Biology subjects

Ledoux, C.

Publications and source records attributed to Ledoux, C..

4 recordsLinked to original sources

bioRxiv2025

Vasoactive Neuropeptide Dysregulation: A Novel Mechanism of Microvascular Dysfunction in Vascular Cognitive Impairment

INTRODUCTIONNeuropeptide dysregulation and microvascular injury are involved in pathogenesis of vascular cognitive impairment (VCI); however, the underlying etiology of this pathological axis remains unclear. METHODSWe investigated pathological mediators across varying severities of VCI in a rat model of chronic cerebral hypoperfusion (CCH). Proteomic analysis guided the evaluation of neuropeptide and non-neuropeptide markers associated with vascular and nonvascular dysfunction, which were correlated with cognitive function to determine their role in VCI. RESULTSProteomic analysis revealed vasomotor dysfunction as the primary pathological pathway in VCI. Microvascular vasoconstriction was the earliest and most persistent event, initiating a cascade of both microvascular and nonvascular dysfunction. Dysregulation of vasoactive neuropeptides was identified as the key driver of this process. CGRP supplementation effectively prevented vasoconstriction, and improving cognitive function in CCH. DISCUSSIONThis study suggests dysregulation of vasoactive neuropeptides plays a central role in CCH pathomechanism, with microvascular vasoconstriction acting as the primary mediator. HIGHLIGHTSO_LINeuropeptides are the primary drivers of dominant pathomechanisms underlying CCH. C_LIO_LIEarly vasoactive neuropeptides dysregulation is a key driver of cognitive decline. C_LIO_LIMicrovascular dysfunction precedes classical non-vascular pathologies in CCH. C_LIO_LICapillary constriction precedes and drives amyloid accumulation in CCH. C_LIO_LICGRP mitigates microvascular constriction, enhancing cognitive function in VCI. C_LI Research in ContextO_LISystematic review: The authors reviewed literature from PubMed and Google Scholar, as well as meeting abstracts and presentations. Neuropeptide dysregulation and microvascular injury are increasingly recognized for involvement in the pathogenesis of VCID; however, the underlying etiology of this pathological axis remains unclear. C_LIO_LIInterpretation: Our evidence shows that early, progressive vasoactive neuropeptide dysregulation drives microvascular constriction, constituting a pivotal mechanism in microvascular dysfunction and subsequent cognitive deterioration in chronic cerebral hypoperfusion. The data further elucidate the significant therapeutic efficacy of pharmacological and non-pharmacological interventions directed at vasoactive neuropeptide pathways, which resulted in marked enhancement of cognitive function. C_LIO_LIFuture directions: Our results indicate that aberrant vasoactive neuropeptide regulation constitutes a fundamental pathophysiological mechanism underlying the development and clinical manifestation of VCID. These findings have potentially substantial implications for the development of novel therapeutic strategies targeting this disorder, which represents the second most common etiology of cognitive deterioration. C_LI

neuroscience↗

bioRxiv2023

Prediction and experimental evidence of differentgrowth phases of the Podospora anserina hyphalnetwork

The growth of the network of a filamentous fungus is monotonous, showing an ever increasing complexity with time. The components of network growth are very simple and based on two mechanisms, the elongation of each hyphae and their multiplication by successive branching. These two mechanisms are sufficient to produce a complex network, and could only be localized at the tips of the hyphae. However, branching can be of two types, apical or lateral, depending on its location on the hyphae, imposing the redistribution of the necessary material in the whole network. From an evolutionary point of view, maintaining different branching processes, with its associated cost, is intriguing. We propose in this work to discuss the advantages of each of the two branching types using a new observable for the network growth allowing to compare growth configurations. For this purpose, we build on experimental observations of the Podospora anserina thallus growth, allowing us to feed and constrain a lattice-free modeling of this network based on a binary tree. First, we report the set of statistics related to the branches of P. anserina that we have implemented in the model. Then, we build the density observable, allowing us to discuss the growth phases. We predict that the evolution of the density is not monotonic but presents a marked stationary phase, clearly separating two other phases of growth. The location of this stable region appears to be driven solely by the growth rate. Finally, we show that the density is a good observable for stress differentiation.

biophysics↗

bioRxiv2022

Trabecular bone remodeling in the ageing mouse: a micro-multiphysics agent-based in silico model using cell-type-specific mechanomic profiles

Bone remodeling is regulated by the interaction between different cells and tissues across many spatial and temporal scales. Notably, in silico models are regarded as powerful tools to further understand the signaling pathways that regulate this intricate spatial cellular interplay. To this end, we have established a 3D multiscale micro-multiphysics agent-based (micro-MPA) in silico model of trabecular bone remodeling using longitudinal in vivo data from the sixth caudal vertebra (CV6) of PolgA(D257A/D257A) mice, a mouse model of premature aging. Our model includes a variety of cells as single agents and receptor-ligand kinetics, mechanomics, diffusion and decay of cytokines which regulate the cells behavior. We highlighted its capabilities by simulating trabecular bone remodeling in the CV6 of 5 mice over 4 weeks and we evaluated the static and dynamic morphometry of the trabecular bone microarchitecture. Based on the progression of the average trabecular bone volume fraction (BV/TV), we identified a configuration of the model parameters to simulate homeostatic trabecular bone remodeling, here named basal. Crucially, we also produced anabolic, anti-anabolic, catabolic and anti-catabolic responses with an increase or decrease by one standard deviation in the levels of osteoprotegerin (OPG), receptor activator of nuclear factor kB ligand (RANKL), and sclerostin (Scl) produced by the osteocytes. Our results showed that changes in the levels of OPG and RANKL were positively and negatively correlated with the BV/TV values after 4 weeks in comparison to basal levels, respectively. Conversely, changes in Scl levels produced small fluctuations in BV/TV in comparison to the basal state. From these results, Scl was deemed to be the main driver of equilibrium while RANKL and OPG were shown to be involved in changes in bone volume fraction with potential relevance for age-related bone features. Ultimately, this micro-MPA model provides valuable insights into how cells respond to their local mechanical environment and can help to identify critical pathways affected by degenerative conditions and ageing.

bioengineering↗

bioRxiv2019

Mapping cellular-scale internal stiffness in 3D tissues with smart material hydrogel probes

Local stiffness plays a critical role in cell function, but measuring rigidity at cellular length scales in living 3D tissues presents considerable challenges. Here we present thermoresponsive, smart material microgels that can be dispersed or injected into tissues and optically assayed to measure internal tissue stiffness over several weeks. We first develop the material design principles to measure tissue stiffness across physiological ranges, with spatial resolutions approaching that of individual cells. Using the microfabricated sensors, we demonstrate that mapping internal stiffness profiles of live multicellular spheroids at high resolutions reveal distinct architectural patterns, that vary with subtle differences in spheroid aggregation method. Finally, we determine that small sites of unexpectedly high stiffness (> 250 kPa) develop in invasive breast cancer spheroids, and in in vivo mouse model tumors as the cancer progresses towards metastatic disease. These highly focal sites of increased intratumoral stiffness likely form via active cell mechanical behavior, and suggest new possibilities for how early mechanical cues that drive cancer cells towards invasion might arise within the evolving tumor microenvironment.

biophysics↗