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Publications (70)
Under neuroinflammatory conditions, astrocytes acquire a reactive phenotype that drives acute inflammatory injury as well as chronic neurodegeneration. We hypothesized that astrocytic Delta-like 4 (DLL4) may interact with its receptor NOTCH1 on neighboring astrocytes to regulate astrocyte reactivity via downstream juxtacrine signaling pathways. Her...
Under neuroinflammatory conditions, astrocytes acquire a reactive phenotype that drives acute inflammatory injury as well as chronic neurodegeneration. We hypothesized that astrocytic Delta-like 4 (DLL4) may interact with its receptor NOTCH1 on neighboring astrocytes to regulate astrocyte reactivity via downstream juxtacrine signaling pathways. Her...
BACKGROUND
Heart failure with preserved ejection fraction is proposed to be caused by endothelial dysfunction in cardiac microvessels. Our goal was to identify molecular and cellular mechanisms underlying the development of cardiac microvessel disease and diastolic dysfunction in the setting of type 2 diabetes.
METHODS
We used Lepr db/db (leptin r...
Introduction
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.
Objective
To characterize the phenotype...
Multiple sclerosis is an autoimmune inflammatory disease of the central nervous system leading to neurodegeneration. It affects 2.3 million people worldwide, generally younger than 50. There is no known cure for the disease, and current treatment options - mainly immunotherapies to limit disease progression - are few and associated with serious sid...
Under neuroinflammatory conditions, astrocytes acquire a reactive phenotype that drives acute inflammatory injury as well as chronic neurodegeneration. We hypothesized that astrocytic DLL4 may interact with its receptor NOTCH1 on neighboring astrocytes to regulate astrogliosis via downstream juxtacrine signaling pathways. Here we investigated the r...
Introduction: 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 investigated in animal models of HFpEF and sex differences are not always considered.
Objective...
Background
Although the critical role of pericytes in maintaining vascular integrity has been extensively demonstrated in the brain and the retina, little is known about their role in the heart. We aim to investigate structural and functional consequences of partial pericyte depletion (≈60%) in the heart of adult mice.
Methods and Results
To deple...
Background:
Adaptation of fat depots to change in fuel availability is critical for metabolic flexibility and cardiometabolic health. The mechanisms responsible for fat depot-specific lipid sensing and shuttling remain elusive. Adipose tissue microvascular endothelial cells (AT-EC) regulates bidirectional fatty acid fluxes depending on fed or fast...
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.
Objective
To determine whether endothelial dysfunctio...
Background:
Lower-limb peripheral artery disease is one of the major complications of diabetes. Peripheral artery disease is associated with poor limb and cardiovascular prognoses, along with a dramatic decrease in life expectancy. Despite major medical advances in the treatment of diabetes, a substantial therapeutic gap remains in the peripheral...
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. Metho...
Introduction
Lower-limb peripheral artery disease (PAD) is a prevalent and challenging complication of diabetes, requiring innovating therapies. Praliciguat is an orally available stimulator of soluble guanylate cyclase (sGC) reported to have favorable effects on metabolic and hemodynamic endpoints in preclinical and clinical studies, suggesting th...
Introduction
Heart failure with preserved ejection fraction is proposed to be caused by endothelial dysfunction in cardiac small vessels.
Objective
Our goal is to demonstrate that endothelial dysfunction is sufficient to induce diastolic dysfunction using mice with genetically induced endothelial dysfunction.
Method
We used Desert Hedgehog (Dhh)...
Introduction
Schiattarella et al. introduced a new mouse model mimicking heart failure with preserved ejection fraction (HFpEF). In this model, diastolic dysfunction is induced by a high fat diet (HFD) regimen with L-NAME treatment. Small vessel disease is currently proposed to be responsible for HFpEF. Moreover, blocking Cdon, a negative co-recept...
Contact mediated interactions between the astrocytic endfeet and infiltrating immune cells within the perivascular space are underexplored, yet represent potential regulatory check-points against CNS autoimmune disease and disability. Reactive astrocytes upregulate Junctional Adhesion Molecule-A (JAM-A), an immunoglobulin-like cell surface receptor...
