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Introduction
Additional affiliations
January 2016 - October 2016
January 2014 - December 2015
July 2012 - December 2013
Education
September 2006 - November 2009
September 2004 - May 2006
September 2003 - May 2004
Publications
Publications (95)
Hypertrophic scarring is a major source of morbidity. Sex hormones are not classically considered modulators of scarring. However, based on increased frequency of hypertrophic scarring in patients on testosterone, we hypothesized that androgenic steroids induce abnormal scarring and developed a preclinical porcine model to explore these effects. Mi...
Background: Atherosclerosis is accompanied by distinct vascular phenotypes that underly its initiation and progression, though their contribution to its pathogenesis is currently unknown. By integrating polygenetic risk profiles from genome-wide association studies (GWAS) of vascular disease with single-cell transcriptional analyses, it is possible...
Background: Hypertrophic scarring is a major source of morbidity for surgery patients. An increasing number of transgender patients undergo surgery while on exogenous hormones. Based on clinical observations of increased frequency of post-op hypertrophic scarring in transgender males, we hypothesized that androgenic steroids lead to abnormal scarri...
Introduction: Bicuspid aortic valve (BAV) is the most common cause of adult congenital heart disease. Patients with BAVs comprise <2% of the population but represent ~50% of valve replacement surgeries and the pathogenic mechanisms underlying this disproportionate incidence of calcific aortic valve disease (CAVD) are unknown. We aimed to identify m...
Background:
Panx1 (pannexin 1) forms high conductance channels that secrete ATP upon stimulation. The role of Panx1 in mediating constriction in response to direct sympathetic nerve stimulation is not known. Additionally, it is unknown how the expression level of Panx1 in smooth muscle cells (SMCs) influences α-adrenergic responses. We hypothesize...
Pannexin 1 (Panx1) forms high conductance channels that secrete ATP upon stimulation. The role of Panx1 in mediating constriction in response to direct sympathetic nerve stimulation is not known. Additionally, it is unknown how the expression level of Panx1 in SMCs influences a-adrenergic responses. We hypothesized that the amount of Panx1 in SMCs...
Background
Calcific aortic valve disease (CAVD) is the pathological remodeling of the valve leaflets which leads to heart failure and high stroke risk. While several mechanisms are known to drive cardiovascular calcification, the initial steps orchestrating the osteogenic reprogramming of cells are not fully understood. Non-canonical functions of t...
The aim of this study was to determine whether specific three-dimensional aortic shape features, extracted via statistical shape analysis (SSA), correlate with the development of thoracic ascending aortic dissection (TAAD) risk and associated aortic hemodynamics. Thirty-one patients followed prospectively with ascending thoracic aortic aneurysm (AT...
Pericytes are essential components of small blood vessels and are found in human aortic vasa vasorum. Prior work uncovered lower vasa vasorum density and decreased levels of pro‐angiogenic growth factors in adventitial specimens of human ascending thoracic aortic aneurysm. We hypothesized that adventitial extracellular matrix (ECM) from normal aort...
Objectives:
We hypothesized that expression and activity of nitric oxide synthase-3 enzyme (Nos3) in bicuspid aortic valve (BAV) aortopathy are related to tissue layer and Nos3 genotype.
Methods:
Gene expression of Nos3 and platelet and endothelial cell adhesion molecule-1 (Pecam1) and NOS activity were measured in intima-containing media and ad...
Calcific aortic valve disease (CAVD) is the leading heart valve disorder in the US. It is characterized by an active accumulation of calcium nodules on the aortic valve leaflets which lead to stiffening and remodeling of the valve leaflets causing valve dysfunction, cardiac failure and increased stroke risk. Inflammation and mechanical stresses con...
Bicuspid aortic valve (BAV) with ∼1-2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (LVOTO), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta...
Pannexin 1 (PANX1)-mediated ATP release in vascular smooth muscle coordinates α1-adrenergic receptor (α1-AR) vasoconstriction and blood pressure homeostasis. We recently identified amino acids 198-200 (YLK) on the PANX1 intracellular loop that are critical for α1-AR-mediated vasoconstriction and PANX1 channel function. We report herein that the YLK...
Objective:
To assess ascending aortic distensibility and build geometry and distensibility-based patient-specific stress distribution maps in patients sustaining type A aortic dissection (TAAD) using predissection noninvasive imaging.
Methods:
Review of charts from patients undergoing surgical repair of TAAD (n = 351) led to the selection of a s...
