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1.
Antioxidants (Basel) ; 11(6)2022 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-35739974

RESUMO

Flow (shear stress)-mediated dilation (FMD) of resistance arteries is a rapid endothelial response involved in tissue perfusion. FMD is reduced early in cardiovascular diseases, generating a major risk factor for atherosclerosis. As alteration of mitochondrial fusion reduces endothelial cells' (ECs) sprouting and angiogenesis, we investigated its role in ECs responses to flow. Opa1 silencing reduced ECs (HUVECs) migration and flow-mediated elongation. In isolated perfused resistance arteries, FMD was reduced in Opa1+/- mice, a model of the human disease due to Opa1 haplo-insufficiency, and in mice with an EC specific Opa1 knock-out (EC-Opa1). Reducing mitochondrial oxidative stress restored FMD in EC-Opa1 mice. In isolated perfused kidneys from EC-Opa1 mice, flow induced a greater pressure, less ATP, and more H2O2 production, compared to control mice. Opa1 expression and mitochondrial length were reduced in ECs submitted in vitro to disturbed flow and in vivo in the atheroprone zone of the mouse aortic cross. Aortic lipid deposition was greater in Ldlr-/--Opa1+/- and in Ldlr-/--EC-Opa1 mice than in control mice fed with a high-fat diet. In conclusion, we found that reduction in mitochondrial fusion in mouse ECs altered the dilator response to shear stress due to excessive superoxide production and induced greater atherosclerosis development.

2.
Int J Mol Sci ; 23(12)2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35742839

RESUMO

Aneurysm is the second-most common disease affecting the aorta worldwide after atherosclerosis. While several clinical metabolomic studies have been reported, no study has reported deep metabolomic phenotyping in experimental animal models of aortic aneurysm. We performed a targeted metabolomics study on the blood and aortas of an experimental mice model of aortic aneurysm generated by high-cholesterol diet and angiotensin II in Ldlr-/- mice. The mice model showed a significant increase in media/lumen ratio and wall area, which is associated with lipid deposition within the adventitia, describing a hypertrophic remodeling with an aneurysm profile of the abdominal aorta. Altered aortas showed increased collagen remodeling, disruption of lipid metabolism, decreased glucose, nitric oxide and lysine metabolisms, and increased polyamines and asymmetric dimethylarginine (ADMA) production. In blood, a major hyperlipidemia was observed with decreased concentrations of glutamine, glycine, taurine, and carnitine, and increased concentrations of the branched amino acids (BCAA). The BCAA/glycine and BCAA/glutamine ratios discriminated with very good sensitivity and specificity between aneurysmatic and non-aneurysmatic mice. To conclude, our results reveal that experimental induction of aortic aneurysms causes a profound alteration in the metabolic profile in aortas and blood, mainly centered on an alteration of NO, lipid, and energetic metabolisms.


Assuntos
Aneurisma da Aorta Abdominal , Hipercolesterolemia , Hiperlipidemias , Receptores de LDL/metabolismo , Angiotensina II/metabolismo , Animais , Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Modelos Animais de Doenças , Metabolismo Energético , Glutamina/metabolismo , Glicina/metabolismo , Hipercolesterolemia/metabolismo , Hiperlipidemias/metabolismo , Lipídeos , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo
3.
Int J Mol Sci ; 23(10)2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35628350

RESUMO

Hypoxia and inflammation play a major role in revascularization following ischemia. Sildenafil inhibits phosphodiesterase-5, increases intracellular cGMP and induces revascularization through a pathway which remains incompletely understood. Thus, we investigated the effect of sildenafil on post-ischemic revascularization. The left femoral artery was ligated in control and sildenafil-treated (25 mg/kg per day) rats. Vascular density was evaluated and expressed as the left/right leg (L/R) ratio. In control rats, L/R ratio was 33 ± 2% and 54 ± 9%, at 7- and 21-days post-ligation, respectively, and was significantly increased in sildenafil-treated rats to 47 ± 4% and 128 ± 11%, respectively. A neutralizing anti-VEGF antibody significantly decreased vascular density (by 0.48-fold) in control without effect in sildenafil-treated animals. Blood flow and arteriolar density followed the same pattern. In the ischemic leg, HIF-1α and VEGF expression levels increased in control, but not in sildenafil-treated rats, suggesting that sildenafil did not induce angiogenesis. PI3-kinase, Akt and eNOS increased after 7 days, with down-regulation after 21 days. Sildenafil induced outward remodeling or arteriogenesis in mesenteric resistance arteries in association with eNOS protein activation. We conclude that sildenafil treatment increased tissue blood flow and arteriogenesis independently of VEGF, but in association with PI3-kinase, Akt and eNOS activation.


