Biology subjects

Foulquier, S.

Publications and source records attributed to Foulquier, S..

7 recordsLinked to original sources

bioRxiv2026

Extracellular methylglyoxal; the passage across brain endothelial cells and the effect on barrier function

BackgroundMethylglyoxal (MGO), a highly reactive by-product of glycolysis, has been associated with cognitive decline and Alzheimers disease, though the mechanistic role of MGO remains unclear. Moreover, conflicting findings exist regarding MGOs toxicity on the blood-brain barrier (BBB). This study investigated whether MGO can cross the BBB under physiologically relevant conditions and whether MGO affects BBB permeability. MethodsMice were intravenously injected with highly purified home-made MGO or PBS, and MGO concentration was measured at five timepoints in the cerebral cortex up to 4 hours after injection. MGO toxicity was screened on a human brain endothelial cell line (hCMEC/D3) using a live/dead assay prior to the study of selected MGO concentrations and on hiPSC-derived brain microvascular endothelial cells (EECM-BMECs). EECM-BMECs were cultured on Transwell(R) inserts, and barrier function was assessed by sodium fluorescein permeability and transendothelial passage of 13C3-MGO quantified by UPLC-MS/MS. ResultsMGO levels in the mouse cortex did not increase post-injection. MGO was not toxic to hCMEC/D3 cells, and it had no impact on barrier properties of EECM-BMECs. After 1-hour exposure, [~]13% of total 13C3-MGO was recovered in its free form, and only [~]1% of supplemented MGO was recovered from the abluminal side. ConclusionMGO does not cross the BBB in vivo and does not affect barrier properties of a human in vitro model of the BBB. In vitro MGO passage across the BBB is minimal. These findings suggest that circulating MGO is unlikely to directly affect neuronal function via BBB disruption or enter the brain in its free from.

neuroscience↗

bioRxiv2025

Vascular contribution to cognitive impairment in heart failure with preserved ejection fraction: TRPV4 and KLF2 as key mediators of neurovascular dysfunction in the ZSF1 model

Vascular cognitive impairment (VCI) shares major risk factors with heart failure with preserved ejection fraction (HFpEF), including obesity, diabetes and hypertension. Yet VCI research often relies on single-stimulus models, whereas patients experience combined risk factors. We therefore assessed cerebrovascular and cognitive phenotypes in an HFpEF model and investigated underlying mechanisms. Male Lean and Obese ZSF1 rats underwent longitudinal assessments of blood pressure, glucose, cardiac function, and behavioural performance. Cerebral blood flow and neurovascular coupling were assessed by laser speckle contrast imaging. White matter integrity, blood-brain barrier (BBB) permeability, and vascular density were analysed by (immuno)histochemistry. Cortical microvessels were isolated for transcriptomic profiling, and selected targets were validated using multiplex in-situ hybridization. Obese rats exhibited neurovascular uncoupling and impaired short- and long-term memory and spatial learning, accompanied by brain atrophy and reduced myelin. BBB permeability increased at 22-23 weeks and vascular density at 34-35 weeks in Obese vs Lean rats. Transcriptomic analysis of brain microvessels revealed altered processes related to angiogenesis, vasoreactivity, immune mechanisms and vascular remodelling, with consistent downregulation of Trpv4 and Klf2. Obese ZSF1 rats develop progressive neurovascular dysfunction associated with HFpEF onset and reduced Trpv4 and Klf2 expression in cerebral microvessels, two key vasoprotective genes.

neuroscience↗

bioRxiv2023

Increased levels of circulating methylglyoxal have no consequence for cerebral microvascular integrity and cognitive function in young healthy mice

Diabetes and other age-related diseases are associated with an increased risk of cognitive impairment, but the underlying mechanisms remain poorly understood. Methylglyoxal (MGO), a by-product of glycolysis and a major precursor in the formation of advanced glycation end- products (AGEs), is increased in individuals with diabetes and other age-related diseases, and is associated with microvascular dysfunction. We now investigated whether increased levels of circulating MGO can lead to cerebral microvascular dysfunction, blood brain barrier (BBB) dysfunction, and cognitive impairment. Mice were supplemented or not with 50 mM MGO in drinking water for 13 weeks. Plasma and cortical MGO and MGO-derived AGEs were measured with UPLC-MS/MS. Peripheral and cerebral microvascular integrity and inflammation were investigated. Cerebral blood flow and neurovascular coupling were investigated with laser speckle contrast imaging, and cognitive tests were performed. We found a 2-fold increase in plasma MGO and an increase in MGO-derived AGEs in plasma and cortex. Increased plasma MGO did not lead to cerebral microvascular dysfunction, inflammation, nor cognitive decline. This study shows that increased concentrations of plasma MGO are not associated with cerebral microvascular dysfunction and cognitive impairment in healthy mice. Future research should focus on the role of endogenously formed MGO in cognitive impairment.

