Biology subjects

Alzieu, P.

Publications and source records attributed to Alzieu, P..

3 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↗

bioRxiv2022

Crest maturation at the cardiomyocyte surface contributes to a new late postnatal development stage that controls the diastolic function of the adult heart

RATIONALEIn addition to its typical rod-shape, the mammalian adult cardiomyocyte (CM) harbors a unique lateral membrane surface architecture with periodic crests, relying on the presence of subsarcolemmal mitochondria (SSM) the role of which is still unknown. OBJECTIVETo investigate the development and functional role of CM crests during the postnatal period. METHODS AND RESULTSElectron/confocal microscopy and western-blot of left ventricular tissues from rat hearts indicated a late CM surface crest maturation, between postnatal day 20 (P20) and P60, as shown by substantial SSM swelling and increased claudin-5 cell surface expression. The P20-P60 postnatal stage also correlates with an ultimate maturation of the T-Tubules and the intercalated disk. At the cellular level, we identified an atypical CM hypertrophy characterized by an increase in long- and short-axes without myofibril addition and with sarcomere lateral stretching, indicative of lateral stretch-based CM hypertrophy. We confirmed the P20-P60 hypertrophy at the organ level by echocardiography but also demonstrated a transcriptomic program after P20 targeting all the cardiac cell populations. At the functional level, using Doppler echocardiography, we found that the P20-P60 period is specifically dedicated to the improvement of relaxation. Mechanistically, using CM-specific knock-out mice, we identified ephrin-B1 as a determinant of CM crest maturation after P20 controlling lateral CM stretch-hypertrophy and relaxation. Interestingly, while young adult Efnb1CMspe-/- mice essentially show a relaxation impairment with exercise intolerance, they progressively switch toward heart failure with 100% KO mice dying after 13 months. CONCLUSIONSThis study highlights a new late P20-P60 postnatal developmental stage of the heart in rodents during which the CM surface crests mature through an ephrin-B1-dependant mechanism and regulate the diastolic function. Moreover, we demonstrate for the first time that the CM crest architecture is cardioprotective.

cell biology↗