Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: Implications for microvascular aging

M. Noa Valcarcel-Ares, Tripti Gautam, Junie P. Warrington, Lora Bailey-Downs, Danuta Sosnowska, Rafael De Cabo, Gyorgy Losonczy, William E. Sonntag, Zoltan Ungvari, Anna Csiszar

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

The redox-sensitive transcription factor NF-E2-related factor 2 (Nrf2) plays a key role in preserving a healthy endothelial phenotype and maintaining the functional integrity of the vasculature. Previous studies demonstrated that aging is associated with Nrf2 dysfunction in endothelial cells, which alters redox signaling and likely promotes the development of large vessel disease. Much less is known about the consequences of Nrf2 dysfunction at the level of the microcirculation. To test the hypothesis that Nrf2 regulates angiogenic capacity of endothelial cells, we determined whether disruption of Nrf2 signaling (by siRNA knockdown of Nrf2 and overexpression of Keap1, the cytosolic repressor of Nrf2) impairs angiogenic processes in cultured human coronary arterial endothelial cells stimulated with vascular endothelial growth factor and insulin-like growth factor-1. In the absence of functional Nrf2, coronary arterial endothelial cells exhibited impaired proliferation and adhesion to vitronectin and collagen. Disruption of Nrf2 signaling also reduced cellular migration (measured by a wound-healing assay using electric cell-substrate impedance sensing technology) and impaired the ability of coronary arterial endothelial cells to form capillary-like structures. Collectively, we find that Nrf2 is essential for normal endothelial angiogenic processes, suggesting that Nrf2 dysfunction may be a potential mechanism underlying impaired angiogenesis and microvascular rarefaction in aging.

Original languageEnglish
Pages (from-to)821-829
Number of pages9
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume67 A
Issue number8
DOIs
Publication statusPublished - Aug 1 2012

Keywords

  • Angiogenesis
  • Capillary density
  • Heart
  • Microcirculation
  • Vascular aging

ASJC Scopus subject areas

  • Ageing
  • Geriatrics and Gerontology

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    Valcarcel-Ares, M. N., Gautam, T., Warrington, J. P., Bailey-Downs, L., Sosnowska, D., De Cabo, R., Losonczy, G., Sonntag, W. E., Ungvari, Z., & Csiszar, A. (2012). Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: Implications for microvascular aging. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 67 A(8), 821-829. https://doi.org/10.1093/gerona/glr229