Macrophage-derived tumor necrosis factor-alpha is an early component of the molecular cascade leading to angiogenesis in response to aortic injury
- PMID: 21372301
- PMCID: PMC3113655
- DOI: 10.1161/ATVBAHA.111.223917
Macrophage-derived tumor necrosis factor-alpha is an early component of the molecular cascade leading to angiogenesis in response to aortic injury
Abstract
Objective: The goal of this study was to define the role of tumor necrosis factor-α (TNFα) 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. TNFα gene disruption and recombinant TNFα or blocking antibodies against vascular endothelial growth factor (VEGF) or TNF receptors were used to investigate TNFα-mediated angiogenic mechanisms. Resident aortic macrophages were depleted with liposomal clodronate. Angiogenesis was preceded by overexpression of TNFα and TNFα-inducible genes. Studies with isolated cells showed that macrophages were the main source of TNFα. Angiogenesis, VEGF production, and macrophage outgrowth were impaired by TNFα gene disruption and promoted by exogenous TNFα. Antibody-mediated inhibition of TNF receptor 1 significantly inhibited angiogenesis. The proangiogenic effect of TNFα was suppressed by blocking VEGF or by ablating aortic macrophages. Exogenous TNFα, however, maintained a limited proangiogenic capacity in the absence of macrophages and macrophage-mediated VEGF production.
Conclusions: Overexpression of TNFα is required for optimal VEGF production and angiogenesis in response to injury. This TNFα/VEGF-mediated angiogenic pathway requires macrophages. The residual capacity of TNFα to stimulate angiogenesis in macrophage-depleted aortic cultures implies the existence of a VEGF-independent alternate pathway of TNFα-induced angiogenesis.
Conflict of interest statement
The authors have no conflicts of interest to disclose.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3113655/bin/nihms283939f1.gif)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3113655/bin/nihms283939f2.gif)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3113655/bin/nihms283939f3.gif)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3113655/bin/nihms283939f4.gif)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3113655/bin/nihms283939f5.gif)
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3113655/bin/nihms283939f6.gif)
Similar articles
-
The acute phase reactant orosomucoid-1 is a bimodal regulator of angiogenesis with time- and context-dependent inhibitory and stimulatory properties.PLoS One. 2012;7(8):e41387. doi: 10.1371/journal.pone.0041387. Epub 2012 Aug 14. PLoS One. 2012. PMID: 22916107 Free PMC article.
-
The angiogenic response of the aorta to injury and inflammatory cytokines requires macrophages.J Immunol. 2008 Oct 15;181(8):5711-9. doi: 10.4049/jimmunol.181.8.5711. J Immunol. 2008. PMID: 18832730 Free PMC article.
-
Angiopoietin-1 and vascular endothelial growth factor induce expression of inflammatory cytokines before angiogenesis.Physiol Genomics. 2006 Oct 3;27(1):20-8. doi: 10.1152/physiolgenomics.00048.2006. Physiol Genomics. 2006. PMID: 17018690
-
Tumor cells and tumor-associated macrophages: secreted proteins as potential targets for therapy.Clin Dev Immunol. 2011;2011:565187. doi: 10.1155/2011/565187. Epub 2011 Nov 17. Clin Dev Immunol. 2011. PMID: 22162712 Free PMC article. Review.
-
Tumor necrosis factor-α signaling in macrophages.Crit Rev Eukaryot Gene Expr. 2010;20(2):87-103. doi: 10.1615/critreveukargeneexpr.v20.i2.10. Crit Rev Eukaryot Gene Expr. 2010. PMID: 21133840 Free PMC article. Review.
Cited by
-
Unraveling the complex roles of macrophages in obese adipose tissue: an overview.Front Med. 2024 Apr;18(2):205-236. doi: 10.1007/s11684-023-1033-7. Epub 2024 Jan 2. Front Med. 2024. PMID: 38165533 Review.
-
Ifi30 Is Required for Sprouting Angiogenesis During Caudal Vein Plexus Formation in Zebrafish.Front Physiol. 2022 Jul 13;13:919579. doi: 10.3389/fphys.2022.919579. eCollection 2022. Front Physiol. 2022. PMID: 35910561 Free PMC article.
-
TNFα-Induced LDL Cholesterol Accumulation Involve Elevated LDLR Cell Surface Levels and SR-B1 Downregulation in Human Arterial Endothelial Cells.Int J Mol Sci. 2021 Jun 9;22(12):6236. doi: 10.3390/ijms22126236. Int J Mol Sci. 2021. PMID: 34207810 Free PMC article.
-
Adventitial Progenitor Cells of Human Great Saphenous Vein Enhance the Resolution of Venous Thrombosis via Neovascularization.Stem Cells Int. 2021 Feb 23;2021:8816763. doi: 10.1155/2021/8816763. eCollection 2021. Stem Cells Int. 2021. PMID: 33679991 Free PMC article.
-
Recombinant Myxoma Virus-Derived Immune Modulator M-T7 Accelerates Cutaneous Wound Healing and Improves Tissue Remodeling.Pharmaceutics. 2020 Oct 22;12(11):1003. doi: 10.3390/pharmaceutics12111003. Pharmaceutics. 2020. PMID: 33105865 Free PMC article.
References
-
- Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–257. - PubMed
-
- Fischer C, Schneider M, Carmeliet P. Principles and therapeutic implications of angiogenesis, vasculogenesis and arteriogenesis. Handb Exp Pharmacol. 2006:157–212. - PubMed
-
- Ferrara N. Vascular endothelial growth factor. Arterioscler Thromb Vasc Biol. 2009;29:789–791. - PubMed
-
- Ferrara N. VEGF-A: a critical regulator of blood vessel growth. Eur Cytokine Netw. 2009;20:158–163. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Molecular Biology Databases