Biology subjects

Bruder-Nascimento, T.

Publications and source records attributed to Bruder-Nascimento, T..

10 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↗

bioRxiv2023

Adjusted vascular contractility relies on integrity of progranulin pathway: Insights into mitochondrial function

ObjectiveCardiovascular disease (CVD) is a global health crisis and a leading cause of mortality. The intricate interplay between vascular contractility and mitochondrial function is central to CVD pathogenesis. The progranulin gene (GRN) encodes glycoprotein progranulin (PGRN), a ubiquitous molecule with known anti-inflammatory property. However, the role of PGRN in CVD remains enigmatic. In this study, we sought to dissect the significance of PGRN in the regulation vascular contractility and investigate the interface between PGRN and mitochondrial quality. MethodOur investigation utilized aortae from male and female C57BL6/J wild-type (PGRN+/+) and B6(Cg)-Grntm1.1Aidi/J (PGRN-/-) mice, encompassing wire myograph assays to assess vascular contractility and primary aortic vascular smooth muscle cells (VSMCs) for mechanistic insights. ResultsOur results showed suppression of contractile activity in PGRN-/- VSMCs and aorta, followed by reduced -smooth muscle actin expression. Mechanistically, PGRN deficiency impaired mitochondrial oxygen consumption rate (OCR), complex I activity, mitochondrial turnover, and mitochondrial redox signaling, while restoration of PGRN levels in aortae from PGRN-/- mice via lentivirus delivery ameliorated contractility and boosted OCR. In addition, VSMC overexpressing PGRN displayed higher mitochondrial respiration and complex I activity accompanied by cellular hypercontractility. Furthermore, increased PGRN triggered lysosome biogenesis by regulating transcription factor EB and accelerated mitophagy flux in VSMC, while treatment with spermidine, an autophagy inducer, improved mitochondrial phenotype and enhanced vascular contractility. Finally, angiotensin II failed to induce vascular contractility in PGRN-/- suggesting a key role of PGRN to maintain the vascular tone. ConclusionOur findings suggest that PGRN preserves the vascular contractility via regulating mitophagy flux, mitochondrial complex I activity, and redox signaling. Therefore, loss of PGRN function appears as a pivotal risk factor in CVD development.

pharmacology and toxicology↗

bioRxiv2023

Role Of The C-C Motif Chemokine Ligand 5 (CCL5) And Its Receptor, C-C Motif Chemokine Receptor 5 (CCR5) In The Genesis Of Aldosterone-induced Hypertension, Vascular Dysfunction, And End-organ Damage

BackgroundAldosterone, a mineralocorticoid steroid hormone, has been described to initiate cardiovascular diseases by triggering exacerbated sterile vascular inflammation. The functions of C-C Motif Chemokine Ligand 5 (CCL5) and its receptor, C-C Motif Chemokine Receptor 5 (CCR5), are well known in infectious diseases, but their roles in the genesis of aldosterone-induced vascular injury and hypertension are unknown. MethodsWe analyzed the vascular profile, blood pressure, and renal damage in wild-type (CCR5+/+) and CCR5 knockout (CCR5-/-) mice treated with aldosterone (600 {micro}g/kg/day for 14 days) while receiving 1% saline to drink. ResultsHere, we show that CCR5 plays a central role in aldosterone-induced vascular injury, hypertension, and renal damage. Long-term infusion of aldosterone in CCR5+/+ mice resulted in exaggerated CCL5 circulating levels and vascular CCR5 expression. Aldosterone treatment also triggered vascular injury, characterized by endothelial dysfunction and inflammation, hypertension, and renal damage. Mice lacking CCR5 were protected from aldosterone-induced vascular damage, hypertension, and renal injury. Mechanistically, we demonstrated that CCL5 increased NADPH oxidase 1 (Nox1) expression, reactive oxygen species (ROS) formation, NF{kappa}B activation, and inflammation and reduced nitric oxide production in isolated endothelial cells. These effects were abolished by antagonizing CCR5 with Maraviroc. Finally, aortae incubated with CCL5 displayed severe endothelial dysfunction, which is prevented by blocking Nox1, NF{kappa}B, or with Maraviroc treatment. ConclusionsOur data demonstrate that CCL5/CCR5, through activation of NFkB and Nox1, is critically involved in aldosterone-induced vascular and renal damage and hypertension. Our data place CCL5 and CCR5 as potential targets for therapeutic interventions in conditions with aldosterone excess.

