Endothelial-specific transgenesis of TNFR2 promotes adaptive arteriogenesis and angiogenesis.
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.
Luo
Yan
Y
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Xu
Zhe
Z
Wan
Ting
T
He
Yun
Y
Jones
Dennis
D
Zhang
Haifeng
H
Min
Wang
W
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
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
Curr Drug Targets Cardiovasc Haematol Disord. 2004 Sep;4(3):259-63
15379618
Am J Pathol. 2007 Mar;170(3):1108-20
17322393
J Clin Invest. 1998 Jan 1;101(1):40-50
9421464
J Vasc Res. 2006;43(2):193-204
16410682
Circ Res. 2004 Sep 3;95(5):449-58
15345667
FASEB J. 2005 Oct;19(12):1637-45
16195372
Semin Arthritis Rheum. 2005 Apr;34(5 Suppl1):3-6
15852247
Mol Ther. 2002 May;5(5 Pt 1):547-54
11991745
J Clin Invest. 2008 Dec;118(12):3904-16
19033661
J Vasc Surg. 2003 Aug;38(2):374-9
12891123
Curr Med Chem. 2004 Aug;11(16):2205-12
15279559
EXS. 2005;(94):181-91
15617479
Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):128-33
15611473
Int J Cardiol. 2002 Dec;86(2-3):123-30
12419548
Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):495-502
19150880
Annu Rev Med. 2005;56:249-72
15660512
Am J Pathol. 2006 Nov;169(5):1886-98
17071609
Trends Cell Biol. 2001 Sep;11(9):372-7
11514191
Circ Res. 2006 Apr 14;98(7):897-904
16543497
J Clin Invest. 2006 Sep;116(9):2344-55
16932810
J Biol Chem. 2003 Dec 19;278(51):51267-76
14532277
Circulation. 2007 Feb 13;115(6):752-62
17261656
Mol Cell Biol. 2002 Nov;22(21):7512-23
12370298