Biology subjects

Fuster, V.

Publications and source records attributed to Fuster, V..

4 recordsLinked to original sources

bioRxiv2026

Endothelial β3-Adrenergic Receptor activation prevents pulmonary hypertension

BackgroundPulmonary hypertension (PH) is a progressive vascular disease characterized by endothelial dysfunction, vascular remodeling and increased pulmonary vascular resistance. The {beta}3-adrenergic receptor ({beta}3-AR) has been implicated in cardiovascular regulation and cardioprotective mechanisms; however, its role in pulmonary vascular disease remains poorly understood. We investigated whether activation of {beta}3-AR protects pulmonary endothelial function and prevents the development of pre-capillary PH. Methods{beta}3-AR expression was evaluated in pulmonary endothelium from patients with Chronic Obstructive Pulmonary Disease (COPD) and in murine models of hypoxia-induced PH. Genetic mouse models including {beta}3-AR knockout (KO) and conditional {beta}3-AR overexpression in endothelial cells (EC) or in smooth muscle cells (SMC), were used to determine cell-specific roles. Pharmacological activation of {beta}3-AR was achieved using the selective {beta}3-agonist mirabegron in hypoxia-induced PH mice and monocrotaline-induced PH rats. Pulmonary vascular reactivity and vasodilatory responses to {beta}3-AR stimulation were evaluated by wire myography in isolated pulmonary arteries. Mechanistic studies were performed in human pulmonary artery endothelial cells (HPAEC) under hypoxic conditions, in human pulmonary arterial smooth muscle cells (HPASMC) and in endothelial nitric oxide synthase (NOS3) KO mice. Results{beta}3-AR was upregulated in pulmonary endothelium of COPD patients and mice exposed to chronic hypoxia. Genetic deletion of {beta}3-AR aggravated PH, whereas endothelial-specific overexpression attenuated the disease phenotype, reducing right ventricular systolic pressure (RVSP), vascular remodeling and right ventricular (RV) hypertrophy. Activation of {beta}3-AR with mirabegron improved pulmonary hemodynamics, reduced vascular remodeling and preserved RV function. {beta}3-AR activation promoted endothelial nitric oxide synthase (eNOS)-dependent NO production, indirectly inhibiting SMC proliferation. Additionally, {beta}3-AR activation improved mitochondrial fitness in endothelial cells by increasing uncoupling protein 2 (UCP2) expression, reducing reactive oxygen species (ROS) generation and preventing mitochondrial fragmentation. ConclusionsThese findings identify endothelial {beta}3-AR as a previously unrecognized regulator of pulmonary vascular homeostasis and provide a strong translational rationale for targeting the {beta}3-adrenergic pathway in PH. Given that mirabegron is already approved for clinical use, our results support its repurposing as a therapeutic strategy for pre-capillary forms of PH.

pharmacology and toxicology↗

bioRxiv2025

Integrative Omics Identifies Candidate Plasma Biomarkers and Cellular Targets Associated with Thoracic Aortic Aneurysm

