA and ANGPT2 double humanized mouse models obtained by mating VEGFA humanized mouse models (Catalog No. C001555) with ANGPT2 humanized mouse models (Catalog No. C001615). B6-hVEGFA/hANGPT2 mice express human VEGFA and ANGPT2 genomic sequences under the control of mouse promoters. This model is capable of reproducing human VEGFA and ANGPT2 and is a valuable tool for studying cancer, vascular diseases and autoimmune disorders. In addition, this model also provides a powerful preclinical research platform for evaluating the efficacy and mechanism of therapeutic drugs targeting VEGFA and ANGPT2.

 

Strain Strategy

  • Gene editing strategy of B6-hVEGFA mice. The sequence from the CTG start codon to 3'UTR of the mouse Vegfa gene was replaced with the sequence from the CTG start codon to 3'UTR of the human VEGFA gene.

 

  • 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.



Application

  • VEGFA/ANGPT2-targeted drug screening, development, and evaluation;
  • Mechanistic studies of tumorigenesis and cancer progression;
  • Pathogenesis of vascular diseases and autoimmune disorders.

 

References
[1]Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004 Dec;56(4):549-80.
[2]Apte RS, Chen DS, Ferrara N. VEGF in Signaling and Disease: Beyond Discovery and Development. Cell. 2019 Mar 7;176(6):1248-1264.
[3]Mesquita J, Castro-de-Sousa JP, Vaz-Pereira S, Neves A, Passarinha LA, Tomaz CT. Vascular endothelial growth factors and placenta growth factor in retinal vasculopathies: Current research and future perspectives. Cytokine Growth Factor Rev. 2018 Feb;39:102-115.
[4]Chekhonin VP, Shein SA, Korchagina AA, Gurina OI. VEGF in tumor progression and targeted therapy. Curr Cancer Drug Targets. 2013 May;13(4):423-43.
[5]Hu B, Cheng SY. Angiopoietin-2: development of inhibitors for cancer therapy. Curr Oncol Rep. 2009 Mar;11(2):111-6.
[6]Parikh SM. Angiopoietins and Tie2 in vascular inflammation. Curr Opin Hematol. 2017 Sep;24(5):432-438.
[7]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.
[8]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.
[9]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.
[10]Gourley C. Trebananib: an alternative anti-angiogenic strategy. Lancet Oncol. 2014 Jul;15(8):776-7.
[11]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.
[12]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.