pharmacology and toxicology↗

bioRxiv2023

NADPH oxidase 4-derived hydrogen peroxide counterbalances testosterone-induced endothelial dysfunction and migration

BackgroundHigh levels of testosterone (Testo) are associated with cardiovascular risk by increasing reactive oxygen species (ROS) formation. NADPH oxidases (NOX) are the major source of ROS in the vasculature in cardiovascular diseases. NOX4 is a unique isotype, which produces hydrogen peroxide (H2O2), and its participation in cardiovascular biology is controversial. So far, it is unclear whether NOX4 protects from Testo-induced endothelial injury. Thus, we hypothesized that supraphysiological levels of Testo induce endothelial NOX4 expression to attenuate endothelial injury. MethodsHuman Mesenteric Vascular Endothelial Cells (HMEC) and Human Umbilical Vein Endothelial Cells (HUVEC) were treated with Testo (10-7 M) with or without a NOX4 inhibitor [GLX351322 (10-4 M)]. In vivo, 10-week-old C57Bl/6J male mice were treated with Testo (10 mg/kg) for 30 days to study endothelial function. ResultsTesto increased mRNA and protein levels of NOX4 in HMEC and HUVEC. Testo increased superoxide anion (O2-) and H2O2 production, which were abolished by NOX1 and NOX4 inhibition, respectively. Testo also attenuated bradykinin-induced NO production, which was further impaired by NOX4 inhibition. In vivo, Testo decreased H2O2 production in aortic segments and triggered endothelial dysfunction [decreased relaxation to acetylcholine (ACh)], which was further impaired by GLX351322 and by a superoxide dismutase and catalase mimetic (EUK134). Finally, Testo led to a dysregulated endothelial cells migration, which was exacerbated by GLX351322. ConclusionThese data indicate that supraphysiological levels of Testo increase the endothelial expression and activity of NOX4 to counterbalance the deleterious effects caused by Testo in endothelial function.

pharmacology and toxicology↗

bioRxiv2023

Suppressed vascular Rho-kinase activation is a protective cardiovascular mechanism in obese female mice

BackgroundObesity is the number one cardiovascular risk factor for both men and women and is a complex condition. Although a sex dimorphism on vascular function has already been noted, the underlying processes remain unclear. The Rho-kinase pathway has a unique role in controlling vascular tone, and in obese male mice, hyperactivation of this system results in worsened vascular constriction. We investigated whether female mice exhibit decreased Rho-kinase activation as a protective mechanism in obesity. MethodsWe exposed male and female mice to a high-fat diet (HFD) for 12 weeks. At the end, energy expenditure, glucose tolerance, adipose tissue inflammation, and vascular function were investigated. ResultsMale mice were more sensitive to HFD-induced body weight gain, glucose tolerance, and inflammation than female mice. After establishing obesity, female mice demonstrated increase in energy expenditure, characterized by an increase in heat, whereas male mice did not. Interestingly, obese female mice, but not male, displayed attenuated vascular contractility to different agonists, such difference was blunted by inhibition of Rho-kinase. Finally, aortae from obese female mice, but not male, responded prematurely to Rho-kinase inhibitor, which was accompanied by a suppressed Rho-kinase activation, measured by western blot. ConclusionIn obesity, female mice demonstrate a vascular protective mechanism - suppression of vascular Rho-kinase - to minimize the cardiovascular risk associated with obesity, whereas male mice do not generate any adaptive response. Future investigations can help to understand how Rho-kinase becomes suppressed in female during obesity.

physiology↗

bioRxiv2023

Progranulin maintains blood pressure and vascular tone dependent on EphrinA2 and Sortilin1 receptors and eNOS activation