ObjectivesTo define the cellular landscape of thoracic aortic aneurysm (TAA) and identify circulating biomarkers associated with disease burden. BackgroundTAA is marked by progressive aortic wall weakening and dilation, predisposing to rupture and dissection. However, its cellular architecture remains incompletely defined, and reliable circulating biomarkers are lacking. MethodsSingle-cell RNA sequencing was performed on 17 aortic tissue samples from 10 patients undergoing TAA repair and integrated with publicly available datasets to characterize disease-associated cell states. In parallel, tomographic imaging and plasma proteomics were used to identify biomarkers associated with aortic diameter. Key findings were further assessed through integration with single-cell data, external validation, and in vitro stimulation of primary human adventitial fibroblasts with fibroblast growth factor 23 (FGF-23). ResultsWe identified 25 cellular subsets, including macrophages, endothelial cells, vascular smooth muscle cells, and fibroblasts, with substantial heterogeneity in cellular composition and transcriptional state. Genome-wide association study candidate genes, including JUN and TPM3, showed cell type-specific upregulation. Plasma proteomics identified multiple biomarkers associated with aortic diameter, of which FGF-23 was independently validated in the UK Biobank as elevated in individuals with TAA. FGFR1, the receptor for FGF-23, was selectively expressed in fibroblasts and subsets of vascular smooth muscle cells, with strongest downstream signaling in fibroblasts. FGF-23 stimulation induced inflammatory and extracellular matrix remodeling programs in primary human adventitial fibroblasts. ConclusionsThese findings define the cellular landscape of TAA and identify the FGF-23-FGFR1 axis as a biomarker-linked pathway that may contribute to aneurysm progression. Condensed AbstractThoracic aortic aneurysm (TAA) is characterized by progressive aortic dilation and risk of rupture, yet its cellular architecture and circulating biomarkers remain incompletely defined. We performed single-cell RNA sequencing on 17 aortic samples from 10 patients and integrated these data with public datasets to define the cellular landscape of TAA. In parallel, imaging and plasma proteomics (n=10) were used to identify biomarkers associated with aortic diameter. We identified 25 cellular subsets, including macrophages, endothelial cells, vascular smooth muscle cells, and fibroblasts, with notable transcriptional heterogeneity and cell type-specific upregulation of GWAS-associated genes (e.g., JUN, TPM3). Plasma proteomics identified fibroblast growth factor 23 (FGF-23) as associated with aortic diameter and elevated in TAA in the UK Biobank. FGFR1, its receptor, was selectively expressed in fibroblasts and VSMCs, and FGF-23 stimulation induced inflammatory and extracellular matrix remodeling programs in fibroblasts. These findings link a circulating biomarker to stromal cell signaling in TAA. HighlightsO_LIIntegrative single-cell RNA sequencing defined a diverse cellular landscape in thoracic aortic aneurysm tissue, identifying 25 distinct cell populations. C_LIO_LICross-dataset harmonization revealed marked differences in cellular composition across studies while supporting shared stromal and immune programs in thoracic aortic aneurysm. C_LIO_LIPlasma proteomics identified FGF-23 as a candidate biomarker associated with aortic diameter and independently linked to thoracic aortic aneurysm presence in the UK Biobank C_LIO_LIFGFR1 was enriched in fibroblasts and subsets of vascular smooth muscle cells, and FGF-23 induced inflammatory and extracellular matrix remodeling programs in human primary adventitial fibroblasts. C_LI

cell biology↗

bioRxiv2020

A White Matter Atlas and Common Connectivity Space Facilitate the Pig as a Translational Model in Neuroscience

Neuroimagings capability to quickly and rapidly phenotype the cortical organization of the whole brain brings with it the possibility to extend our understanding of cortical organization across the mammalian lineage. However, neuroimaging has thus far generally limited itself to a small number of species, with most animal studies being performed in either rodents or Non-Human Primates. Here we perform a first pass characterization of an animal which has recently seen its stock rise in the neuroscience community with the development of new models of neurological disease; the domestic pig. Characterizing the structural connectome of the pig, we create a white matter atlas, and an anatomical template which we use to build a horizontal translation between the pig and human based on a connectivity blueprint approach. We find that conserved trends of structural connectivity across species enabled spatial prediction of regions of interest between the pig and human, showing the potential horizontal translations have as a tool to assess the translational validity of porcine models of neurological disease. Releasing the anatomical template, white matter atlas, and connectivity blueprints, we hope to ease and promote the acceptance of the pig as an alternative large-animal model by the neuroimaging community.

neuroscience↗

bioRxiv2020

Remote Ischemic Preconditioning Ameliorates Anthracycline-induced Cardiotoxicity and Preserves Mitochondrial Integrity

AimsAnthracycline-induced cardiotoxicity (AIC) is a serious adverse effect in a significant proportion of cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Methods and ResultsForty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischemic pre-conditioning (RIPC, 3 cycles of 5 min leg ischemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each of five intracoronary doxorubicin injections (0.45 mg/kg) given at weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at weeks 6, 8, 12, and 16. After 16-week CMR, pigs were sacrificed and tissue samples collected. In study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed 2 weeks after the third dose. In Study 1, LVEF remained unchanged in doxorubicin-treated pigs until week 6 (time of the fourth doxorubicin injection). From there on, LVEF progressively declined, but LVEF depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5{+/-}9.1% vs 32.5{+/-}8.7%, p=0.04). Preserved LVEF was mainly due to conserved contractile function, as evidenced by smaller LVESV, and better regional contractile function. In Study 2, transmission electron microscopy (TEM) after 3 doxorubicin doses showed fragmented mitochondria with severe morphological abnormalities in RIPC+Doxo pigs, together with upregulation of fission proteins and autophagy markers on western blot. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was significantly less severe in the RIPC+Doxo pigs. ConclusionIn a translatable large animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from the early stages of AIC. RIPC is a promising intervention for testing in clinical trials in AIC.

molecular biology↗