Biology subjects

Bruder, A.

Publications and source records attributed to Bruder, A..

7 recordsLinked to original sources

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

CASC15 dictates vascular smooth muscle cell growth fate and pathological vascular remodeling through post-transcription regulation of mitotic fidelity

Vascular smooth muscle cell (SMC) growth, whether hyperplastic or hypertrophic, is a central determinant of vascular remodeling in cardiovascular disease, yet the molecular regulators that direct SMC toward a specific growth fate remain poorly understood. Here, we identify the long non-coding RNA CASC15 as a critical regulator of SMC growth and vascular remodeling. CASC15 is enriched in the vasculature and SMC-rich tissues in humans and mice, and its locus harbors SNPs significantly associated with coronary artery disease and blood pressure. We identify a novel SMC-selective CASC15 isoform (S-CASC15) whose expression level determines SMC growth fate: elevated S-CASC15 promotes proliferation, while its loss drives hypertrophy, polyploidization, and binucleation. In vivo depletion of CASC15 limits vascular injury-induced neointima formation and atherosclerotic lesion expansion. Conversely, CASC15 overexpression exacerbates injury-induced neointimal hyperplasia. However, CASC15 KO mice exhibit spontaneous medial hypertrophy and vascular hypercontractility. Mechanistically, loss of S-CASC15 expression causes mitotic defects, followed by arrest in the G1 phase of hypertrophic and polyploid cells. We found that S-CASC15 pro-proliferative function is mediated through its interaction with RNA-binding proteins, including Nucleolin, and by regulating the stability of cell cycle checkpoint gene transcripts, thereby ensuring mitotic fidelity. Together, these findings establish CASC15 as a pivotal molecular switch governing the balance between hyperplastic and hypertrophic vascular remodeling and as a potential therapeutic target in cardiovascular disease.

Cell Biology↗

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↗

bioRxiv2025

Progranulin deficiency aggravates aging-induced vascular injury

SignificanceVascular aging is a major contributor to cardiovascular disease, yet the molecular mechanisms of age-associated vascular dysfunction remain incompletely defined. This study reveals a critical role for progranulin (PGRN) in regulating vascular senescence, function, and remodeling during aging. MethodsWe assessed PGRN expression in human and mouse arteries and senescent vascular smooth muscle cells (VSMCs). Functional vascular studies were performed in PGRN-deficient (PGRN-/-) mice. Senescence was modulated pharmacologically using the senolytic agent navitoclax (ABT-263), and vascular phenotype was evaluated in adult (6-month-old) and aged mice (18-month-old). ResultsPGRN expression increased with age in human and mouse arteries, correlating with elevated p21 expression. PGRN deficiency in adult mice induced endothelial dysfunction, increased vasoconstriction, and induced vascular inflammation and remodeling. Transcriptomic analysis of PGRN-/- VSMCs revealed a senescence-associated signature, including perturbed oxidative phosphorylation, altered epigenetic regulation, and collagen pathways. Pharmacological clearance of senescent cells improved endothelial function but increased vascular contractility in PGRN-/- mice. In aged mice, PGRN deficiency aggravated vascular dysfunction, remodeling, and renal injury without further increasing senescence markers--suggesting premature, rather than progressive, senescence in the PGRN-/- mice. ConclusionPGRN is a novel regulator of vascular aging, coordinating senescence, inflammation, and remodeling. While endothelial senescence contributes to dysfunction, VSMCs senescence may serve an adaptive role in modulating vascular tone. Targeting PGRN or senescence pathways may offer therapeutic opportunities for age-related vascular diseases, especially in patients with PGRN mutations associated with frontotemporal dementia.

cell biology↗

bioRxiv2024

A global synthesis on land-cover changes in watersheds shaping freshwater detrital food webs

