A mechanism for the disrupted redox regulation of vascular contractility during aging.

Vascular dysfunction contributes to aging-related phenotype, but mechanisms remain unclear. We propose that aging promotes a deregulated convergence between cellular redox processes and mechanoregulation. We focus on Protein Disulfide Isomerase-A1 (PDI), an endoplasmic reticulum redox chaperone known to modulate NADPH oxidase complexes and to fine-tune cytoskeletal remodeling. Our hypothesis is that PDI connects oxidant generation to actin cytoskeleton remodeling via the modulation of protein sulfenylation, an oxidative post-translational modification. We first show that protein sulfenylation supports vascular contractility and F-actin assembly during mechanoadaptation or agonist-induced contraction. Meanwhile, PDI supports sulfenylation-dependent actin remodeling. Moreover, aged murine arteries lose the sulfenic acid-related component of contractility, while PDI overexpression over-rides this dysfunction and restores aging-related vascular contractility. We further confirm a direct PDI-actin interaction modulated by sulfenic acid. Overall, signaling connections between PDI and sulfenylated proteins behave as an upstream integrative system regulating F-actin assembly, a mechanism that is impaired during aging-induced vascular dysfunction.