Biology subjects

Gadeau, A.-P.

Publications and source records attributed to Gadeau, A.-P..

5 recordsLinked to original sources

bioRxiv2023

Increased endothelium activation and leakage do not promote diastolic dysfunction in mice fed with a high fat diet and treated with L-NAME

Coronary microvascular disease has been proposed to be responsible for heart failure with preserved ejection fraction (HFpEF) about 10 years ago. However, to date the role and phenotype of the coronary microvasculature has still been poorly considered and investigated in animal models of HFpEF. ObjectiveTo determine whether endothelial dysfunction participates in the development of diastolic dysfunction in mice fed with a high fat diet (HDF) and treated with L-NAME. Approach and ResultsAt first, we thoroughly phenotyped the coronary microvasculature in this model in male, female and ovariectomized (OVX) female considering the sexual dimorphism associated with this disease. We found that both OVX and non OVX females but not males display increased endothelial activation, leakage, and arteriole constriction upon the HFD + L-NAME regimen while both male and OVX females but not non OVX females develop diastolic dysfunction. With the aim to investigate the role of endothelial dysfunction in the pathophysiology of diastolic dysfunction in OVX female mice, we used Cdon deficient mice. Indeed, we previously demonstrated that endothelium integrity, upon inflammatory conditions, is preserved in these mice. Both OVX Cdh5-Cre/ERT2-CdonFlox/Flox (CdonECKO) and CdonFlox/Flox (Ctrl) female mice were fed with the HFD + L-NAME regimen to induced diastolic dysfunction. As expected, CdonECKO mice displayed improved endothelium integrity i.e. decreased endothelium permeability, decreased ICAM-1 expression and decreased infiltration of CD45+ leukocytes in comparison to control mice. However, CdonECKO mice displayed cardiac hypertrophy, cardiac fibrosis and increased end diastolic pressure just like control mice. Moreover, we found that cardiac inflammation does not participate in the pathophysiology of HFpEF either by treating OVX female mice with colchicine. ConclusionAltogether, the data presented in this paper demonstrate that neither endothelium permeability nor endothelial activation or inflammation do participate in the pathophysiology of diastolic dysfunction in mice exposed to HFD+L-NAME.

pathology↗

bioRxiv2022

Cardiac pericytes are necessary for coronary vasculature integrity and cardiomyocyte differentiation

Introduction: While the critical role of pericytes in maintaining vascular integrity has been extensively demonstrated in the brain and in the retina, very little is known about their role in the heart. Objective: We aim to investigate structural and functional consequences of partial pericyte depletion (about 60%) in the heart of adult mice. Methods: To deplete pericyte in adult mice, we used Pdgfrb-Cre/ERT2; Rosa-DTA mice and compared their phenotype to the one of control mice (Rosa-DTA) chosen among their littermates. Cardiac function was assessed via echocardiography and left ventricle (LV) catheterization one month after the first tamoxifen injection. Results: Mice depleted with pericytes displayed increased coronary endothelium leakage and activation which was associated with increased CD45 + cell infiltration in the heart. Pericyte depletion also modified the phenotype of cardiomyocytes with an increased expression of Myosin Heavy Chain 7, a decreased expression of ATPase Sarcoplasmic/Endoplasmic Reticulum Ca2+ Transporting 2, Connexin 43 and a decreased phosphorylation of Phospholamban suggesting cardiomyocyte dedifferentiation and impaired contractility. As a consequence, mice depleted with pericytes had a reduced LV ejection fraction and an increased end-diastolic pressure demonstrating both systolic and diastolic dysfunction. Accordingly, mice depleted with pericytes presented a decreased LV contractility and an increased LV relaxation time (dP/dtmin). Besides this study reveals that cardiac pericytes may undergo strong remodeling upon injury. Conclusion: Cardiac pericyte depletion induces both systolic and diastolic dysfunction suggesting that pericyte dysfunction may contribute to the occurrence of cardiac diseases.

physiology↗

bioRxiv2020

Mast cells participate in the development of diastolic dysfunction in diabetic obese mice

