Development of age-associated vascular diseases like atherosclerosis depends not only on genetic predisposition but also on environmental influences. Ligands of the aryl hydrocarbon receptor (AhR), a ubiquitously expressed transcription factor upregulating detoxifying enzymes, like dioxin and benzo[a]pyrene (BaP) have been shown to promote atherosclerosis. Furthermore, recovery of the blood flow after hindlimb ischemia is significantly enhanced in AhR-deficient mice demonstrating increased angiogenesis in the absence of AhR. Thus, there seems to be a link between AhR, vessel functionality and age-related cardiovascular diseases.
To investigate the role of the AhR in health span and vessel function, we analyzed AhR-deficient Caenorhabditis elegans, vessel stiffness in AhR-knockout mice and human subjects of different age and with varying levels of AhR expression as well as functional parameters in primary human endothelial cells (EC) after AhR activation.
AhR-deficient C. elegans showed not only an extended life span, but also enhanced motility. In AhR-knockout mice, we observed a reduced PWV in both old and young animals, suggesting that AhR impairs vessel function already at young age. Concomitantly, eNOS phosphorylation at serine 1178, a surrogate marker for eNOS activation, was enhanced in aortas of knockout animals. In line with this, the AhR agonist BaP increased an inhibitory phosphorylation on eNOS in EC. Moreover, BaP reduced migration of EC without changes in proliferation or apoptosis, an effect that was reversed by addition of the AhR antagonist 3’methoxy-4’nitroflavone. In human subjects we demonstrated not only a positive correlation between age and pulse wave velocity (PWV), a readout for vessel stiffness, but also between AhR expression in blood cells and PWV, again suggesting a negative impact of AhR on vessel functionality.
Our data demonstrate that loss of AhR extends life span as well as health span in C. elegans. Knockout of AhR in mice leads to improvement of vessel functionality by decreasing vessel stiffness. Finally, the PWV in humans positively correlates not only with age but also with the expression of AhR. Thus, AhR expression may be useful as a new predictor of healthy aging from nematodes to humans.
Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span