Introduction
Endothelium integrity is critical to vascular homeostasis, as failure of this system results in serious consequences such as hemorrhage, edema, inflammation and tissue ischemia. We recently identified Desert Hedgehog (DHH) as a critical regulator of endothelium integrity, downstream of KLF2.
Objective
The purpose of the present study...
Introduction
Heart Failure with Preserved Ejection Fraction is proposed to be caused by endothelial dysfunction in cardiac small vessels.
Objective
Our goal is to demonstrate that endothelial dysfunction is sufficient to induce diastolic dysfunction by using a mouse model with genetically-induced endothelial dysfunction.
Methods
We used Desert He...
Introduction
In 2019, Schiattarella et al introduced a new mouse model mimicking heart failure with preserved ejection fraction (HFpEF). In this model, diastolic dysfunction is induced by a high fat diet (HFD) regimen together with L-NAME treatment. Even though small vessel disease is currently proposed to be responsible for HFpEF, the phenotype of...
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
To investigate the cardiac structural and functional consequences of partial pericyte depletion (about 60%) in adult mice.
Method
To dep...
Glioblastoma is among the most common tumor of the central nervous system in adults. Overall survival has not significantly improved over the last decade, even with optimizing standard therapeutic care including extent of resection and radio- and chemotherapy. In this article, we review features of the brain vasculature found in healthy cerebral ti...
Objective:
Heart failure with preserved ejection fraction is a major health care issue which has been difficult to manage to date, due to its complex and not well understood pathophysiology. Specifically, if a wealth of literature focuses on heart failure with preserved ejection fraction cardiac component, very little information can be found on i...
Inflammation of the central nervous system (CNS) induces endothelial blood–brain barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only during neuroinflammation but...
Aims
The therapeutic potential of Hedgehog (Hh) signalling agonists for vascular diseases is of growing interest. However, molecular and cellular mechanisms underlying the role of the Hh signalling in vascular biology remain poorly understood. The purpose of the present article is to clarify some conflicting literature data.
Methods and results
Wi...
Objective:
Evidences accumulated within the past decades identified hedgehog signaling as a new regulator of endothelium integrity. More specifically, we recently identified desert hedgehog (Dhh) as a downstream effector of Klf2 (Kruppel-like factor 2) in endothelial cells (ECs). The purpose of this study is to investigate whether hedgehog corecep...
Introduction
Heart failure with preserved ejection fraction (HFpEF) which results from diastolic dysfunction is a growing epidemiologic problem. The pathophysiology of this disease is poorly understood nevertheless a theory suggests a central role of microvessel disease.
Objective
Our goal is to investigate the role of pericyte in the pathophysiol...
Introduction
The therapeutic potential of Hedgehog (Hh) signaling agonists for vascular diseases is of growing interest. However, the molecular mechanisms underlying Hh signaling effects on the vasculature remains unclear and conflicting results have been published.
Objective
Our goal is to clarify and compare the vascular effects of endothelial-d...
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 (Lepr db/db )...
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).
Objective
The purpose of this study is to investigate whether Hh co-receptors Gas1 and Cdon may...
Recent work demonstrated that Central Nervous System (CNS) inflammation induces endothelial Blood Brain Barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that these two barriers may be reciprocally regulated by each other state and further, that the CNS paren...
Rationale
The 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.
Objective
The purpose of the present paper is to clarify some conflicting literature data.
Findings
W...
The role of Hedgehog (Hh) signaling in vascular biology has first been highlighted in embryos by Pepicelli et al. in 1998 and Rowitch et al. in 1999. Since then, the proangiogenic role of the Hh ligands has been confirmed in adults, especially under pathologic conditions. More recently, the Hh signaling has been proposed to improve vascular integri...
Introduction
Heart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic problem and a major source of morbidity and mortality. However, to date, there are no therapies available to treat HFpEF mainly because of its poorly understood pathophysiology.
Objective
The purpose of this study is to investigate whether Leptin recepto...