Rational Heart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic issue. However, to date, its pathophysiology remains poorly understood.Objective Our goal was to investigate the role of microvessel disease in the pathophysiology of diastolic dysfunction.Findings To do so, we used Leptin receptor deficient (Leprdb/db) female mice as a model of diastolic dysfunction. In these mice, the increased end diastolic pressure (EDP) signing diastolic dysfunction is associated with vascular leakage, endothelial cell activation and leucocyte infiltration. Strikingly, a RNA sequencing analysis of the cardiac vascular fraction of both Leprdb/db and control female mice confirmed endothelial dysfunction and systemic inflammation but also revealed a strong increase in several mast cell markers (notably FceR1a, Tryptase and Chymase). We then histologically confirmed an accumulation of activated mast cells in the heart of Leprdb/db mice. Importantly, mast cell degranulation inhibition reduced EDP, vascular leakage and leucocyte infiltration in Leprdb/db mice.Conclusion Mast cells play a critical role in the development of cardiac microvessel disease and diastolic dysfunction.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2020

Desert Hedgehog-driven endothelium integrity is enhanced by Gas1 but negatively regulated by Cdon

Evidences accumulated within the past decades, identified Hedgehog (Hh) signaling as a new regulator of micro-vessel integrity. More specifically, we recently identified Desert Hedgehog (Dhh) as a downstream effector of Klf2 in endothelial cells (ECs). ObjectiveThe purpose of this study is to investigate whether Hh co-receptors Gas1 and Cdon may be used as therapeutic targets to modulate Dhh signaling in ECs. Methods and resultsWe demonstrated that both Gas1 and Cdon are expressed in adult ECs and relied on either siRNAs or EC specific conditional KO mice to investigate their role. We found that Gas1 deficiency mainly photocopies Dhh deficiency especially by inducing VCAM-1 and ICAM-1 overexpression while Cdon deficiency has opposite effects by promoting endothelial junction integrity. At a molecular level, Cdon prevents Dhh binding to Ptch1 and thus acts a decoy receptor for Dhh, while Gas1 promotes Dhh binding to Smo and as a result potentiates Dhh effects. Since Cdon is overexpressed in ECs treated by inflammatory cytokines including TNF and Il1{beta}, we then tested whether Cdon inhibition would promote endothelium integrity in acute inflammatory conditions and found that both fibrinogen and IgG extravasation were decreased in association with an increased Cdh5 expression in the brain cortex of EC specific Cdon KO mice administered locally with Il1{beta}. ConclusionAltogether these results demonstrate that Gas1 is a positive regulator of Dhh in ECs while Cdon is a negative regulator. Interestingly Cdon blocking molecules may then be used to promote endothelium integrity at least in inflammatory conditions.

cell biology↗

bioRxiv2020

Endothelial cell response to Hedgehog ligands depends on their processing

RationaleThe therapeutic potential of Hedgehog (Hh) signaling agonists for vascular diseases is of growing interest. However, molecular and cellular mechanisms underlying the role of the Hh signaling in vascular biology remain poorly understood. ObjectiveThe purpose of the present paper is to clarify some conflicting literature data. FindingsWith this goal we have demonstrated that, unexpectedly, ectopically administered N-terminal Sonic Hedgehog (N-Shh) and endogenous endothelial-derived Desert Hedgehog (Dhh) induce opposite effects in endothelial cells. (ECs). Notably, endothelial Dhh acts under its full-length soluble form (FL-Dhh) and activates Smoothened in ECs, while N-Shh inhibits it. At molecular level, N-Shh prevents FL-Dhh binding to Patched-1 demonstrating that N-Shh acts as competitive antagonist to FL-Dhh. Besides, we found that even though FL-Hh ligands and N-Hh ligands all bind Patched-1, they induce specific Patched-1 localization. Finally, we confirmed that in a pathophysiological setting i.e. brain inflammation, astrocyte-derived N-Shh act as a FL-Dhh antagonist. ConclusionThe present study highlights for the first time that FL-Dhh and N-Hh ligands have antagonistic properties especially in ECs, and demonstrates that Hh ligands or forms of Hh ligands cannot be used instead of another for therapeutic purposes.

physiology↗