Continuous endothelial cell activation increases angiogenesis: evidence for the direct role of endothelium linking angiogenesis and inflammation.
There is increasing evidence that chronic inflammation is tightly linked to diseases associated with endothelial dysfunction, including the induction of aberrant angiogenesis. While leukocytes have been described as mediators of inflammation-associated angiogenesis, the effects of direct chronic endothelial activation have not been addressed in this context. Using an uncleavable mutant of the transmembrane form of tumor necrosis factor-alpha (TNF-alpha), we have established models of stable TNF-alpha expression in endothelial cells in vitro and in transgenic mice in vivo. In the in vitro model, continuous endothelial activation leads to increased leukocyte cellular adhesion molecule expression and intracellular reactive oxygen species, hallmarks of a proinflammatory and dysfunctional endothelium. In addition, stable expression of TNF-alpha in endothelial cells increased angiogenic sprout formation in the presence but also in the absence of angiogenic growth factors. The partial neutralization of this effect by TNF-alpha antibodies and the inability of conditioned media from stable TNF-alpha-expressing endothelial cells to induce angiogenic activities in control endothelial cells suggest that this effect does not require expression of additional autocrine factors, but is an autonomous effect of the transmembrane TNF on the endothelial cells. Furthermore, using the Matrigel plug assay in vivo, increased angiogenesis was observed in endothelial TNF-alpha-expressing transgenic versus control mice. In conclusion, chronic inflammatory changes mediated by TNF-alpha can induce angiogenesis in vitro and in vivo, suggesting endothelial cell activation as a direct link between inflammation and angiogenesis.
Rajashekhar
Gangaraju
G
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Ind. 46202, USA.
Willuweit
Antje
A
Patterson
Carolyn E
CE
Sun
Peichuan
P
Hilbig
Andreas
A
Breier
Georg
G
Helisch
Armin
A
Clauss
Matthias
M
D000818:Animals; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000502:physiology*; D007249:Inflammation / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007797:Laminin; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011120:Polyomavirus; D011509:Proteoglycans; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C059485:matrigel; D018799:Intercellular Adhesion Molecule-1; D003094:Collagen