Abstract
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.
Highlights
Complications due to cardiovascular disease increase dramatically with age [1]
The results suggest that the functional effects of vascular cell senescence are dominated by the endothelium
Senescence in cord blood-derived endothelial colony forming cells (CBECFCs) was measured by immunofluorescence of the cell-cycle inhibitor p21 [27]
Summary
Complications due to cardiovascular disease increase dramatically with age [1]. In particular, a decline in the endothelium-dependent vasoreactivity occurs, even in healthy, low-risk individuals, which predisposes them to cardiovascular disease [2]. Vascular cells accumulate damage in a variety of ways. This damage results in cellular senescence, a phenotype in which cells have exhausted their proliferative capacity yet resist apoptosis [3,4]. Five-day treatment with H2 O2 did not significantly affect VCAM-1 expression unless co-treated with 100 U/mL TNF-α. H2 O2 caused a significant increase in VCAM-1 expression (Figure 2B). Treatment with 100 μM H2 O2 for seven days caused a significant increase in E-Selectin expression that was comparable to TNF-α induced E-Selectin expression in controls (Figure 2C,D). Treatment with 100 U/mL TNF-α caused significant E-selectin expression in ECFCs cultured for seven days, regardless of H2 O2 concentration (Figure 2C,D). E-selectin expression in cells treated for five days with 100 μM H2 O2 and given
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