BackgroundThe mechanisms determining vascular tone are still not completely understood, even though it is a significant factor in blood pressure management. Many circulating proteins have a significant impact on controlling vascular tone. Progranulin (PGRN) displays anti-inflammatory effects and has been extensively studied in neurodegenerative illnesses. We investigated whether PGRN sustains the vascular tone that helps regulate blood pressure. MethodsWe used male and female C57BL6/J wild type (PGRN+/+) and B6(Cg)-Grntm1.1Aidi/J (PGRN-/-) to understand the impact of PGRN on vascular contractility and blood pressure. ResultsWe found that male and female PGRN-/- mice display elevated blood pressure followed by hypercontractility to noradrenaline in mesenteric arteries, which are restored by supplementing the mice with recombinant PGRN (rPGRN). In ex vivo experiments, rPGRN attenuated the vascular contractility to noradrenaline in male and female PGRN+/+ arteries, which was blunted by blocking EphrinA2 or Sortlin1. To understand the mechanisms whereby PGRN evokes anti-contractile effects, we inhibited endothelial factors. L-NAME [nitric oxide (NO) synthase (NOS) inhibitor] prevented the PGRN effects, whereas indomethacin (cyclooxygenases inhibitor) only affected the contractility in arteries incubated with vehicle, indicating the PGRN increases nitric oxide and decreases contractile prostanoids. Finally, rPGRN induced endothelial NOS (eNOS) phosphorylation and NO production in isolated mesenteric endothelial cells. ConclusionCirculating PGRN regulates vascular tone and blood pressure via EphrinA2 and Sortlin1 receptors and eNOS activation. Collectively, our data suggest that deficiency in PGRN is a cardiovascular risk factor and that PGRN might be a new therapeutic avenue to treat high blood pressure. Clinical PerspectiveWhat is new? O_LIPGRN displays vascular anti-contractile effects dependent on EphrinA2 and Sortilin1 receptors and nitric oxide formation in male and female C_LIO_LIDeficiency in PGRN triggers high blood pressure and induces vascular dysfunction characterized by hypercontractility to noradrenaline C_LIO_LIPGRN supplementation restores blood pressure and vascular dysfunction in PGRN-deficient mice C_LI What are the clinical implications? O_LIPGRN deficiency is associated with neurodegenerative diseases including neuronal ceroid lipofuscinosis and frontotemporal dementia (FTD). Our study reveals that a lack of PGRN might be associated with vascular dysfunction and high blood pressure C_LIO_LISupplementation with PGRN might be a potential therapeutic route to treat high blood pressure and diseases associated with vascular dysfunction C_LIO_LIReduction in PGRN might be a target to screen for higher cardiovascular risk C_LI

pharmacology and toxicology↗

bioRxiv2022

Progression of vascular function and blood pressure in a mouse model of Kawasaki disease

BackgroundKawasaki disease (KD) is a systemic vasculitis of childhood characterized by vascular damage in the acute stage, which can persist into the late stage. Aneurysms, myocardial infarction, and death are long-standing complications associated with KD. The vascular mechanisms in the cardiovascular risk of KD are not fully studied. Herein, we investigated the vascular function and blood pressure regulation in a murine model of KD. Material and methodsWe used the Candida albicans water soluble (CAWS) fraction model. Mice were injected with 4 mg CAWS for five consecutive days and separated into 3 groups. Control (Ctrl): water injected for 5 days; CAWS 7 days (C7): CAWS injected for 5 days plus 2 additional days of wait; CAWS 28 days (C28): CAWS injected for 5 days plus 23 additional days of wait. Blood pressure was analyzed via radiotelemetry. In the end, the heart and arteries were harvested for vasculitis characterization and vascular function in a wire myograph. Rat Aortic Vascular Smooth Muscle cells (RASMC) were used to dissect the molecular mechanisms in vitro. Main findingsC7 presented elevated inflammatory markers in the coronary area (CA) and abdominal aortae (AA), whereas C28 showed severe vasculitis in CA and AA. No difference was found in blood pressure and heart rate. Vascular dysfunction characterized by higher contractility to norepinephrine (NA) in C7 and C28 was abolished by blocking nitric oxide (NO) production, reactive oxygen species (ROS), and cyclooxygenase (COX)-derived products. RASMC treated with CAWS (10ug/mL) presented an increase in COX2 expression, which was prevented by pre-treating the cells with TAK-242 [Toll like receptor 4 (TLR4) antagonist, 3x10-5M]. ConclusionOur data indicate that the murine model of KD is associated with vascular dysfunction likely dependent on COX-derived products, oxidant properties, and NO bioavailability. Furthermore, VSMC may present an important role in the genesis of vascular dysfunction and vasculitis via the TLR4 pathway. Finally, the CAWS model seems not to be appropriate to study KD-associated shock. More studies are necessary to understand whether vascular dysfunction and COXs are triggers for vasculitis.

pharmacology and toxicology↗