Assuntos
Membro Posterior , Isquemia , Óxido Nítrico Sintase Tipo III , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Citrato de Sildenafila , Animais , Membro Posterior/irrigação sanguínea , Membro Posterior/efeitos dos fármacos , Membro Posterior/metabolismo , Isquemia/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais , Citrato de Sildenafila/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Int J Mol Sci ; 23(5)2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35270003

RESUMO

Flow-mediated dilation (FMD) of resistance arteries is essential for tissue perfusion but it decreases with ageing. As estrogen receptor alpha (Erα encoded by Esr1), and more precisely membrane ERα, plays an important role in FMD in young mice in a ligand-independent fashion, we evaluated its influence on this arteriolar function in ageing. We first confirmed that in young (6-month-old) mice, FMD of mesenteric resistance arteries was reduced in Esr1-/- (lacking ERα) and C451A-ERα (lacking membrane ERα). In old (24-month-old) mice, FMD was reduced in WT mice compared to young mice, whereas it was not further decreased in Esr1-/- and C451A-ERα mice. Markers of oxidative stress were similarly increased in old WT and C451A-ERα mice. Reduction in oxidative stress with superoxide dismutase plus catalase or Mito-tempo, which reduces mitochondrial superoxide restored FMD to a normal control level in young C451A-ERα mice as well as in old WT mice and old C451A-ERα mice. Estradiol-mediated dilation was absent in old WT mice. We conclude that oxidative stress is a key event in the decline of FMD, and that an early defect in membrane ERα recapitulates phenotypically and functionally ageing of these resistance arteries. The loss of this function could take part in vascular ageing.


Assuntos
Receptor alfa de Estrogênio , Artérias Mesentéricas , Envelhecimento/genética , Animais , Estradiol , Receptor alfa de Estrogênio/genética , Artérias Mesentéricas/fisiologia , Camundongos
5.
Int J Mol Sci ; 22(21)2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34769516

RESUMO

(1) Background: Chronic increases in blood flow, as in cardiovascular diseases, induce outward arterial remodeling. Thrombospondin-1 (TSP-1) is known to interact with matrix proteins and immune cell-surface receptors, but its contribution to flow-mediated remodeling in the microcirculation remains unknown. (2) Methods: Mesenteric arteries were ligated in vivo to generate high- (HF) and normal-flow (NF) arteries in wild-type (WT) and TSP-1-deleted mice (TSP-1-/-). After 7 days, arteries were isolated and studied ex vivo. (3) Results: Chronic increases in blood flow induced outward remodeling in WT mice (increasing diameter from 221 ± 10 to 280 ± 10 µm with 75 mmHg intraluminal pressure) without significant effect in TSP-1-/- (296 ± 18 to 303 ± 14 µm), neutropenic or adoptive bone marrow transfer mice. Four days after ligature, pro inflammatory gene expression levels (CD68, Cox2, Gp91phox, p47phox and p22phox) increased in WT HF arteries but not in TSP-1-/- mice. Perivascular neutrophil accumulation at day 4 was significantly lower in TSP-1-/- than in WT mice. (4) Conclusions: TSP-1 origin is important; indeed, circulating TSP-1 participates in vasodilation, whereas both circulating and tissue TSP-1 are involved in arterial wall thickness and diameter expansion.


Assuntos
Endotélio Vascular/metabolismo , Artérias Mesentéricas/fisiologia , Trombospondina 1/metabolismo , Animais , Artérias Mesentéricas/metabolismo , Camundongos , Camundongos Knockout , Microcirculação , Modelos Animais , Fluxo Sanguíneo Regional , Trombospondina 1/genética , Vasodilatação
6.
Elife ; 102021 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-34842136

RESUMO

Estrogen receptor alpha (ERα) activation by estrogens prevents atheroma through its nuclear action, whereas plasma membrane-located ERα accelerates endothelial healing. The genetic deficiency of ERα was associated with a reduction in flow-mediated dilation (FMD) in one man. Here, we evaluated ex vivo the role of ERα on FMD of resistance arteries. FMD, but not agonist (acetylcholine, insulin)-mediated dilation, was reduced in male and female mice lacking ERα (Esr1-/- mice) compared to wild-type mice and was not dependent on the presence of estrogens. In C451A-ERα mice lacking membrane ERα, not in mice lacking AF2-dependent nuclear ERα actions, FMD was reduced, and restored by antioxidant treatments. Compared to wild-type mice, isolated perfused kidneys of C451A-ERα mice revealed a decreased flow-mediated nitrate production and an increased H2O2 production. Thus, endothelial membrane ERα promotes NO bioavailability through inhibition of oxidative stress and thereby participates in FMD in a ligand-independent manner.


