Continuous endothelial cell activation increases angiogenesis: Evidence for the direct role of endothelium linking angiogenesis and inflammation

Gangaraju Rajashekhar, Antje Willuweit, Carolyn E. Patterson, Peichuan Sun, Andreas Hilbig, Georg Breier, Armin Helisch, Matthias Clauss

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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-α (TNF-α), we have established models of stable TNF-α 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-α 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-α antibodies and the inability of conditioned media from stable TNF-α-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-α-expressing transgenic versus control mice. In conclusion, chronic inflammatory changes mediated by TNF-α can induce angiogenesis in vitro and in vivo, suggesting endothelial cell activation as a direct link between inflammation and angiogenesis.

Original languageEnglish
Pages (from-to)193-204
Number of pages12
JournalJournal of Vascular Research
Volume43
Issue number2
DOIs
StatePublished - Feb 2006

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Endothelium
Endothelial Cells
Tumor Necrosis Factor-alpha
Inflammation
Angiogenesis Inducing Agents
Inflammation Mediators
Cell Adhesion Molecules
Conditioned Culture Medium
Transgenic Mice
Reactive Oxygen Species
Intercellular Signaling Peptides and Proteins
Leukocytes
Antibodies
In Vitro Techniques

Keywords

  • Angiogenesis
  • Endothelial dysfunction
  • Inflammation
  • Intracellular adhesion molecule 1
  • Matrigel plug assay
  • Reactive oxygen species
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Physiology

Cite this

Continuous endothelial cell activation increases angiogenesis : Evidence for the direct role of endothelium linking angiogenesis and inflammation. / Rajashekhar, Gangaraju; Willuweit, Antje; Patterson, Carolyn E.; Sun, Peichuan; Hilbig, Andreas; Breier, Georg; Helisch, Armin; Clauss, Matthias.

In: Journal of Vascular Research, Vol. 43, No. 2, 02.2006, p. 193-204.

Research output: Contribution to journalArticle

Rajashekhar, Gangaraju ; Willuweit, Antje ; Patterson, Carolyn E. ; Sun, Peichuan ; Hilbig, Andreas ; Breier, Georg ; Helisch, Armin ; Clauss, Matthias. / Continuous endothelial cell activation increases angiogenesis : Evidence for the direct role of endothelium linking angiogenesis and inflammation. In: Journal of Vascular Research. 2006 ; Vol. 43, No. 2. pp. 193-204.
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