Human ascending aortic aneurysms characteristically exhibit cystic medial degeneration of the aortic wall encompassing elastin degeneration, proteoglycan accumulation and smooth muscle cell loss. Most studies have focused on the aortic media and there is a limited understanding of the importance of the adventitial layer in the setting of human aneu...
Recent smooth muscle cell (SMC) lineage tracing studies have revealed SMCs undergo remarkable changes in phenotype during development of atherosclerosis. Of major interest, we demonstrated that KLF4 in SMC is detrimental for overall lesion pathogenesis in that SMC-specific conditional knockout of Klf4 resulted in smaller, more stable lesions that e...
Table S1. Real-Time qPCR Assay Information Related to Transcript Analysis of Purified Perivascular Progenitor Cells Compared with Human Adventitial Tissue
Movie S1. Time-Lapse Movie of Pericyte Culture on Matrigel Substrates Revealing Spontaneous Spheroid Formation
In the microcirculation, pericytes are believed to function as mesenchymal stromal cells (MSCs). We hypothesized that the vasa vasorum harbor progenitor cells within the adventitia of human aorta. Pericytes, endothelial progenitor cells, and other cell subpopulations were detected among freshly isolated adventitial cells using flow cytometry. Purif...
Objective
Congenital bicuspid aortic valve (BAV) is distinctly associated with the development of ascending aortopathy in adulthood portending risk of both ascending aortic aneurysm and dissection. Our prior work implicated deficiency in oxidative stress response as a mediator of the BAV-associated aortopathy. We hypothesize that reactive oxygen sp...
Background:
Bicuspid aortic valve (BAV) is associated with asymmetric dilatation of the proximal ascending aorta. We previously demonstrated increased susceptibility of smooth muscle cells to oxidative stress in the BAV-aneurysmal aorta and hypothesized that antioxidant expression is regionally defined and influenced by the BAV morphotype.
Method...
Serotonin (5-HT) is a potent vasoconstrictor agonist and contributes to several vascular diseases including systemic or pulmonary hypertension and atherosclerosis. Although superoxide anion (O2•_) is commonly associated to cellular damages due to O2•_ overproduction, we previously demonstrated that, in physiological conditions, O2•_ also participat...
Extracellular matrix (ECM)-derived bioscaffolds have been shown to elicit tissue repair through retention of bioactive signals. Given that the adventitia of large blood vessels is a richly vascularized microenvironment, we hypothesized that perivascular ECM contains bioactive signals that influence cells of blood vessel lineages. ECM bioscaffolds w...
Objective:
Myogenic tone (MT) of resistance arteries ensures autoregulation of blood flow in organs and relies on the intrinsic property of smooth muscle to contract in response to stretch. Nucleotides released by mechanical strain on cells are responsible for pleiotropic vascular effects, including vasoconstriction. Here, we evaluated the contrib...
Background:
Endothelial nitric oxide (NO) synthase (eNOS) has been implicated in the development of bicuspid aortic valve (BAV) and with differential expression in the ascending aorta of BAV patients. However, little is known about functional disruptions in the eNOS pathway and the effect on BAV-associated aortic dilatation. We tested the hypothes...
Hemoglobin H is a tetramer made up of 2 alpha globin subunits and 2 beta globin subunits. The alpha globin subunit requires chaperone activity by alpha hemoglobin stabilizing protein (AHSP) in order to properly associate with hemoglobin beta. In addition to erythrocytes, alpha globin is expressed in endothelial cells (EC), specifically in the small...
Introduction: Bicuspid aortic valve (BAV) is associated with an aortopathy that manifests as a dilatation of the proximal ascending aorta. The mechanisms of aneurysm formation in BAV patients are not completely understood. Our group established that medial smooth muscle cells (SMC) from aneurysmal BAV patients exhibit a weakened oxidative stress de...
Pannexin channels are newly discovered ATP release channels expressed throughout the body. Pannexin 1 (Panx1) channels have become of great interest as they appear to participate in a multitude of signalling cascades, including regulation of vascular function. Although numerous Panx1 pharmacological inhibitors have been discovered, these inhibitors...
Introduction
We have investigated signalling pathways implicated in the 5-HT-induced contraction dependent on O2• production by focusing on:
– sources of reactive oxygen species, especially, NADPH oxidases (Nox) and mitochondria;
– caveoli.
Methods
Experiments were conducted on IPA and pulmonary arterial smooth muscle cells (PA-SMC) of male Wistar...