Assuntos
Circulação Sanguínea , Receptor alfa de Estrogênio/genética , Peróxido de Hidrogênio/metabolismo , Animais , Receptor alfa de Estrogênio/metabolismo , Feminino , Ligantes , Masculino , Camundongos
7.
FASEB J ; 35(7): e21678, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34133045

RESUMO

Hypertension is associated with excessive reactive oxygen species (ROS) production in vascular cells. Mitochondria undergo fusion and fission, a process playing a role in mitochondrial function. OPA1 is essential for mitochondrial fusion. Loss of OPA1 is associated with ROS production and cell dysfunction. We hypothesized that mitochondria fusion could reduce oxidative stress that defect in fusion would exacerbate hypertension. Using (a) Opa1 haploinsufficiency in isolated resistance arteries from Opa1+/- mice, (b) primary vascular cells from Opa1+/- mice, and (c) RNA interference experiments with siRNA against Opa1 in vascular cells, we investigated the role of mitochondria fusion in hypertension. In hypertension, Opa1 haploinsufficiency induced altered mitochondrial cristae structure both in vascular smooth muscle and endothelial cells but did not modify protein level of long and short forms of OPA1. In addition, we demonstrated an increase of mitochondrial ROS production, associated with a decrease of superoxide dismutase 1 protein expression. We also observed an increase of apoptosis in vascular cells and a decreased VSMCs proliferation. Blood pressure, vascular contractility, as well as endothelium-dependent and -independent relaxation were similar in Opa1+/- , WT, L-NAME-treated Opa1+/- and WT mice. Nevertheless, chronic NO-synthase inhibition with L-NAME induced a greater hypertension in Opa1+/- than in WT mice without compensatory arterial wall hypertrophy. This was associated with a stronger reduction in endothelium-dependent relaxation due to excessive ROS production. Our results highlight the protective role of mitochondria fusion in the vasculature during hypertension by limiting mitochondria ROS production.


Assuntos
GTP Fosfo-Hidrolases/fisiologia , Hipertensão/prevenção & controle , Dinâmica Mitocondrial , Substâncias Protetoras/administração & dosagem , Animais , Apoptose , Inibidores Enzimáticos/toxicidade , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NG-Nitroarginina Metil Éster/toxicidade , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
8.
Int J Obes (Lond) ; 45(5): 1074-1085, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33637953

RESUMO

BACKGROUND/OBJECTIVES: Maternal obesity impacts vascular functions linked to metabolic disorders in offspring, leading to cardiovascular diseases during adulthood. Even if the relation between prenatal conditioning of cardiovascular diseases by maternal obesity and vascular function begins to be documented, little is known about resistance arteries. They are of particular interest because of their specific role in the regulation of local blood flow. Then our study aims to determine if maternal obesity can directly program fetal vascular dysfunction of resistance arteries, independently of metabolic disorders. METHODS: With a model of rats exposed in utero to mild maternal diet-induced obesity (OMO), we investigated third-order mesenteric arteries of 4-month old rats in absence of metabolic disorders. The methylation profile of these vessels was determined by reduced representation bisulfite sequencing (RRBS). Vascular structure and reactivity were investigated using histomorphometry analysis and wire-myography. The metabolic function was evaluated by insulin and glucose tolerance tests, plasma lipid profile, and adipose tissue analysis. RESULTS: At 4 months of age, small mesenteric arteries of OMO presented specific epigenetic modulations of matrix metalloproteinases (MMPs), collagens, and potassium channels genes in association with an outward remodeling and perturbations in the endothelium-dependent vasodilation pathways (greater contribution of EDHFs pathway in OMO males compared to control rats, and greater implication of PGI2 in OMO females compared to control rats). These vascular modifications were detected in absence of metabolic disorders. CONCLUSIONS: Our study reports a specific methylation profile of resistance arteries associated with vascular remodeling and vasodilation balance perturbations in offspring exposed in utero to maternal obesity, in absence of metabolic dysfunctions.