neuroscience↗

bioRxiv2023

Evaluating flash freezing for preservation of rat abdominal aorta for delayed biomechanical characterization

Most studies investigating arterial stiffening use animal rather than human arteries. This is because human tissue becomes available in small amounts and at irregular times, which complicates planning of experimental work. Suitable tissue preservation methods for delayed biomechanical testing prevents the need for testing fresh tissue and alleviates some of the logistical challenges of human ex vivo studies. Therefore, the present study aimed to investigate whether the existing method of flash freezing and subsequent cryostorage provides is suitable for delaying the characterization of arterial biomechanics. Fresh and flash frozen abdominal aortas (n=16 and 14, respectively) were quasi- statically and dynamically tested using a biaxial testing set-up with dynamic pressurization capabilities. The acquired biomechanical data was modeled using a constituent-based quasi-linear viscoelastic modeling framework, deriving directional stiffness parameters, individual constituent biomechanical contributions, and viscoelastic stiffening under dynamic pressurization conditions. Flash freezing reduced arterial wall thickness, increased circumferential stiffness, as well as reduced viscoelastic stiffening at higher pressures. These findings reflected those in the modeled contribution of collagen to arterial biomechanics, showing increased collagen load bearing at higher pressures. However, despite the above mentioned detectable changes, flash freezing did not alter the mechanical relation between elastin and collagen, maintaining a non-linear response to pressurization and stretch. Flash freezing may thus be suitable for studies requiring delayed characterization of passive arterial biomechanics, assuming care is taken to ascert that the impact of flash freezing on study groups can be approached as a systematic error.

bioengineering↗

bioRxiv2021

Facilitation of TRKB activation by the angiotensin II receptor type-2 (AT2R) agonist C21

Blockers of angiotensin II type-1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type-2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1-10M/15min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10M/15min or 3 days) facilitated the effect of BDNF (0.1ng/ml/15min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect.

pharmacology and toxicology↗

bioRxiv2020

Pharmacological depletion of microglia prevents vascular cognitive impairment in Ang II-induced hypertension

Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Ang II infusion is associated with increased permeability of the blood-brain barrier (BBB) and chronic activation of microglia. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach. Methods: For this study, adult Cx3Cr1gfp/wtxThy1yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF-1R inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory were assessed during an Object Location task and a Morris Water Maze task (MWM). At the end of the study, microglia depletion efficacy and BBB leakages were assessed using flow cytometry and immunohistochemistry. Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, but not in Ang II mice treated with PLX5622. Histological and flow cytometry analyses revealed almost complete ablation of microglia upon CSF1R inhibition, while brain resident perivascular macrophages, were reduced by 60%. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Conclusion: Our results show that depletion of microglia, and less so PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. This novel finding supports the critical role of brain immune cells, and most in particular microglia, in the pathogenesis of hypertension-related cognitive impairment.

neuroscience↗

bioRxiv2018

High-resolution bladder morphology in the intact mouse bladder: an intravital two-photon study

We developed a platform for intravital bladder two-photon microscopy (TPM) in healthy wild-type mice. It was our aim to make intravital bladder TPM simple and reproducible for researchers with access to TPM. In this study, the intact murine bladder was examined by means of autofluorescence (AF), second-harmonic generation (SHG), and different i.v. injected fluorescent dyes. All bladder layers with containing structures, such as cells, nerves, and vessels were detected in different colour-coded spectral channels, and shown in high-resolution images and real-time movies. The presented method opens up avenues for many future studies and applications, such as to reveal mechanisms and physiology in the natural state of the bladder. Researcher can use intravital bladder TPM to investigate events, such as migration and metabolism of (inflammatory) cells, nanoparticle uptake, or micro contractions in response to stimuli.

cell biology↗