Both purinergic signaling through nucleotides such as ATP (adenosine 5'-triphosphate) and noradrenergic signaling through molecules such as norepinephrine regulate vascular tone and blood pressure. Pannexin1 (Panx1), which forms large-pore, ATP-releasing channels, is present in vascular smooth muscle cells in peripheral blood vessels and participat...
Objective:
Hemoglobin α (Hb α) and endothelial nitric oxide synthase (eNOS) form a macromolecular complex at myoendothelial junctions; the functional role of this interaction remains undefined. To test if coupling of eNOS and Hb α regulates nitric oxide signaling, vascular reactivity, and blood pressure using a mimetic peptide of Hb α to disrupt t...
It has become increasingly clear that the accumulation of proteins in specific regions of the plasma membrane can facilitate cellular communication. These regions, termed signaling microdomains, are found throughout the blood vessel wall where cellular communication, both within and between cell types, must be tightly regulated to maintain proper v...
New Findings
What is the central question of this study?
Experimental results on intrapulmonary arteries indicate that the relationship between gap junctional intercellular communication and its functional involvement in tissue reactivity is very complex, both in normoxic and in chronically hypoxic conditions. The relationship between the gap junct...
Heparan sulfate proteoglycans act as co-receptors for many chemokines and growth factors. The sulfation pattern of the heparan sulfate chains is a critical regulatory step affecting the binding of chemokines and growth factors. N-deacetylase-N-sulfotransferase1 (Ndst1) is one of the first enzymes to catalyze sulfation. Previously published work has...
Collectrin is an orphan member of the renin-angiotensin system and is a homologue of ACE2, sharing ~50% sequence identity. Unlike ACE2, collectrin lacks any catalytic domain. Collectrin has been shown to function as a chaperone of amino acid transporters. In rodents, the renal expression of collectrin is increased after sub-total nephrectomy and du...
Models of unregulated nitric oxide (NO) diffusion do not consistently account for the biochemistry of NO synthase (NOS)-dependent signalling in many cell systems. For example, endothelial NOS controls blood pressure, blood flow and oxygen delivery through its effect on vascular smooth muscle tone, but the regulation of these processes is not adequa...
S-Nitrosylation is a post-translational modification on cysteine(s) that can regulate protein function, and pannexin 1 (Panx1)
channels are present in the vasculature, a tissue rich in nitric oxide (NO) species. Therefore, we investigated whether Panx1
can be S-nitrosylated and whether this modification can affect channel activity. Using the biotin...
Extracellular nucleotides promote vascular constriction through cell membrane P2 receptors. This effect involves neurogenic activation of vascular smooth muscle cell P2X1 (ATP) and some pyrimidine-sensitive (UDP, UTP) P2Y receptors. We used knockout mouse models to unravel the role of extracellular nucleotides in myogenic tone of resistance arterie...
Posttranslational modification is a common cellular process that is used by cells to ensure a particular protein function. This can happen in a variety of ways, e.g., from the addition of phosphates or sugar residues to a particular amino acid, ensuring proper protein life cycle and function. In this review, we assess the evidence for ubiquitinatio...
Pannexins (Panx) form ATP release channels and it has been proposed that they play an important role in the regulation of vascular tone. However, distribution of Panx across the arterial vasculature is not documented.
We tested antibodies against Panx1, Panx2 and Panx3 on human embryonic kidney cells (which do not endogenously express Panx proteins...
The nucleotide adenosine 5'-triphosphate (ATP) has classically been considered the cell's primary energy currency. Importantly, a novel role for ATP as an extracellular autocrine and/or paracrine signalling molecule has evolved over the past century and extensive work has been conducted to characterize the ATP-sensitive purinergic receptors express...
Heparan sulfate proteoglycans are abundant matrix and membrane molecules. Smooth muscle specific deletion of one heparan sulfate biosynthetic enzyme, N-deacetylase-N-sulfotransferase1 leads to decreased vascular smooth muscle cell proliferation, and vascular wall thickness. We hypothesized that this may lead to changes in blood pressure in consciou...
Dehydroepiandrosterone (DHEA) prevents chronic hypoxia-induced pulmonary hypertension and the associated right ventricle dysfunction in rats. In this animal model, reoxygenation following hypoxia reverses pulmonary hypertension but not right ventricle dysfunction. We thus studied the effect of DHEA on the right ventricle after reoxygenation i.e. af...