Introduction
Sonic Hedgehog (Shh), when administered as recombinant protein or via gene therapy was shown to be proangiogenic. However, studies performed in mice deficient for Hedgehog (Hh) signaling pathway elements have revealed that, on the contrary, endogenous Hh signaling is necessary for endothelium integrity and limits angiogenesis, suggesti...
Rationale:
Klf (kruppel-like factor) 2 is critical to establish and maintain endothelial integrity.
Objective:
Therefore, determining upstream and downstream mediators of Klf2 would lead to alternative therapeutic targets in cardiovascular disease management.
Methods and results:
Here we identify Dhh (desert hedgehog) as a downstream effector...
Lesions and neurologic disability in inflammatory CNS diseases such as multiple sclerosis (MS) result from the translocation of leukocytes and humoral factors from the vasculature, first across the endothelial blood-brain barrier (BBB) and then across the astrocytic glia limitans (GL). Factors secreted by reactive astrocytes open the BBB by disrupt...
Author
Myelin, a membranous sheet that surrounds the axons of neurons and facilitates the transmission of nerve impulses, is formed by oligodendrocytes in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS). Failure to myelinate, or demyelination, produces the symptoms of serious diseases such as leukodystrop...
Individual values used for quantitation in the text, figures, and supplementary materials.
(XLSX)
Identification and validation of Klf6-dependent transcripts in oligodendrocyte lineage cells.
Data complement findings in Fig 4 and S1–S3 Tables. (A,B) Silencing strategy for samples used in RNA-seq analysis. (A) Primary mouse OLP are isolated and expanded, then nucleofected with siRNA specific for Klf6 or non-targeting (NT) control. Klf6-silenced...
RNA-seq identification of Klf6-regulated genes in iOL.
Data here accompany findings in Figs 4 and S5 and in S1 and S3 Tables. RNA-seq profiling results from primary mouse iOL silenced for Klf6 versus non-targeting control. Data from two separate cultures have been filtered for statistically significant differential expression with FDR correction p...
Identification of Klf6-dependent genes that are directly Klf6-regulated.
This table complements Figs 4 and 5 and S1–S4 Tables. It shows results of superimposition of RNA-seq profiling of OLP and iOL silenced for Klf6 versus non-targeting control (from S1–S3 Tables and Fig 4), and Klf6 ChIP-seq profiling of the same cell types (from S4 Table and Fig...
Primer sequences for genotyping and qPCR.
Additional details for the Materials and Methods section. This table shows primer sequences for genotyping of mouse lines and for qPCR for validation of RNA-seq data and maturation data presented in the manuscript.
(XLSX)
Related to Fig 1. Tremor and ataxia in Olig1Cre:Klf6fl/fl mice.
Video sequence showing two representative P11 Olig1Cre:Klf6fl/fl mutants (center and right), and a sex-matched Klf6fl/fl littermate control (left). The mutants are smaller than the control and display tremor and ataxia. All Olig1Cre:Klf6fl/fl pups display similar signs, which are progr...
ARRIVE guidelines checklist for reporting in vivo experiments.
(PDF)
Myelination failure in Olig1Cre:Klf6fl/fl spinal cord.
Data shown complement results in Fig 1. (A–D) Confocal imaging analysis of lumbar spinal cords of P14 Olig1Cre:Klf6fl/fl mice, mGfapCre:Klf6fl/fl mice, and Klf6fl/fl controls. Areas outlined in (A) are shown at higher magnification, inset. In contrast to controls and samples from mice with astr...
Failure of myelination throughout the CNS in Olig1Cre:Klf6fl/fl mice.
Results are complementary to and extend data in Fig 1. (A–F) Analysis of P14 Olig1Cre:Klf6fl/fl, mGfapCre:Klf6fl/fl, and control Klf6fl/fl cerebellum and corpus callosum. In contrast to results from the other two genotypes, myelin markers are almost completely absent from cerebel...
Klf6 inactivation in OLP using different Cre drivers produces convergent phenotypes.