Anthropogenic land-cover changes are among the most pressing global threats to both aquatic and terrestrial ecosystems, jeopardising biodiversity and the critical connections between these systems. Resource flows and trophic interactions intricately link aquatic and terrestrial ecosystems, with terrestrial-derived detritus playing a foundational role in supporting aquatic food webs. These detrital inputs form essential cross-ecosystem linkages, underpinning key ecological processes and providing vital resources for aquatic communities. Yet, little research has focused on how land-cover changes cascade across this linkage. To better understand how land-cover changes in the watershed influence freshwater detrital food webs, we conducted a meta-analysis of field studies reporting the effects of vegetation changes on freshwater detrital consumers and organic matter decomposition. The results from 144 studies, reporting 1235 comparisons, showed that, overall, land-cover changes in the watershed vegetation, especially through harvest and land-use conversion, have negative effects on aquatic biodiversity and ecosystem processes. These vegetation changes reduced diversity, abundance, and biomass across multiple trophic levels in freshwater detrital food webs. Studies examining multiple organism groups most often observed negative responses across multiple trophic levels, suggesting that the land-cover changes negatively affected multiple detrital food web components simultaneously. Our results also show that outcomes of restoration of watershed vegetation were context-dependent, and no clear trend of improvement was visible. Therefore, conservation of natural riparian and catchment vegetation are key to maintain freshwater ecosystem processes and aquatic biodiversity worldwide, and more efficient and evidence-based restoration measures are urgently needed. As our global synthesis shows that direct human-induced alterations of vegetation type in watersheds have significant negative effects on freshwater detrital food webs, there is a pressing need to consider cross-ecosystem consequences of land-cover changes in conservation and ecosystem management.

ecology↗

bioRxiv2024

Biodiversity and riparian forests are mutual biological drivers of ecosystem functions in temperate and tropical streams

Fluxes of energy, matter, and organisms sustain linkages and functions within and between ecosystems. Yet, how biological drivers influence interactions and functions at the interface between aquatic and terrestrial environments (i.e., aquatic-terrestrial ecosystem functions) locally and across regions has received little attention. To test the relative importance of biological drivers on multiple aquatic-terrestrial ecosystem functions, we subsidised local terrestrial detritus in forested and non-forested stream sites in a temperate and tropical region. We also manipulated leaf litter diversity (horizontal biodiversity of resources) and macroinvertebrate access (vertical biodiversity of consumers). We measured secondary production of aquatic fungi, in-stream leaf litter nitrogen loss, and decomposition rates. The simultaneous provision of all three ecosystem functions (i.e., multifunctionality) was positively driven by vertical biodiversity and riparian forests in both regions. In both tropical and temperate streams, nitrogen loss was associated with vertical biodiversity. Decomposition rates were also enhanced by vertical biodiversity and linked to other ecosystem functions. These results reveal strong and consistent effects of biodiversity and riparian forests on aquatic-terrestrial ecosystem functions in freshwater detrital food webs in both temperate and tropical headwater streams. Thus, disentangling the drivers of ecosystem functions in these systems requires an understanding of underlying mechanisms beyond ecosystem borders.

ecology↗

bioRxiv2023

Riparian forests shape trophic interactions in detrital stream food webs

Freshwater and terrestrial biodiversity is linked through resource flows. For example, subsidies from the riparian vegetation form the base of food webs in small streams. Despite the key role of detritivores in these food webs, consequences of altered resource availability and riparian vegetation type on their trophic strategies are largely unknown. Therefore, we experimentally tested direct and indirect effects of riparian vegetation type on trophic interactions and dietary imbalances of detritivores. We used stoichiometric and isotopic differences between consumers and resources as functional measures of trophic link strength. Our results show that the lack - compared to the presence - of riparian forests directly affected both stoichiometric and isotopic differences in detrital food webs, yet with diverging patterns between resources and consumers, ultimately leading to aquatic-terrestrial decoupling. Consequently, our findings demonstrate that riparian forests are essential for aquatic food webs by influencing both organisms and interactions networks.

ecology↗