As endothelial cells (ECs) age, morphological and physiological changes occur that may alter macromolecular transport and cause subsequent disease development. ECs in atherosclerotic regions exhibit high cell turnover and high levels of oxidative stress due to transient flow patterns and low and oscillating shear stress. This leads to replicative or stress-induced senescence. Resveratrol indirectly reverses senescence-associated phenotypes via competitive inhibition of cAMP-degrading phosphodiesterases (PDEs). Elevated levels of membrane-associated cAMP activate the cyclic AMP-regulated guanosine nucleotide exchange factor Epac1 which, in turn, leads to guanosine triphosphate (GTP) binding to the small G protein Rap1. GTP bound Rap1 activates the deacetylase SIRTUIN1 (SIRT1) but also causes changes to the cortical cytoskeleton and organization of VE-cadherin mechanosensor in the endothelial junctions (Figure 1).

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