Breaking the Chains of Vascular Stiffness: The Role of Fibulin-1 and its Regulatory Network

Abstract

Introduction: Vascular stiffness, a hallmark of aging and cardiovascular disease, involves vascular smooth muscle cell (VSMC) senescence and extracellular matrix (ECM) dysregulation.  This study investigates the role of fibulin-1 (Fbln1) in these processes.Methods: Plasma proteomic profiling identified dysregulated proteins in vascular stiffness pedigrees. Fbln1 knockout mice and dual vascular stiffness models (natural aging and chronic angiotensin II [Ang II] infusion) were established. Phenotypic assessments included pulse wave velocity (PWV), histology, and molecular markers. Mechanistic investigations integrating DNA pull-down assays, dual-luciferase reporter assays, and RNA sequencing (RNA-seq) were employed to dissect the transcriptional and signaling axis regulating Fbln1 expression and function.Results: Elevated plasma Fbln1 correlated with hereditary vascular stiffness. Both aging and Ang II promote vascular stiffness, whereas Fbln1 knockdown ameliorates this phenotype by reducing PWV, reversing VSMC senescence, and attenuating collagen deposition. Zinc Finger Protein 384 (ZNF384) was identified as a transcriptional activator of Fbln1, which promoted VSMC senescence and collagen deposition via transforming growth factor-beta (TGF-β)/SMAD family member 3 (Smad3). Inhibiting TGF-β/Smad3 signaling abolished Fbln1-driven senescence and ECM remodeling.  Conclusion: Fbln1 exacerbates vascular stiffness through ZNF384-mediated transcriptional activation and TGF-β/Smad3-dependent ECM/senescence pathways.  Targeting Fbln1 or its regulators may offer therapeutic strategies for age-related vascular pathologies.

Note:
Funding declaration: This work was supported by the Hubei Province Innovation Project (Grant Number: 2024BCB045; principal investigator: LR).

Conflict of Interests: None.

Ethical Approval: The study protocol received approval from the Ethics Committee of Tongji Hospital, Huazhong University of Science and Technology (Ethics Committee approval number: S248-1), adhering to the Declaration of Helsinki guidelines. Written informed consent was secured from all participants prior to sample acquisition. All animal experiments were conducted in accordance with the guidelines of the National Institutes of Health and approved by the Experimental Animal Research Committee of Tongji Medical College, Huazhong University of Science and Technology. The ethical approval number for this experiment is TJH-202104016.

Keywords: Cell senescence, Fibulin-1, vascular stiffness, ZNF384, TGF-β