Results extend and complement findings shown in Figs 1, 2 and 3. (A) BeadArray transcriptional analysis of total CNS of P1 Olig1Cre:Klf6fl/fl pups and sex-matched Klf6fl/fl littermates, five per group. These data were used to generate the Ingenuity gene ontology an...
Validation of the gp130-Klf-importin axis in oligodendrocyte lineage cells.
Data complement results presented in Figs 5 and 6. (A) Confocal image of lumbar spinal cord of an E16.5 wild-type mouse embryo labeled for Stat3 and the marker of ventral horn motor neurons, Mnr. Immunoreactivity for Stat3 is ubiquitous, but is strongest within ventral Mnr+...
RNA-seq profiling of Klf6-regulated transcripts in OLP.
Results shown here complement data in Figs 4 and S5 and in S2 and S3 Tables. Results of RNA-seq profiling of primary mouse OLP silenced for Klf6 versus non-targeting control to identify Klf6-regulated transcripts, as described in the text and illustrated in S5 Fig. Data from two separate cultu...
RNA-seq profiling of Klf6-regulated transcripts shared by OLP and iOL.
Findings here extend and complement results shown in Figs 4 and S5 and in S1 and S2 Tables. RNA-seq profiling data from primary mouse OLP and iOL silenced for Klf6 versus non-targeting control to identify Klf6-regulated transcripts, as described in the text and illustrated in S5...
Construction and technical validation of Klf6 conditional knockout lines.
Data presented here support findings in Fig 1. (A) QPCR analysis of Klf6 responses to the pro-myelinating factors Cntf (100 ng/ml), Lif (100 ng/ml), and T3 (40 ng/ml) in Oli-neu cells. Data extend results in Fig 1B. (B) To inactivate Klf6 in oligodendrocyte lineage cells or a...
Results of ChIP-seq screening for Klf6 binding to promoters of prospective effectors.
Data shown here complement Fig 5 and illustrate results of ChIP-seq profiling of primary mouse OLP and iOL subjected to chromatin immunoprecipitation for Klf6 versus input as described in the text. Data from one of two representative studies are presented for both...
Aim:
In the present paper we have identified the role of Hedgehog (Hh) signalling in endoneurial microvessel integrity and evaluated the impact of impaired Hh signalling in endothelial cells on nerve function.
Methods and results:
By using Desert Hedgehog (Dhh) deficient mice, we have revealed, that in the absence of Dhh, endoneurial capillaries...
Background
In elderly and diabetic patients, the increased risk of developing ischemic disease is associated with impaired regenerative properties of most tissues including skeletal muscle, which make those patients a challenging population to treat. We recently demonstrated that in skeletal muscle, Hedgehog (Hh) signaling promotes ischemia-induced...
In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vas...
Key Points
Maturation of vascular endothelial growth factor–induced new vessels in cornea involves a PDGF-Shh axis. Shh promotes PDGF-BB–mediated SMC migration by inducing ERK1/2 and phosphatidylinositol 3-kinase γ activation and increased motility.
The purpose of this study is to further document alteration of signal transduction pathways, more particularly of hedgehog (Hh) signaling, causing impaired ischemic muscle repair in old mice.
We used 12-week-old (young mice) and 20- to 24-month-old C57BL/6 mice (old mice) to investigate the activity of Hh signaling in the setting of hindlimb ischem...
Rationale:
A better understanding of the mechanism underlying skeletal muscle repair is required to develop therapies that promote tissue regeneration in adults. Hedgehog signaling has been shown previously to be involved in myogenesis and angiogenesis: 2 crucial processes for muscle development and regeneration.
Objective:
The objective of this...
Rationale:
Blood vessel growth and patterning have been shown to be regulated by nerve-derived signals. Desert hedgehog (Dhh), one of the Hedgehog family members, is expressed by Schwann cells of peripheral nerves.
Objective:
The purpose of this study was to investigate the contribution of Dhh to angiogenesis in the setting of ischemia.
Methods...
Mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), is used to treat systemic lupus erythematosus (SLE). MMF and EC-MPS pharmacokinetics were examined to devise guidance for therapeutic drug monitoring (TDM) for SLE patients with normal renal function.
This observational study in...
