Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging.
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.
Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, 975 N. E. 10th Street-BRC 1303, Oklahoma City, OK 73104, USA.
M Noa
MN
Valcarcel-Ares
Tripti
T
Gautam
Junie P
JP
Warrington
Lora
L
Bailey-Downs
Danuta
D
Sosnowska
Rafael
R
de Cabo
Gyorgy
G
Losonczy
William E
WE
Sonntag
Zoltan
Z
Ungvari
Anna
A
Csiszar
D017209:Apoptosis / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D003331:Coronary Vessels / Q000166:cytology*; D042783:Endothelial Cells / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000502:physiology; D006801:Humans; D008833:Microcirculation / Q000502:physiology; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress / Q000502:physiology
D016326:Extracellular Matrix Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human