Beling, T. | bioRxiv Science

bioRxiv2026

GENETIC AND PHARMACOLOGIC ACTIVATION OF BECLIN1 PREVENTS ALDOSTERONE-INDUCED CARDIOVASCULAR DAMAGE

BackgroundAldosterone promotes endothelial dysfunction and cardiovascular injury through mineralocorticoid receptor (MR) activation. Autophagy is essential for endothelial homeostasis, yet its role in aldosterone-mediated vascular dysfunction remains unclear. We tested whether aldosterone impairs autophagic flux and whether restoring autophagy via Beclin1 (BCN1) activation protects vascular and cardiac function. MethodsEndothelial and vascular responses to aldosterone were assessed in wild-type mice, BCN1 gain-of-function mice (Becn1), and mice treated with spermidine or a BCN1- activating TB-peptide. Vascular function, nitric oxide (NO)/reactive oxygen species (ROS) production, autophagy markers, endothelial migration, and cardiac fibrosis were evaluated using wire myography, fluorescence assays, Western blotting, confocal microscopy, migration assays, and histology. ResultsAldosterone impaired endothelium-dependent relaxation, decreased NO, increased ROS, and disrupted autophagic flux in an MR-dependent manner, indicated by LC3 accumulation and reduced p62 and BCN1 expression. Spermidine restored endothelial function and normalized NO and ROS levels. BCN1 gain-of-function mice were protected from aldosterone-induced endothelial dysfunction and exhibited reduced coronary and myocardial fibrosis. TB-peptide activation of BCN1 enhanced autophagic flux, improved vascular function, decreased cardiac fibrosis, and rescued endothelial migration impaired by aldosterone. ConclusionsAldosterone induces endothelial dysfunction by suppressing autophagic flux through MR activation. Genetic or pharmacologic enhancement of BCN1-dependent autophagy restores endothelial homeostasis and prevents vascular and cardiac injury, identifying autophagy activation as a promising therapeutic approach for cardiovascular diseases associated with mineralocorticoid excess.

physiology↗

bioRxiv2026

CCR5/CCL5 Links Mitochondrial Dysfunction to Angiotensin II Vascular Injury

AIMChemokine signaling contributes to vascular inflammation and dysfunction in hypertension, yet the intracellular mechanisms linking CCL5/CCR5 activation to vascular impairment remain unclear. We tested the hypothesis that angiotensin II (Ang II) amplifies CCL5/CCR5 signaling to promote mitochondrial dysfunction and oxidative stress in the vasculature. METHODSWild-type and CCR5-deficient mice were infused with Ang II for 14 days, and separate cohorts received recombinant CCL5. Vascular function and remodeling were assessed in aorta and mesenteric arteries, while mitochondrial respiration, membrane potential, and reactive oxygen species (ROS) production were evaluated in vascular smooth muscle cells (VSMCs). RESULTSAng II increased circulating CCL5 levels and upregulated vascular CCR5 expression. CCR5 deficiency protected against Ang II-induced vascular dysfunction, remodeling, and inflammation. CCL5 infusion impaired endothelium-dependent relaxation and enhanced contractility without inducing structural remodeling. In VSMCs, CCL5 disrupted mitochondrial respiration, reduced maximal respiratory capacity, altered membrane potential, and increased mitochondrial ROS in a CCR5-dependent manner. Mitochondrial antioxidant treatment restored endothelial function but did not normalize enhanced contractility. In addition, vessels from CCL5-treated mice were unresponsive to acute mitochondrial uncoupling, consistent with impaired mitochondrial bioenergetic reserve. CONCLUSIONAng II amplifies CCL5/CCR5 signaling to drive mitochondrial dysfunction and oxidative stress, thereby promoting vascular impairment, and identify this pathway as a potential therapeutic target in hypertension.

physiology↗