Macrophage-derived tumor necrosis factor-alpha is an early component of the molecular cascade leading to angiogenesis in response to aortic injury.

ABSTRACT: The goal of this study was to define the role of tumor necrosis factor-? (TNF?) in the cascade of gene activation that regulates aortic angiogenesis in response to injury.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. TNF? gene disruption and recombinant TNF? or blocking antibodies against vascular endothelial growth factor (VEGF) or TNF receptors were used to investigate TNF?-mediated angiogenic mechanisms. Resident aortic macrophages were depleted with liposomal clodronate. Angiogenesis was preceded by overexpression of TNF? and TNF?-inducible genes. Studies with isolated cells showed that macrophages were the main source of TNF?. Angiogenesis, VEGF production, and macrophage outgrowth were impaired by TNF? gene disruption and promoted by exogenous TNF?. Antibody-mediated inhibition of TNF receptor 1 significantly inhibited angiogenesis. The proangiogenic effect of TNF? was suppressed by blocking VEGF or by ablating aortic macrophages. Exogenous TNF?, however, maintained a limited proangiogenic capacity in the absence of macrophages and macrophage-mediated VEGF production.Overexpression of TNF? is required for optimal VEGF production and angiogenesis in response to injury. This TNF?/VEGF-mediated angiogenic pathway requires macrophages. The residual capacity of TNF? to stimulate angiogenesis in macrophage-depleted aortic cultures implies the existence of a VEGF-independent alternate pathway of TNF?-induced angiogenesis.

SUBMITTER: Ligresti G 

PROVIDER: S-EPMC3113655 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature