Endogenous Transmembrane TNF-Alpha Protects Against Premature Senescence in Endothelial Colony Forming Cells

Linden A. Green, Victor Njoku, Julie Mund, Jamie Case, Mervin Yoder, Michael Murphy, Matthias Clauss

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Rationale: Transmembrane tumor necrosis factor-α (tmTNF-α) is the prime ligand for TNF receptor 2, which has been shown to mediate angiogenic and blood vessel repair activities in mice. We have previously reported that the angiogenic potential of highly proliferative endothelial colony-forming cells (ECFCs) can be explained by the absence of senescent cells, which in mature endothelial cells occupy >30% of the population, and that exposure to a chronic inflammatory environment induced premature, telomere-independent senescence in ECFCs. Objective: The goal of this study was to determine the role of tmTNF-α in the proliferation of ECFCs. Methods and Results: Here, we show that tmTNF-α expression on ECFCs selects for higher proliferative potential and when removed from the cell surface promotes ECFC senescence. Moreover, the induction of premature senescence by chronic inflammatory conditions is blocked by inhibition of tmTNF-α cleavage. Indeed, the mechanism of chronic inflammation-induced premature senescence involves an abrogation of tmTNF/TNF receptor 2 signaling. This process is mediated by activation of the tmTNF cleavage metalloprotease TNF-α-converting enzyme via p38 MAP kinase activation and its concurrent export to the cell surface by means of increased iRhom2 expression. Conclusions: Thus, we conclude that tmTNF-α on the surface of highly proliferative ECFCs plays an important role in the regulation of their proliferative capacity.

Original languageEnglish (US)
Pages (from-to)1512-1524
Number of pages13
JournalCirculation Research
Volume118
Issue number10
DOIs
StatePublished - May 13 2016

Fingerprint

Tumor Necrosis Factor-alpha
Tumor Necrosis Factors
Tumor Necrosis Factor Receptors
Cell Aging
Telomere
Metalloproteases
p38 Mitogen-Activated Protein Kinases
Blood Vessels
Endothelial Cells
Inflammation
Enzymes
Population

Keywords

  • apoptosis
  • endothelium
  • inflammation
  • metalloprotease
  • vasodilation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Endogenous Transmembrane TNF-Alpha Protects Against Premature Senescence in Endothelial Colony Forming Cells. / Green, Linden A.; Njoku, Victor; Mund, Julie; Case, Jamie; Yoder, Mervin; Murphy, Michael; Clauss, Matthias.

In: Circulation Research, Vol. 118, No. 10, 13.05.2016, p. 1512-1524.

Research output: Contribution to journalArticle

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