Biology subjects

Lenoir, O.

Publications and source records attributed to Lenoir, O..

6 recordsLinked to original sources

bioRxiv2026

A novel mouse model of hypertensive emergency with multiorgan microvascular disease implicating the VEGFA/sFlt-1 balance

BackgroundHypertensive emergency (HTEM) is defined by abrupt blood pressure elevation with acute multi-organ damage, yet the mechanisms predisposing only a subset of hypertensive individuals to HTEM remain unclear. Progress has been limited by the lack of a mouse model that faithfully replicates human disease. We aimed to identify determinants of susceptibility to hypertensive microvascular injury and characterize a murine model of HTEM. MethodsMale C57BL/6J (B6J) and 129S2/SvPasCrl (129Sv) mice were exposed to severe hypertension via angiotensin II infusion combined with a high-salt diet. We assessed survival, renal and retinal injury, cardiac function and electrophysiology, vascular permeability, circulating angiogenic factors, and glomerular transcriptional profiles using single-cell RNA sequencing. Bone marrow transplantation and recombinant human PlGF-2 treatment were used to investigate mechanisms driving endothelial injury. ResultsDespite comparable blood pressure, 129Sv mice, but not B6J, developed malignant hypertension with albuminuria, acute kidney injury, retinal hemorrhages, microvascular leakage, cardiac dysfunction, and arrhythmias. Hypertensive 129Sv mice exhibited markedly elevated circulating sFlt-1. PlGF-2 supplementation partially reversed albuminuria, preserved glomerular ultrastructure, and reduced retinal hemorrhages. Bone marrow transfers revealed contributions from both hematopoietic and non-hematopoietic 129Sv compartments to sFlt-1 overproduction and organ injury. Single-cell transcriptomics revealed profound repression of angiogenic, metabolic, and stress-response pathways in glomerular endothelial cells, a repression partially restored by PlGF-2. ConclusionsWe identify 129Sv mice as a robust model of HTEM, exhibiting multi-organ microvascular injury that closely mirrors the human condition. Our results reveal blood-pressure-independent susceptibility to organ damage and implicate dysregulated VEGFA/sFlt-1 signaling as a central driver of endothelial dysfunction, highlighting angiogenic imbalance as a potential therapeutic target.

pathology↗

bioRxiv2025

UBA1 Mutations Drive RIPK1-Mediated Cell Death and Monocyte Dysfunction in VEXAS Syndrome

VEXAS syndrome is a severe adult-onset autoinflammatory disease caused by somatic mutations in UBA1 gene, disrupting cytoplasmic ubiquitin-activating enzyme E1 function in hematopoietic progenitors. The pathogenesis remains poorly understood, particularly how UBA1 mutations perturb myeloid function. Here, we combine a genetically engineered THP-1 monocytic model with ex vivo analyses of blood and tissue samples from VEXAS patients to investigate the consequences of the canonical UBA1M41V mutation. We show that UBA1-mutated monocytes exhibit TNF--induced cell death, characterized by RIPK1 phosphorylation, and MLKL-and caspase-8-mediated cell death. This is associated with defective transcriptional induction of NF-{kappa}B target genes and reduced cFLIP(L) expression in response to TNF-. Monocytes also display blunted cytokine responses to multiple Toll-like receptor (TLR) agonists despite preserved TLR expression, linked to an impaired NF-{kappa}B response. UBA1M41V-derived macrophages exhibit an inflammatory transcriptional profile and increased secretion of chemokines that promote monocyte recruitment. We demonstrate that these UBA1M41V macrophages display impaired efferocytosis due to lysosomal dysfunction. Together, these findings reveal a pathogenic axis in VEXAS syndrome linking UBA1 loss of function and defective ubiquitination to RIPK1-mediated inflammatory cell death, impaired antimicrobial signaling, and defective resolution mechanisms. Our study provides novel mechanistic insights into the myeloid dysfunction that drives inflammation and cytopenia in VEXAS and highlights the necroptosis and efferocytosis pathways as potential therapeutic targets. Key points1/ UBA1-mutated monocytes are susceptible to RIPK1 dependent cell death and display impaired NF-{kappa}B-mediated cytokine responses to TLR agonists. 2/ UBA1-mutated macrophages promote inflammation and chemokine-mediated monocyte recruitment, while exhibiting defective efferocytosis.

immunology↗

bioRxiv2025

Blood-borne sphingosine 1-phosphate maintains vascular resistance and cardiac function.

