Biology subjects

Dabertrand, F.

Publications and source records attributed to Dabertrand, F..

7 recordsLinked to original sources

bioRxiv2026

Perivascular fibroblasts locally regulate the vasomotor dynamics of pial arterioles

Perivascular fibroblasts (PVFs) ensheath pial arterioles on the brain surface, yet their physiological role on the healthy cerebrovasculature remains unknown. Here, we show that PVFs display calcium dynamics that are temporally aligned with arteriolar vasomotion. Depletion of fibroblasts disrupted vasomotion whereas enhancement of PVF-Gq signaling increased vasomotor activity and accelerated fluid influx into the peri-arteriolar space. These findings identify PVFs as unrecognized regulators of cerebral vasodynamics and cerebrospinal fluid movement.

neuroscience↗

bioRxiv2026

Electromechanical Dynamics and Myogenic Responses in Cerebral Smooth Muscle Cells and Capillary Pericytes

Cerebral blood flow (CBF) control is essential for normal brain function and is disrupted in pathological conditions. Arterial diameters are tightly regulated to provide on demand increases in blood flow in regions of neuronal activity. Pericytes (PCs) exhibit robust myogenic tone and may also respond to neuronal activity to fine-tune local resistance and blood flow. Thus, mural control of microcirculatory resistance may extend beyond arteries and arterioles. Yet, PCs electrophysiology and contractility have not been thoroughly characterized, and this prohibits an integrated view of brain blood flow control. In this study, we develop a detailed mathematical model of mural cell electrophysiology, Ca2+ dynamics and biomechanics. The model is informed by electrophysiological data in smooth muscle cells (SMCs) or PCs and predictions are compared against pressure-induced responses in isolated arterioles and capillaries, respectively. Simulations recapitulate myogenic constrictions and examine differences in contractile dynamics as we move from arterioles to proximal and distal capillaries. In arteriole-to-capillary transitional (ACT) zone PCs, increased mechanosensitivity, more Ca2+ influx through non-selective cation (NSC) channels and/or a higher sensitivity of the contractile apparatus to Ca2+ can compensate for reduced L-type voltage-operated (VOCC) Ca2+ influx and allow for robust constrictions at the lower operating pressures of capillaries relative to the arterioles. A significant Ca2+ influx through NSC relative to VOCC, however, can decouple the PCs contractile apparatus from electrical signaling. Vasoactivity to chemomechanical stimuli along the arteriole to capillary axis is progressively driven by VOCC-independent Ca2+ influx and Ca2+ sensitization with slow kinetics. The proposed cell model can form the basis for detailed multiscale and multicellular models that will examine physiological function at a single vessel or vascular network levels and investigate CBF control in health and in disease. Key pointsO_LIA mural cell model of electrophysiology, calcium (Ca2+) dynamics and biomechanics is informed by data and adapted for modeling cerebral arteriole smooth muscle cells and capillary pericytes. C_LIO_LIIon channel activities are characterized by patch-clamp electrophysiology in isolated cerebral smooth muscle cell and pericytes, and capillary and arteriole electromechanical responses to transmural pressure changes are assessed using novel ex vivo preparations. C_LIO_LIMyogenic constrictions in arterioles can be reproduced by pressure-induced non-selective cation channel (NSC) activation that depolarizes the cell, opens L-type Ca2+ channels (VOCCs) and increases Ca2+ influx. C_LIO_LIRobust myogenic constrictions in arteriole-to-capillary transition (ACT) zone pericytes may reflect significant Ca2+ influx through NSC, increased mechanosensitivity, or higher sensitivity of the contractile apparatus to Ca2+, potentially compensating for reduced VOCC density relative to arteriolar smooth muscle. C_LIO_LIA significant contribution of NSC relative to VOCC in Ca2+ influx, can decouple the contractile apparatus from electrical signaling. C_LIO_LIThe model shows how gradients in ionic activities, mechanosensitivity and/or Ca2+ sensitivity can alter contractile phenotype and electromechanical coupling along the arteriole to capillary continuum. C_LIO_LIThe proposed model can form the basis for detailed multiscale and multicellular models that will investigate cerebral blood flow control in health and in disease. C_LI

physiology↗

bioRxiv2025

Purinergic receptor activation rectifies autism-associated endothelial dysfunction

Early cerebrovascular alterations affect brain maturation by impacting trophic support and energy supply. Recent evidence in a 16p11.2 deletion mouse model of autism spectrum disorder (ASD) revealed brain endothelial abnormalities postnatally. Yet, the endothelial alterations eliciting these changes remain unknown. Isolation of brain endothelial cells (ECs) from 14-day old male 16p11.2-deficient and wild-type mice revealed that 16p11.2 deletion-induced endothelial dysfunction is linked to a bioenergetic failure, with reduced intracellular ATP. Intra- or extra-cellular ATP supplementation rescued the function of 16p11.2-deficient ECs in vitro via P2 purinergic receptor activation, specifically P2Y2 receptors. Activating P2Y2 receptors restored cerebrovascular reactivity in 16p11.2-deficient parenchymal arterioles ex vivo and rescued 16p11.2 deletion-associated mouse behaviors. Taken together, this study demonstrates that metabolic reprogramming of brain ECs via purinergic receptor engagement represents a possible therapeutic avenue for ASD.

cell biology↗

bioRxiv2025

VasoTracker 2: An Open-source Platform for Quantitative Analysis of Vascular Reactivity and Function

