title: Endothelial-specific transgenesis of TNFR2 promotes adaptive arteriogenesis and angiogenesis.
abstract: OBJECTIVE
  We have previously shown that the tumor necrosis factor receptor 2 (TNFR2) protein is highly upregulated in vascular endothelium in response to ischemia, and a global deletion of TNFR2 in mice blunts ischemia-induced arteriogenesis and angiogenesis. However, the role of endothelial TNFR2 is not defined. In this study, we used endothelial cell (EC)-specific transgenesis of TNFR2 (TNFR2-TG) in mice to determine the in vivo function of TNFR2 in arteriogenesis and angiogenesis.
  
  
  RESULTS
  In a femoral artery ligation model, TNFR2-TG mice had enhanced limb perfusion recovery and ischemic reserve capacity. TNFR2-TG mice also exhibited significantly enhanced arteriogenesis in the upper limb, whereas capillary formation and maturation in the lower limb were associated with reduction in cellular apoptosis and increased proliferation. Consistently, ischemia-induced TNFR2-dependent bone marrow tyrosine kinase in chromosome X-vascular endothelial growth factor receptor 2 proangiogenic signaling was augmented in TNFR2-TG mice. To further determine whether EC-expressed TNFR2 is sufficient to mediate ischemia-induced angiogenesis, we crossed TNFR2-TG with TNFR2-deficient mice to generate TNFR2-knockout (KO)/TG mice, in which only vascular ECs express TNFR2. The EC-expressed TNFR2 partially rescued the defects of TNFR2-KO in ischemia-induced angiogenic signaling and flow recovery.
  
  
  CONCLUSIONS
  These in vivo data support a critical role for endothelial TNFR2 in ischemia-mediated adaptive angiogenesis. Therefore, specific expression and activation of TNFR2 in ECs may provide a novel strategy for the treatment of vascular diseases such as coronary artery disease and peripheral arterial disease.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xu
authors.forename: Ting
authors.initials: T
authors.lastname: Wan
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.forename: Dennis
authors.initials: D
authors.lastname: Jones
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Wang
authors.initials: W
authors.lastname: Min
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005263:Femoral Artery / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D006614:Hindlimb; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function; D012039:Regional Blood Flow; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D047889:Receptors, Tumor Necrosis Factor, Type II; C415902:TNFRSF1B protein, human; C492366:Bmx protein, mouse; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2
references.citation: Curr Drug Targets Cardiovasc Haematol Disord. 2004 Sep;4(3):259-63
references.pmid: 15379618
references.citation: Am J Pathol. 2007 Mar;170(3):1108-20
references.pmid: 17322393
references.citation: J Clin Invest. 1998 Jan 1;101(1):40-50
references.pmid: 9421464
references.citation: J Vasc Res. 2006;43(2):193-204
references.pmid: 16410682
references.citation: Circ Res. 2004 Sep 3;95(5):449-58
references.pmid: 15345667
references.citation: FASEB J. 2005 Oct;19(12):1637-45
references.pmid: 16195372
references.citation: Semin Arthritis Rheum. 2005 Apr;34(5 Suppl1):3-6
references.pmid: 15852247
references.citation: Mol Ther. 2002 May;5(5 Pt 1):547-54
references.pmid: 11991745
references.citation: J Clin Invest. 2008 Dec;118(12):3904-16
references.pmid: 19033661
references.citation: J Vasc Surg. 2003 Aug;38(2):374-9
references.pmid: 12891123
references.citation: Curr Med Chem. 2004 Aug;11(16):2205-12
references.pmid: 15279559
references.citation: EXS. 2005;(94):181-91
references.pmid: 15617479
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):128-33
references.pmid: 15611473
references.citation: Int J Cardiol. 2002 Dec;86(2-3):123-30
references.pmid: 12419548
references.citation: Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):495-502
references.pmid: 19150880
references.citation: Annu Rev Med. 2005;56:249-72
references.pmid: 15660512
references.citation: Am J Pathol. 2006 Nov;169(5):1886-98
references.pmid: 17071609
references.citation: Trends Cell Biol. 2001 Sep;11(9):372-7
references.pmid: 11514191
references.citation: Circ Res. 2006 Apr 14;98(7):897-904
references.pmid: 16543497
references.citation: J Clin Invest. 2006 Sep;116(9):2344-55
references.pmid: 16932810
references.citation: J Biol Chem. 2003 Dec 19;278(51):51267-76
references.pmid: 14532277
references.citation: Circulation. 2007 Feb 13;115(6):752-62
references.pmid: 17261656
references.citation: Mol Cell Biol. 2002 Nov;22(21):7512-23
references.pmid: 12370298