Assuntos
Endotélio Vascular , Epigênese Genética , Obesidade Materna/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fatores Sexuais , Resistência Vascular , Animais , Colágeno/genética , Metilação de DNA , Dieta Hiperlipídica , Endotélio Vascular/fisiopatologia , Feminino , Masculino , Metaloproteinases da Matriz/genética , Canais de Potássio/genética , Gravidez , Ratos , Ratos Sprague-Dawley
10.
J Vasc Res ; 58(1): 16-26, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33264773

RESUMO

Flow-mediated outward remodeling (FMR) is involved in postischemic revascularization. Angiotensin II type 2 receptor (AT2R), through activation of T-cell-mediated IL-17 production, and estrogens are involved in FMR. Thus, we investigated the interplay between estrogens and AT2R in FMR using a model of ligation of feed arteries supplying collateral pathways in mouse mesenteric arteries in vivo. Arteries were collected after 2 (inflammatory phase), 4 (diameter expansion phase), and 7 days (remodeling completed). We used AT2R+/+ and AT2R-/- ovariectomized (OVX) female mice treated or not with 17-beta-estradiol (E2). Seven days after ligation, arterial diameter was larger in high flow (HF) compared to normal flow (NF) arteries. FMR was absent in OVX mice and restored by E2. AT2R gene expression was higher in HF than in NF arteries only in E2-treated OVX AT2R+/+ mice. CD11b and TNF alpha levels (inflammatory phase), MMP2 and TIMP1 (extracellular matrix digestion), and NOS3 (diameter expansion phase) expression levels were higher in HF than in NF arteries only in E2-treated AT2R+/+ mice, not in the other groups. Thus, E2 is necessary for AT2R-dependent diameter expansion, possibly through activation of T-cell AT2R, in arteries submitted chronically to high blood flow.


Assuntos
Estradiol/farmacologia , Terapia de Reposição de Estrogênios , Mecanotransdução Celular , Artérias Mesentéricas/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/metabolismo , Remodelação Vascular/efeitos dos fármacos , Animais , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Feminino , Regulação da Expressão Gênica , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Ovariectomia , Receptor Tipo 2 de Angiotensina/genética , Fluxo Sanguíneo Regional , Estresse Mecânico , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
11.
PLoS One ; 15(7): e0235604, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645079

RESUMO

BACKGROUND: Cardiopulmonary bypass (CPB) induces a systemic inflammatory response (SIRS) and affects the organ vascular bed. Experimentally, the lack of pulsatility alters myogenic tone of resistance arteries and increases the parietal inflammatory response. The purpose of this study was to compare the vascular reactivity of the internal thoracic arteries (ITAs) due to the inflammatory response between patients undergoing coronary artery bypass grafting (CABG) under CPB with a roller pump or with a centrifugal pump. METHODS: Eighty elective male patients undergoing CABG were selected using one or two internal thoracic arteries under CPB with a roller pump (RP group) or centrifugal pump (CFP group). ITA samples were collected before starting CPB (Time 1) and before the last coronary anastomosis during aortic cross clamping (Time 2). The primary endpoint was the endothelium-dependent relaxation of ITAs investigated using wire-myography. The secondary endpoint was the parietal inflammatory response of arteries defined by the measurements of superoxide levels, leukocytes and lymphocytes rate and gene expression of inflammatory proteins using. Terminal complement complex activation (SC5b-9) and neutrophil activation (elastase) analysis were performed on arterial blood at the same times. RESULTS: Exposure time of ITAs to the pump flow was respectively 43.3 minutes in the RP group and 45.7 minutes in the CFP group. Acetylcholine-dependent relaxation was conserved in the two groups whatever the time. Gene expression of C3 and C4a in the artery wall decreased from Time 1 to Time 2. No oxidative stress was observed in the graft. There was no difference between the groups concerning the leukocytes and lymphocytes rate. SC5b-9 and elastase increased between Time 1 and Time 2. CONCLUSION: Endothelium-dependent relaxation of the internal thoracic arteries was preserved during CPB whatever the type of pump used. The inflammatory response observed in the blood was not found in the graft wall within this time frame. TRIAL REGISTRATION: Name of trial study protocol: IPITA Registration number (ClinicalTrials.gov): NCT04168853.


