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

Abstract

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 wildtype 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-Bdependent 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.

Tumor Necrosis Factor α Primes Cerebral Endothelial Cells for Erythropoietin-Induced Angiogenesis

“…Studies in neuroprotection have shown that TNFR1 targets EPOR and vascular endothelial growth factor (VEGF) to reduce cortical neuronal damage after cerebral ischemia (Taoufik et al, 2008). The TNFR1 and TNFR2 mediate hindlimb ischemia-induced angiogenesis (Luo et al, 2006). Adult cerebral endothelial cells express EPOR (Pillai and Mahadik, 2006;Siren and Ehrenreich, 2001).…”

TNF Receptor 1/2 Predict Heart Failure Risk in Type 2 Diabetes Mellitus Patients

“…TNFR1 is expressed in nearly all cell types (except erythrocytes), while TNFR2 is found primarily in cells of the immune system and myocardial cells. 28,29) Previous research suggests TNFR1/2 signaling is complex; TNFR1 could aggravate while TNFR2 ameliorates chamber remodeling and hypertrophy due to their different effects on NF-kB, JNK, inflammatory activation, and apoptosis. 30) In our study, we compared inflammatory expression in different groups.…”

TRAF5 Deficiency Accelerates Atherogenesis in Mice by Increasing Inflammatory Cell Recruitment and Foam Cell Formation

“…[3][4][5][6] However, only a few reports have investigated TRAF-dependent functions in the context of vascular disease: TRAF3 and TRAF2 have been implicated in transducing shear stress, 7,8 and Luo et al recently demonstrated that activation of TNFR2 mediates ischemia-induced atherogenesis by inducing TRAF2-dependent survival pathways. 9 Endothelial cells (ECs) and smooth muscle cells from unstable plaque regions of human carotid arteries overexpress TRAF4. 4 TRAF6 promotes neointima formation on balloon injury in the carotid artery of mice as well as development of in-stent stenosis in rab-bits.…”