This Article Full Text Full Text (PDF) Supplemental Material A correction has been published Purchase Article View Shopping Cart Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Luo, D. Articles by Min, W. Search for Related Content PubMed Articles by Luo, D. Articles by Min, W.

(American Journal of Pathology. 2006;169:1886-1898.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060603

Differential Functions of Tumor Necrosis Factor Receptor 1 and 2 Signaling in Ischemia-Mediated Arteriogenesis and Angiogenesis

Dianhong Luo^*, Yan Luo, Yun He^*, Haifeng Zhang^*, Rong Zhang^*, Xianghong Li^*, Wawrzyniec L. Dobrucki, Al J. Sinusas, William C. Sessa^* and Wang Min^*

From the Department of Pathology,^* Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, and the Departments of Internal Medicine (Cardiology) and Diagnostic Radiology and Pharmacology, Yale University School of Medicine, New Haven, Connecticut; and State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China

We have previously shown that tumor necrosis factor (TNF) acts via its two receptors TNFR1 and TNFR2 to elicit distinct signaling pathways in vascular endothelial cells (ECs). Here we used a femoral artery ligation model to demonstrate that TNFR1-knockout (KO) mice had enhanced, whereas TNFR2-KO had reduced, capacity in clinical recovery, limb perfusion, and ischemic reserve capacity compared with the wild-type mice. Consistently, ischemia-initiated collateral growth (arteriogenesis) in the upper limb and capillary formation and vessel maturation (angiogenesis) in the lower limb were enhanced in TNFR1-KO but were reduced in TNFR2-KO mice. Furthermore, our results suggest that vascular proliferation, but not infiltration of macrophages and lymphocytes, accounted for the phenotypic differences between the TNFR1-KO and TNFR2-KO mice. In wild-type animals TNFR2 protein in vascular endothelium was highly up-regulated in response to ischemia, leading to increased TNFR2-specific signaling as determined by the formation TNFR2-TRAF2 complex and activation of TNFR2-specific kinase Bmx/Etk. In isolated murine ECs, activation of TNFR2 induced nuclear factor-B-dependent reporter gene expression, EC survival, and migration. In contrast, activation of TNFR1 caused inhibition of EC migration and EC apoptosis. These data demonstrate that TNFR1 and TNFR2 play differential roles in ischemia-mediated arteriogenesis and angiogenesis, partly because of their opposite effects on EC survival and migration.

This article has been cited by other articles:

				M. M. Kavurma, N. Y. Tan, and M. R. Bennett Death Receptors and Their Ligands in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., October 1, 2008; 28(10): 1694 - 1702. [Abstract] [Full Text] [PDF]

				R. C. A. Sainson, D. A. Johnston, H. C. Chu, M. T. Holderfield, M. N. Nakatsu, S. P. Crampton, J. Davis, E. Conn, and C. C. W. Hughes TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype Blood, May 15, 2008; 111(10): 4997 - 5007. [Abstract] [Full Text] [PDF]

				D. Luo, Y. He, H. Zhang, L. Yu, H. Chen, Z. Xu, S. Tang, F. Urano, and W. Min AIP1 Is Critical in Transducing IRE1-mediated Endoplasmic Reticulum Stress Response J. Biol. Chem., May 2, 2008; 283(18): 11905 - 11912. [Abstract] [Full Text] [PDF]

				L. Zhang, P. Sivashanmugam, J.-H. Wu, L. Brian, S. T. Exum, N. J. Freedman, and K. Peppel Tumor Necrosis Factor Receptor-2 Signaling Attenuates Vein Graft Neointima Formation by Promoting Endothelial Recovery Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 284 - 289. [Abstract] [Full Text] [PDF]

				A. Elizur, T. L. Adair-Kirk, D. G. Kelley, G. L. Griffin, D. E. deMello, and R. M. Senior Tumor Necrosis Factor-{alpha} from Macrophages Enhances LPS-Induced Clara Cell Expression of Keratinocyte-Derived Chemokine Am. J. Respir. Cell Mol. Biol., January 1, 2008; 38(1): 8 - 15. [Abstract] [Full Text] [PDF]

				T. A. Markel, P. R. Crisostomo, M. Wang, J. L. Herrmann, A. M. Abarbanell, and D. R. Meldrum Right ventricular TNF resistance during endotoxemia: the differential effects on ventricular function Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2007; 293(5): R1893 - R1897. [Abstract] [Full Text] [PDF]

				T. A. Markel, P. R. Crisostomo, M. Wang, C. M. Herring, and D. R. Meldrum Activation of individual tumor necrosis factor receptors differentially affects stem cell growth factor and cytokine production Am J Physiol Gastrointest Liver Physiol, October 1, 2007; 293(4): G657 - G662. [Abstract] [Full Text] [PDF]

				N. A. Turner, R. S. Mughal, P. Warburton, D. J. O'Regan, S. G. Ball, and K. E. Porter Mechanism of TNF{alpha}-induced IL-1{alpha}, IL-1{beta} and IL-6 expression in human cardiac fibroblasts: Effects of statins and thiazolidinediones Cardiovasc Res, October 1, 2007; 76(1): 81 - 90. [Abstract] [Full Text] [PDF]

				G. Rajashekhar, M. Grow, A. Willuweit, C. E. Patterson, and M. Clauss Divergent and convergent effects on gene expression and function in acute versus chronic endothelial activation Physiol Genomics, September 11, 2007; 31(1): 104 - 113. [Abstract] [Full Text] [PDF]