Post‐translational modification of proteins by S‐nitrosylation at unique cysteine residues can profoundly affect protein function. We recently demonstrated the presence of pannexin 1 (Panx1) channels in the vasculature and thus investigated whether Panx1 can be S‐nitrosylated and if this modification affects channel activity. Application of S‐nitro...
We recently demonstrated that pannexin1 (Panx1) channels release ATP in vascular smooth muscle cells after phenylephrine (PE) stimulation (Billaud et al, Circ Res, 2011). However, the participation of Panx1 in other contractile pathways has not been investigated. Therefore, we stimulated thoracodorsal arteries with angiotensin II, endothelin‐1, ser...
We have shown that hemoglobin subunit alpha (HBα) localizes to the myoendothelial junction(MEJ), the contact point between endothelial cells (EC) and smooth muscle cells (SMC) in small arteries to modulate nitric oxide (NO) scavenging, however, the redox mechanism controlling NO scavenging remains unknown. Since the iron (Fe) domain on Hb is critic...
Pannexins form ATP‐release channels that have both physiological and pathological roles in cells such as regulation of vascular tone and apoptosis, respectively. However, distribution of pannexins across the vasculature is poorly documented. Therefore, we aimed to detail their distribution across different vascular beds. We first tested antibodies...
Endothelial nitric oxide synthase (eNOS) localizes to the myoendothelial (MEJ), a discreet location where the endothelial cells (EC) and smooth muscle cells (SMC) make contact, however the regulation of eNOS‐derived NO at the MEJ remains unknown. Using a vascular cell co‐culture (VCCC) model, we isolated EC, MEJ, and SMC protein fractions and subje...
Arterial stiffness is a key marker in metabolic diseases and can be evaluated by arterial compliance. Most compliance measurements are performed in large conduit arteries in advanced stage of metabolic diseases, which may not provide information on mechanisms associated with the initiation of the pathology. For this reason, we compared arterial com...
In this paper, we describe the histological and contractile properties of the thoracodorsal artery (TDA), which indirectly feeds the spinotrapezius muscle.
We used immunolabelling techniques to histologically characterize the TDA while the contractile properties were assessed using pressure arteriography.
Our results demonstrate that the TDA is com...
Nitric oxide signaling, through eNOS (or possibly nNOS), and gap junction communication are essential for normal vascular function. While each component controls specific aspects of vascular function, there is substantial evidence for cross-talk between nitric oxide signaling and the gap junction proteins (connexins), and more recently, protein-pro...
The coordination of vascular smooth muscle cell constriction plays an important role in vascular function, such as regulation of blood pressure; however, the mechanism responsible for vascular smooth muscle cell communication is not clear in the resistance vasculature. Pannexins (Panx) are purine-releasing channels permeable to the vasoconstrictor...
Gap junction proteins (connexins) facilitate intercellular communication and serve several roles in regulation of tissue function and remodeling. To examine the physiologic effects of depleting two prominent endothelial connexins, Cx40 and Cx43, transgenic mice were generated by breeding Cx40-deficient mice (Cx40(-/-)) with a vascular endothelial c...
Vascular obstructive events can be partially compensated for by remodeling processes that increase vessel diameter and collateral tortuosity. However, methods for visualizing remodeling events in vivo and with temporal comparisons from the same animal remain elusive.
Using a novel infrared conjugated polyethylene glycol dye, we investigated the pos...
Pulmonary hypertension (PH) is characterized by arterial vascular remodelling and alteration in vascular reactivity. Since gap junctions are formed with proteins named connexins (Cx) and contribute to vasoreactivity, we investigated both expression and role of Cx in the pulmonary arterial vasoreactivity in two rat models of PH.
Intrapulmonary arter...
To determine whether S-nitrosylation of connexins (Cxs) modulates gap junction communication between endothelium and smooth muscle.
Heterocellular communication is essential for endothelium control of smooth muscle constriction; however, the exact mechanism governing this action remains unknown. Cxs and NO have been implicated in regulating heteroc...
![Figure 2. A representative trace of [Ca 2 + ] i change upon](profile/Christelle-Guibert/publication/221611388/figure/fig2/AS:305616234008576@1449875996044/A-representative-trace-of-Ca-2-i-change-upon_Q320.jpg)
We study contractile responses and Ca2+ signalization in pulmonary artery smooth muscle cells. Experimental results indicate that the contraction responses to KCl under normoxic conditions are not affected by the contribution of gap junction blockers. On the other side, under hypoxic condition, where the contraction occurs at lower concentrations o...
