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.
Authors
- Beatriz Costa de Oliveira Queiróz de Souza (ORCID: https://orcid.org/0000-0003-3175-2240)
- Ayumi Aurea Miyakawa (ORCID: https://orcid.org/0000-0003-3911-3259)
- Renato Simões Gaspar (ORCID: https://orcid.org/0000-0001-6639-9470)
- Kate S. Carroll (ORCID: https://orcid.org/0000-0002-7624-9617)
- Tiphany De Bessa (ORCID: https://orcid.org/0000-0002-5771-259X)
- Daniela Kajihara (ORCID: https://orcid.org/0000-0001-9239-4198)
- Lívia Teixeira (ORCID: https://orcid.org/0000-0002-6227-3202)
- Percíllia Oliveira (ORCID: https://orcid.org/0000-0002-9076-9707)
- Francisco Rafael Martins Laurindo (ORCID: https://orcid.org/0000-0001-6837-4509)
- Paola Cristina Branco (ORCID: https://orcid.org/0000-0002-0886-1222)
- Iuri Cordeiro Valadão (ORCID: https://orcid.org/0000-0001-8417-6836)
- Geovana S. Garcia (ORCID: https://orcid.org/0000-0001-9945-9329)
- Victor Debbas
- Samantha K. Teixeira (ORCID: https://orcid.org/0000-0001-9534-2174)
- Carolina Morales Portas
- Lucas Gutierre
- Ricardo C. Massucatto (ORCID: https://orcid.org/0009-0009-1615-1579)
- Julia Martins Felipe de Souza
- Arijit Bhowmik (ORCID: https://orcid.org/0000-0001-8321-9996)
- Leonardo Y. Tanaka (ORCID: https://orcid.org/0000-0002-9276-9057)
Institutions
- Scripps Research Institute (US)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR)
Publication Details
- Journal
- iScience
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1016/j.isci.2025.114264
- Primary Topic
- Endoplasmic Reticulum Stress and Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00