| First Author | Ligresti G | Year | 2011 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 31 |
| Issue | 5 | Pages | 1151-9 |
| PubMed ID | 21372301 | Mgi Jnum | J:191480 |
| Mgi Id | MGI:5461804 | Doi | 10.1161/ATVBAHA.111.223917 |
| Citation | Ligresti G, et al. (2011) Macrophage-derived tumor necrosis factor-alpha is an early component of the molecular cascade leading to angiogenesis in response to aortic injury. Arterioscler Thromb Vasc Biol 31(5):1151-9 |
| abstractText | OBJECTIVE: The goal of this study was to define the role of tumor necrosis factor-alpha (TNFalpha) in the cascade of gene activation that regulates aortic angiogenesis in response to injury. METHODS AND RESULTS: Angiogenesis was studied by culturing rat or mouse aortic rings in collagen gels. Gene expression was evaluated by quantitative reverse transcription-polymerase chain reaction, microarray analysis, immunocytochemistry, and ELISA. TNFalpha gene disruption and recombinant TNFalpha or blocking antibodies against vascular endothelial growth factor (VEGF) or TNF receptors were used to investigate TNFalpha-mediated angiogenic mechanisms. Resident aortic macrophages were depleted with liposomal clodronate. Angiogenesis was preceded by overexpression of TNFalpha and TNFalpha-inducible genes. Studies with isolated cells showed that macrophages were the main source of TNFalpha. Angiogenesis, VEGF production, and macrophage outgrowth were impaired by TNFalpha gene disruption and promoted by exogenous TNFalpha. Antibody-mediated inhibition of TNF receptor 1 significantly inhibited angiogenesis. The proangiogenic effect of TNFalpha was suppressed by blocking VEGF or by ablating aortic macrophages. Exogenous TNFalpha, however, maintained a limited proangiogenic capacity in the absence of macrophages and macrophage-mediated VEGF production. CONCLUSIONS: Overexpression of TNFalpha is required for optimal VEGF production and angiogenesis in response to injury. This TNFalpha/VEGF-mediated angiogenic pathway requires macrophages. The residual capacity of TNFalpha to stimulate angiogenesis in macrophage-depleted aortic cultures implies the existence of a VEGF-independent alternate pathway of TNFalpha-induced angiogenesis. |