VasoTracker 2 is an open-source platform for studying blood vessel dynamics, featuring versatile diameter-tracking software and complementary low-cost hardware components. This system surpasses existing tools through accessible, high-resolution analysis across multiple imaging modalities, enabling comprehensive assessment of vascular dynamics in both real-time and pre-recorded experiments. Advanced algorithms enable multi-point diameter tracking in branched vessels, automated pressure-response protocols, and reliable edge detection. The software can assess vessels imaged by brightfield microscopy, fluorescence imaging, and in ultrasound recordings, supporting diverse applications from isolated vessel studies to in vivo assessment. For ex vivo applications, VasoTracker 2 includes modular open-source hardware components that can be used to create a low-cost pressure myograph system: a confocal-compatible vessel chamber and a programmable pressure controller, VasoMoto. By combining powerful analytical capabilities with an open-access approach, VasoTracker 2 provides free software and low-cost hardware alternatives to commercial systems, democratizing access to advanced vascular research tools for scientists worldwide.

physiology↗

bioRxiv2024

Harnessing micrometer-scale tPA beads for high plasmin flux and accelerated fibrinolysis

Rapid restoration of blood flow is critical in treating acute ischemic stroke. Current fibrinolytic therapies using tissue plasminogen activator (tPA) are limited by low recanalization rates and risks of off-target bleeding. Here, we present a strategy using tPA immobilized on micrometer-scale beads to enhance local plasmin generation. We synthesized tPA-functionalized beads of varying sizes (0.1 m and 1.0 m) and evaluated their efficacy. In vitro assays demonstrated that 1.0 m tPA-beads generated higher plasmin generation compared to free tPA and 0.1 m beads, overcoming antiplasmin inhibition and promoting a self-propagating wave of fibrinolysis. In a murine model of acute ischemic stroke, intravenous administration of 1.0 m tPA-beads at doses nearly two orders of magnitude lower than the standard free tPA dose led to rapid and near-complete thrombus removal within minutes. This approach addresses kinetic and transport limitations of current therapies and may reduce the risk of hemorrhagic complications. TeaserMicrometer-scale tPA beads improve stroke treatment by enhancing local clot-dissolving action.

bioengineering↗

bioRxiv2024

Activity-dependent regulation of vascular cholesterol metabolism acts as a negative feedback mechanism for neurovascular coupling

Brain function is dependent on a continuous supply of bloodborne oxygen and nutrients. Because neurons require a greater supply of oxygen and nutrients when active, there is increased local blood flow following neuronal activity. The underlying mechanisms of this hyperemia are termed neurovascular coupling (NVC). Many complex processes contribute to NVC, and there is still much unknown about how vascular physiology adapts to changes in neuronal activity and blood flow. Here we show that neuronal activity increases brain endothelial expression of genes related to cholesterol synthesis and uptake in vivo, and that shear stress is sufficient for upregulation of these genes in vitro. We previously found that treatment with PLX5622 induces upregulation of the same cassette of cholesterol-related genes in brain endothelial cells. In the present study, we find that increasing brain endothelial cholesterol synthesis and/or uptake, either with PLX5622 or targeted AAV-mediated expression of LDLR, inhibits brain arteriole dilation in response to capillary K+ stimulation, and this deficit is rescued by cholesterol depletion. Together, these data suggest that neuronal activity regulates brain endothelial cholesterol, which in turn blocks endothelial retrograde signaling and vasodilation, thus acting as a negative feedback mechanism for NVC.

neuroscience↗

bioRxiv2023

Estrogen regulates myogenic tone in hippocampal arterioles by enhanced basal release of nitric oxide and endothelial SKCa channel activity

Arteries and arterioles exhibit myogenic tone, a partially constricted state that allows further constriction or dilation in response to moment-to-moment fluctuations in blood pressure. The vascular endothelium that lines the internal surface of all blood vessels controls a wide variety of essential functions, including the contractility of the adjacent smooth muscle cells by providing a tonic vasodilatory influence. Studies conducted on large (pial) arteries on the surface of the brain have shown that estrogen lowers myogenic tone in female mice by enhancing nitric oxide (NO) release from the endothelium, however, whether this difference extends to the intracerebral microcirculation remains ambiguous. The existing incomplete picture of sex differences in cerebrovascular physiology combined with a deficiency in treatments that fully restore cognitive function after cerebrovascular accidents places heavy emphasis on the necessity to investigate myogenic tone regulation in the microcirculation from both male and female mice. We hypothesized that sex-linked hormone regulation of myogenic tone extends its influence on the microcirculation level, and sought to characterize it in isolated arterioles from the hippocampus, a major cognitive brain area. Using diameter measurements both in vivo (acute cranial window vascular diameter) and ex vivo (pressure myography experiments), we measured lower myogenic tone responses in hippocampal arterioles from female than male mice. By using a combined surgical and pharmacological approach, we found myogenic tone in ovariectomized (OVX) female mice matches that of males, as well as in endothelium-denuded arterioles. Interestingly, eNOS inhibition induced a larger constriction in female arterioles but only partially abolished the difference in tone. We identified that the remnant difference was mediated by a higher activity and expression of the small-conductance Ca2+-sensitive K+ (SK) channels. Collectively, these data indicate that eNOS and SK channels exert greater vasodilatory influence over myogenic tone in female mice at physiological pressures.

neuroscience↗