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

## TL;DR

This paper explores how aging disrupts blood vessel function by linking redox processes and actin remodeling through PDI, a protein that helps maintain vascular contractility.

## Contribution

The study identifies PDI as a key mediator connecting redox signaling and actin remodeling in age-related vascular dysfunction.

## Key findings

- PDI supports sulfenylation-dependent actin remodeling and vascular contractility.
- Aged arteries lose sulfenic acid-related contractility, which is restored by PDI overexpression.
- PDI interacts directly with actin, regulated by sulfenic acid, to control F-actin assembly.

## Abstract

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.

•Actin reorganization promotes the PDI-dependent local production of hydrogen peroxide•PDI links oxidant generation to protein sulfenylation, supporting vasoconstriction•PDI overexpression prevents aging-associated contractile dysfunction

Actin reorganization promotes the PDI-dependent local production of hydrogen peroxide

PDI links oxidant generation to protein sulfenylation, supporting vasoconstriction

PDI overexpression prevents aging-associated contractile dysfunction

Vascular anatomy; Age; Biochemistry; Cell biology