Tumor Necrosis Factor-α Receptor p75 Is Required in Ischemia-Induced Neovascularization

Abstract

Background-Aging is a risk factor for coronary and peripheral artery disease. Tumor necrosis factor-␣ (TNF-␣), a proinflammatory cytokine, is expressed in ischemic tissue and is known to modulate angiogenesis. Little is known about the role of TNF-␣ receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling. Methods and Results-We studied neovascularization in the hindlimb ischemia model in young and old TNFR2/p75 knockout (p75KO) and wild-type age-matched controls. Between days 7 to 10 after hindlimb surgery, 100% of old p75KOs experienced autoamputation of the operated limbs, whereas none of the age-matched wild-type mice exhibited hindlimb necrosis. Poor blood flow recovery in p75KO mice was associated with increased endothelial cell apoptosis, decreased capillary density, and significant reductions in the expression of vascular endothelial growth factor and basic fibroblast growth factor-2 mRNA transcripts in ischemic tissue and in circulating endothelial progenitor cells. The number of circulating bone marrow-derived endothelial progenitor cells was significantly reduced in p75KO mice. Transplantation of wild-type bone marrow mononuclear cells into irradiated old p75KO mice 1 month before hindlimb surgery prevented limb loss. Conclusions-Our present study suggests that ischemia-induced endothelial progenitor cell-mediated neovascularization is dependent, at least in part, on p75 TNF receptor expressed in bone marrow-derived cells. Specifically, endothelial cell/endothelial progenitor cell survival, vascular endothelial growth factor expression, endothelial progenitor cell mobilization from bone marrow, endothelial progenitor cell differentiation, and ultimately ischemia-induced collateral vessel development are dependent on signaling through TNFR2/p75. Furthermore, because TNFR2/p75 becomes an age-related limiting factor in postischemic recovery, it may be a potential gene target for therapeutic interventions in adult vascular diseases. (Circulation. 2007;115:752-762.)

Genetic deletion of TNFR2 augments inflammatory response and blunts satellite‐cell‐mediated recovery response in a hind limb ischemia model

“…7D-F), suggesting the importance of signaling through TNFR2/ p75 in cell survival and recovery of muscle tissue after ischemia. These findings corroborate our earlier work, in which we observed that BM cells from young WT mice helped rescue limbs of 16 to 18-mo-old p75KO mice from ischemia-induced autoamputation (6), and which also validated that functional TNFR2/p75 is required in old WT tissue for efficient postischemic recovery (6).…”

“…1J). These histologic findings further signify our earlier observations in an identical HLI model, wherein we observed a significant increase in apoptosis in the ischemic HL tissue on d 10 in p75KO mice (6), an indication of impaired recovery in p75KO mice.…”

“…Unilateral HLI models in young WT and p75KO and adult p75KO BMT mice were established by ligation and excision of femoral artery as previously described (6,46). This model allows observation of the recovery processes after the development of HLI (46).…”

“…TNF-a, A PROINFLAMMATORY cytokine, is highly expressed in ischemic tissue (1)(2)(3)(4)(5) and plays a critical role in ischemiainduced recovery and regeneration processes in skeletal muscle and heart tissues (6)(7)(8)(9)(10)(11)(12). TNF-a mediates activation of divergent intracellular signaling pathways through 2 of its receptors, TNFR1 (p55) and TNFR2 (p75) (13)(14)(15)(16).…”

Increased dietary intake of ω-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis

“…ChemR23 was not detected elsewhere in the retina under these conditions. These findings are consistent with the idea that ω-3-PUFA-derived biomediators interact with receptors on microglial cells to decrease proinflammatory cytokine production.We next examined the role of the inflammatory cytokine tumor necrosis factor (TNF)-α. Modulation of TNF-α production influences vascular growth in other systems through endothelial cell cycle regulation 17,18 . Moreover, mice lacking TNF-α have less oxygeninduced retinopathy 19 .…”