G protein-coupled receptors (GPCRs) are key regulators of cardiovascular function that provide targets for the treatment of cardiovascular disease. Sphingosine 1-phosphate (S1P) is an erythrocyte- and platelet-derived lipid mediator with cognate GPCRs on endothelial cells (EC), vascular smooth muscle cells (VSMC) and cardiomyocytes. S1P circulates in plasma bound to apolipoprotein M (ApoM)-containing high-density lipoproteins (HDL) and to albumin. Circulating S1P levels correlate positively with systolic blood pressure in hypertension and negatively with severity in septic shock and with left ventricular (LV) function in coronary heart disease. In mice, impaired S1P binding to HDL or signaling to EC both trigger hypertension, supporting an essential role for HDL-S1P in supporting endothelial function. The roles of albumin-S1P and myocyte S1PRs in cardiovascular homeostasis remain incompletely defined. Contrasting isolated HDL-S1P deficiency, we report that non-selective depletion of circulating S1P pools in mice impairs LV contractile function and induces hypotension and resistance to the spontaneous increase in blood pressure with age. Cardiac output was preserved in naive S1P deficient mice by compensatory LV dilation, but cardiac reserve reduced in a dobutamine stress test. These phenotypes tracked with hematopoietic cell S1P production and were partially or fully reversed by erythrocyte transfusion. Hypotension was accompanied by reduced peripheral resistance, and S1P infusion dose-dependently increased vascular resistance in isolated perfused kidneys from wild-type mice but not mice with compound deficiency in S1PR2&3. Epistatic analysis supported a critical role for S1PR3 in S1P-dependent blood pressure regulation and pointed to a distinct origin of the cardiac phenotype. Although circulating S1P is elevated in hypertensive mice and humans, increasing circulating S1P was not sufficient to induce hypertension in naive mice. These observations suggests that albumin-S1P crosses the endothelium in resistance arteries to gain access to contractile VSMC S1P receptors, and that myocyte S1PR signaling is essential for vascular resistance and blood pressure maintenance in mice. They also highlight the role for plasma chaperones in specifying vascular responses to S1P and the relevance of S1P as a biomarker and potential therapeutic target for blood pressure regulation and heart failure.

physiology↗

bioRxiv2024

A macrophage-smooth muscle cell axis influences vascular remodeling through activation of the EGFR pathway in giant cell arteritis

Background.The role of macrophages and vascular resident cells appears to be predominant in the pathophysiology of giant cell arteritis (GCA). We investigated the role of epithelial growth factor receptor (EGFR) signaling pathway, especially through its activation by heparin-binding epidermal growth factor (HB-EGF) and/or amphiregulin (AREG) in this setting. Materials and Methods.Serum samples and temporal artery biopsies (TAB) were obtained from patients enrolled in a prospective cohort of systemic vasculitis. Human THP-1, a monocytic cell line, and human aortic vascular smooth muscle cells (VSMC) were used for in vitro studies. Results.Using multiplex immunohistochemistry, TAB from GCA patients showed higher expression of AREG, HB-EGF, EGFR and phospho-EGFR as compared to control arteries. AREG, HB-EGF and EGFR were predominantly expressed by macrophages, whereas EGFR and phosphor-EGFR were expressed by SMA-positive cells in the media. Increased levels of AREG and HB-EGF were found in culture supernatants of M1 macrophages, whereas M2 macrophages produced only HB-EFG. AREG and HB-EGF did not increase the production of pro-inflammatory cytokines by THP-1 or macrophages but activated the p38 MAPK pathway. Using transcriptomic and Western blot analysis of human aortic VSMC, AREG and especially HB-EGF induced cell proliferation pathway, enhanced interferon alpha and gamma responses, and activation of the MAPK pathway. Finally, AREG and HB-EGF increased both VSMC proliferation and migration, which were completely inhibited by AG1478, an EGFR inhibitor. Conclusion.We show that both AREG and HB-EGF may play a role in the pathophysiology of GCA, especially in the remodeling phase of the disease.

immunology↗

bioRxiv2022

Protective role of podocytic IL-15/STAT5 pathway in experimental focal and segmental glomerulosclerosis

During glomerular diseases, podocyte-specific pathways can modulate the intensity of the lesions and prognosis. The therapeutic targeting of these pathways could thus improve the management and prognosis of chronic kidney diseases. The Janus Kinase/ Signal Transducer and Activator of Transcription (JAK/STAT) pathway, classically described in immune cells, has been recently described in intrinsic kidney cells. Here, we show, for the first time, that STAT5 is activated in human podocytes in focal segmental glomerulosclerosis (FSGS). Additionally, Stat5 podocyte-specific inactivation aggravates the functional and structural alterations in a mouse model of FSGS. This could be due, at least in part, to an inhibition of the autophagic flux. Finally, Interleukin 15 (IL-15), a classical activator of STAT5 in immune cells, increases STAT5 phosphorylation in human podocytes and its administration alleviates glomerular injury in vivo by maintaining the autophagy flux in podocytes. In conclusion, activating podocytic STAT5 with commercially available IL-15 represents a new therapeutic avenue with the potential for FSGS.

pathology↗

bioRxiv2021

scoMorphoFISH: A Deep-Learning enabled toolbox for single-cell single-mRNA quantification and correlative (ultra-)morphometry

Increasing the information depth of single kidney biopsies can improve diagnostic precision, personalized medicine and accelerate basic kidney research. Until now, information on mRNA abundance and morphologic analysis has been obtained from different samples, missing out on the spatial context and single-cell correlation of findings. Herein, we present scoMorphoFISH, a modular toolbox to get spatial single-cell single-mRNA expression data optimized for routinely generated kidney biopsies. Deep-Learning was used to virtually dissect tissue sections in tissue compartments and cell types to which single-cell expression data was assigned. Furthermore, we show correlative and spatial single-cell expression quantification with super-resolved podocyte foot process morphometry on the same histological section. In contrast to bulk analysis methods, this approach will help to identify local transcription changes even in less frequent kidney cell types on a spatial single-cell level with single-mRNA resolution. As this method performs well with standard formalin-fixed paraffin-embedded samples and we provide pretrained DL-networks embedded in a comprehensive image analysis workflow, this method can be applied immediately in a variety of settings.

pathology↗