Abstract 707: Tumor Necrosis Factor-alpha p75 Receptor, Sattelite-Cell Activation and Neovascularization
Background. Aging is a risk factor for coronary and peripheral artery disease. TNF-alpha(TNF), a pro-inflammatory cytokines, is expressed in ischemic tissues and is known to modulate angiogenesis. However, little is known about the role of TNF receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling and muscle regeneration.
Methods and Results. We studied neovascularization in the hind limb ischemia (HLI) model in young and old p75 TNFR2 knockout (p75KO) and wild type (WT) age-matched controls. Between days 7 and 10 post-HL surgery 100% of old p75KOs experienced auto-amputation of the operated limbs, whereas none of the age-matched WT mice exhibited HL necrosis. We observed mild to moderate necrosis of the distal ischemic HL in 100% of young p75KO mice beginning at day 7–14, but not evidence of HL necrosis in the young WT mice. Poor blood flow recovery in p75KO mice was associated with decreased capillary density and significant reduction in the expression of VEGF and bFGF2 mRNA transcripts in ischemic tissue and in circulating endothelial progenitor cells (EPCs). Moreover, the number of circulating BM-derived EPCs was significantly reduced in p75 KO mice. Compared to presurgery, on days 1–10 post-HL surgery there was 6 – 8-fold increase in the number of sattelite-cells (as shown by embryonic NCAM staining) in WT mice, whereas in p75KOs after day 1 and through day 10 sattelite cells were not detecable. To the contrary, p75KO tissue showed increased and prolonged (up to day 10) inflammation - neutrophil (MPO-1) and macrophage (F/480) infiltration. Transplantation of WT BM mononuclear cells (MNC) into gamma-irradiated p75KO mice one month prior to HL surgery prevented limb loss and preserved limb muscle mass, suggesting that ischemia-induced neovascularization is mediated, at least in part, via p75 TNF receptor expressed in BM derived cells.
Conclusions. Our study suggests that, signaling through p75 receptor is required for collateral vessel development in ischemia-induced neovascularization as well as plays a critical role in muscle preservation or regeneration. Furthermore, our results suggest a potential gene target, which could be used to improve the repair of ischemic tissue in adult vascular diseases.