Endothelial Cell Senescence with Age is Associated with Oxidative Stress‐Mediated Suppression of Endothelial Function in Healthy Adults

Clinical studies have established a connection between oxidative stress, aging, and atherogenesis. These factors contribute to senescence and inflammation in the endothelium and significant reductions in endothelium-dependent vasoreactivity in aged patients. Tissue-engineered blood vessels (TEBVs) recapitulate the structure and function of arteries and arterioles in vitro. We developed a TEBV model for vascular senescence and examined the relative influence of endothelial cell and smooth muscle cell senescence on vasoreactivity. Senescence was induced in 2D endothelial cell cultures and TEBVs by exposure to 100 µM H2O2 for one week to model chronic oxidative stress. H2O2 treatment significantly increased senescence in endothelial cells and mural cells, human neonatal dermal fibroblasts (hNDFs), as measured by increased p21 levels and reduced NOS3 expression. Although H2O2 treatment induced senescence in both the endothelial cells (ECs) and hNDFs, the functional effects on the vasculature were endothelium specific. Expression of the leukocyte adhesion molecule vascular cell adhesion molecule 1 (VCAM-1) was increased in the ECs, and endothelium-dependent vasodilation decreased. Vasoconstriction and endothelium-independent vasodilation were preserved despite mural cell senescence. The results suggest that the functional effects of vascular cell senescence are dominated by the endothelium.

Download Full-text

Oxidative Stress Induces Endothelial Cell Senescence via Downregulation of Sirt6

BioMed Research International ◽

10.1155/2014/902842 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 40

Author(s):

Rong Liu ◽

Hua Liu ◽

Yonju Ha ◽

Ronald G. Tilton ◽

Wenbo Zhang

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Diabetic Retinopathy ◽

Endothelial Cell ◽

Vascular Complications ◽

Cell Senescence ◽

Diabetic Vascular Complications ◽

Key Factor ◽

And Oxidative Stress ◽

Vascular Cell Senescence

Accumulating evidence has shown that diabetes accelerates aging and endothelial cell senescence is involved in the pathogenesis of diabetic vascular complications, including diabetic retinopathy. Oxidative stress is recognized as a key factor in the induction of endothelial senescence and diabetic retinopathy. However, specific mechanisms involved in oxidative stress-induced endothelial senescence have not been elucidated. We hypothesized that Sirt6, which is a nuclear, chromatin-bound protein critically involved in many pathophysiologic processes such as aging and inflammation, may have a role in oxidative stress-induced vascular cell senescence. Measurement of Sirt6 expression in human endothelial cells revealed that H2O2treatment significantly reduced Sirt6 protein. The loss of Sirt6 was associated with an induction of a senescence phenotype in endothelial cells, including decreased cell growth, proliferation and angiogenic ability, and increased expression of senescence-associatedβ-galactosidase activity. Additionally, H2O2treatment reduced eNOS expression, enhanced p21 expression, and dephosphorylated (activated) retinoblastoma (Rb) protein. All of these alternations were attenuated by overexpression of Sirt6, while partial knockdown of Sirt6 expression by siRNA mimicked the effect of H2O2. In conclusion, these results suggest that Sirt6 is a critical regulator of endothelial senescence and oxidative stress-induced downregulation of Sirt6 is likely involved in the pathogenesis of diabetic retinopathy.

Download Full-text

Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00416.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. H890-H895 ◽

Cited By ~ 48

Author(s):

Matthew J. Rossman ◽

Rachelle E. Kaplon ◽

Sierra D. Hill ◽

Molly N. McNamara ◽

Jessica R. Santos-Parker ◽

...

Keyword(s):

Endothelial Cell ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Cell Senescence ◽

Vascular Endothelial ◽

Vascular Endothelial Dysfunction ◽

Vascular Endothelial Function ◽

Healthy Humans ◽

Age Related ◽

Habitual Exercise

Cellular senescence is emerging as a key mechanism of age-related vascular endothelial dysfunction, but evidence in healthy humans is lacking. Moreover, the influence of lifestyle factors such as habitual exercise on endothelial cell (EC) senescence is unknown. We tested the hypothesis that EC senescence increases with sedentary, but not physically active, aging and is associated with vascular endothelial dysfunction. Protein expression (quantitative immunofluorescence) of p53, a transcription factor related to increased cellular senescence, and the cyclin-dependent kinase inhibitors p21 and p16 were 116%, 119%, and 128% greater (all P < 0.05), respectively, in ECs obtained from antecubital veins of older sedentary (60 ± 1 yr, n = 12) versus young sedentary (22 ± 1 yr, n = 9) adults. These age-related differences were not present (all P > 0.05) in venous ECs from older exercising adults (57 ± 1 yr, n = 13). Furthermore, venous EC protein levels of p53 ( r = −0.49, P = 0.003), p21 ( r = −0.38, P = 0.03), and p16 ( r = −0.58, P = 0.002) were inversely associated with vascular endothelial function (brachial artery flow-mediated dilation). Similarly, protein expression of p53 and p21 was 26% and 23% higher (both P < 0.05), respectively, in ECs sampled from brachial arteries of healthy older sedentary (63 ± 1 yr, n = 18) versus young sedentary (25 ± 1 yr, n = 9) adults; age-related changes in arterial EC p53 and p21 expression were not observed ( P > 0.05) in older habitually exercising adults (59 ± 1 yr, n = 14). These data indicate that EC senescence is associated with sedentary aging and is linked to endothelial dysfunction. Moreover, these data suggest that prevention of EC senescence may be one mechanism by which aerobic exercise protects against endothelial dysfunction with age. NEW & NOTEWORTHY Our study provides novel evidence in humans of increased endothelial cell senescence with sedentary aging, which is associated with impaired vascular endothelial function. Furthermore, our data suggest an absence of age-related increases in endothelial cell senescence in older exercising adults, which is linked with preserved vascular endothelial function. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/aging-exercise-and-endothelial-cell-senescence/ .

Download Full-text