Effect of 37-43Gap 27 on the contractile responses to 5-HT, phenylephrine, endothelin-1 and high potassium solutions. Isometric tension measurements were recorded on intrapulmonary arterial rings in response to cumulative concentrations of 5-HT (A) or phenylephrine (B) or endothelin-1 (C) or in response to increasing concentrations of potassium (KC...
Effect of L-NAME on the simultaneously recorded calcium and contractile signals in response to 5-HT. Cumulative concentration-response curves to 5-HT (0.1–100 µM) were performed in the absence or in the presence of L-NAME 100 µM, a NO synthase inhibitor (black squares and circles respectively). Data are means±S.E.M. for 6 vessels and are expressed...
Reproducibility of two cumulative concentration-response curves to 5-HT on the same vessel. Two CCRC to 5-HT (0.1–100 µM) recorded on the same vessel with a delay of one hour in between the two curves were similar for both calcium signal (top) and contraction (bottom). Black squares indicate the first CCRC and the black circles indicate the second...
Effect of endothelium removal on the calcium and contractile responses to high potassium solution. The calcium and contractile signals simultaneously recorded in response to high potassium solution (KCl 40 mM) were similar in control vessels (black column) and in vessels whose endothelium has been denuded with CHAPS (white column). Data are means±S...
Effect of endothelium removal on the relaxant effect of carbamylcholine. Intrapulmonary arteries were preconstricted with high potassium solution (KCl 40 mM) and then stimulated with 10 µM carbamylcholine. Calcium and contractile signals were simultaneously recorded (top and bottom respectively). The experiments were performed in control vessels (b...
Effect of 43Gap 26 on the contractile responses to 5-HT in renal arteries and aorta. Isometric tension measurements were recorded on arterial rings in response to cumulative concentrations of 5-HT in renal arteries (A) or aorta (B). Contractions were recorded in the absence (black squares) or in the presence (black circles) of 300 µM 43Gap 26. Data...
Effect of endothelium removal and xanthine plus xanthine oxidase treatment on superoxide anion production. O2• was measured by using CMH spin trapping method and EPR spectrometry on control vessels (black column), vessels whose endothelium was denuded with CHAPS 0.3% (white column, top panel) and vessels treated with xanthine 50 µM plus xanthine ox...
Effect of 40Gap 27 on the calcium and contractile signals in response to 5-HT. The calcium and contractile signals were simultaneously recorded in response to 5-HT 10 µM in the absence (black column) or in the presence of 300 µM 40Gap 27, the Cx-mimetic peptide targeted against Cx 40 (white column). Data are means±S.E.M. and are expressed as a delt...
Effect of 43Gap 26 on the calcium and contractile signals in response to 5-HT. Cumulative concentration-response curves to 5-HT (0.1–100 µM) were performed in the absence or in the presence of 300 µM 43Gap 26, the Cx-mimetic peptide targeted against Cx 43 (black squares and circles respectively). Data are means±S.E.M. for 7 vessels and are expresse...
Effect of 43Gap 20 on the calcium and contractile signals in response to 5-HT. CCRC to 5-HT (0.1–100 µM) were performed in the absence or in the presence of 300 µM 43Gap 20, an inactive analog of the Cx-mimetic peptide targeted against Cx 43 (black squares and circles respectively). Data are means±S.E.M. for 7 vessels and are expressed as a delta r...
Although cross‐talk between endothelial (EC) and smooth muscle cells (SMC) through myoendothelial gap junctions play a major role in the vasoreactivity, the transduction pathways remain unclear. Here we tested the hypothesis of the role of ROS and gap junctions in this cross‐talk.
Connexin (Cx)‐ mimetic peptide targeted against Cx 37 and Cx 43 ( 37...
Endothelial control of vascular smooth muscle plays a major role in the resulting vasoreactivity implicated in physiological or pathological circulatory processes. However, a comprehensive understanding of endothelial (EC)/smooth muscle cells (SMC) crosstalk is far from complete. Here, we have examined the role of gap junctions and reactive oxygen...
Questions
Question (1)
I have difficulties to detect alpha1D adrenergic receptor using immunofluorescence (IF) lately. In the past, I have used an anitbody from Alomone that worked great for Western Bot and IF but lately, I don't have much luck with it on my IFs. Also, this antibody is made in rabbit, and I need to do colocalization experiments with another antibody that's made in rabbit so I am looking for an alpha1D adrenergic receptor antibody made in another species than rabbit.
Any suggestions are welcome!