Assuntos
Ponte Cardiopulmonar/instrumentação , Ponte de Artéria Coronária/métodos , Coração Auxiliar/efeitos adversos , Artéria Torácica Interna/cirurgia , Complicações Pós-Operatórias/etiologia , Idoso , Idoso de 80 Anos ou mais , Ponte Cardiopulmonar/efeitos adversos , Ponte Cardiopulmonar/métodos , Ponte de Artéria Coronária/efeitos adversos , Ponte de Artéria Coronária/instrumentação , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Feminino , Humanos , Elastase de Leucócito/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Complicações Pós-Operatórias/epidemiologia , Transplantes/fisiologia , Transplantes/cirurgia , Vasoconstrição , Vasodilatação
12.
Autoimmun Rev ; 19(9): 102525, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32240856

RESUMO

Azathioprine (AZA), an oral immunosuppressant, is safe during pregnancy. Some reports suggested different impairments in the offspring of mothers with autoimmune diseases (AI) exposed in utero to AZA. These observations are available from retrospective studies or case reports. However, data with respect to the long-term safety in the antenatally exposed child are still lacking. The aim of this study is to summarize the current knowledge in this field and to focus on the need for a prospective study on this population. We performed a PubMed search using several search terms. The actual data show that although the risk of congenital anomalies in offspring, as well as the infertility risk, are similar to those found in general population, there is a higher incidence of prematurity, of lower weight at birth and an intra-uterine delay of development. There is also an increased risk of materno- fetal infections, especially cytomegalovirus infection. Some authors raise the interrogations about neurocognitive impairment. Even though the adverse outcomes might well be a consequence of maternal illness and disease activity, interest has been raised about a contribution of this drug. However, the interferences between the external agent (in utero exposure to AZA), with the host (child genetic susceptibility, immune system anomalies, emotional status), environment (public health, social context, availability of health care), economic, social, and behavioral conditions, cultural patterns, are complex and represent confounding factors. In conclusion, it is necessary to perform studies on the medium and long-term outcome of children born by mothers with autoimmune diseases, treated with AZA, in order to show the safety of AZA exposure. Only large-scale population studies with long-term follow-up will allow to formally conclude in this field. TAKE HOME MESSAGES.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Complicações na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Azatioprina/uso terapêutico , Criança , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Gravidez , Estudos Retrospectivos
13.
J Am Heart Assoc ; 9(5): e013895, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32102616

RESUMO

Background The cardiovascular protective effects of estrogens in premenopausal women depend mainly on estrogen receptor α (ERα). ERα activates nuclear gene transcription regulation and membrane-initiated signaling. The latter plays a key role in estrogen-dependent activation of endothelial NO synthase. The goal of the present work was to determine the respective roles of the 2 ERα activities in endothelial function and cardiac and kidney damage in young and old female mice with hypertension, which is a major risk factor in postmenopausal women. Methods and Results Five- and 18-month-old female mice lacking either ERα (ERα-/-), the nuclear activating function AF2 of ERα (AF2°), or membrane-located ERα (C451A) were treated with angiotensin II (0.5 mg/kg per day) for 1 month. Systolic blood pressure, left ventricle weight, vascular reactivity, and kidney function were then assessed. Angiotensin II increased systolic blood pressure, ventricle weight, and vascular contractility in ERα-/- and AF2° mice more than in wild-type and C451A mice, independent of age. In both the aorta and mesenteric resistance arteries, angiotensin II and aging reduced endothelium-dependent relaxation in all groups, but this effect was more pronounced in ERα-/- and AF2° than in the wild-type and C451A mice. Kidney inflammation and oxidative stress, as well as blood urea and creatinine levels, were also more pronounced in old hypertensive ERα-/- and AF2° than in old hypertensive wild-type and C451A mice. Conclusions The nuclear ERα-AF2 dependent function attenuates angiotensin II-dependent hypertension and protects target organs in aging mice, whereas membrane ERα signaling does not seem to play a role.


Assuntos
Envelhecimento/metabolismo , Receptor alfa de Estrogênio/metabolismo , Hipertensão/prevenção & controle , Hipertrofia Ventricular Esquerda/prevenção & controle , Nefrite/prevenção & controle , Fatores Etários , Envelhecimento/genética , Angiotensina II , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Pressão Arterial , Modelos Animais de Doenças , Receptor alfa de Estrogênio/deficiência , Receptor alfa de Estrogênio/genética , Feminino , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos Knockout , Nefrite/etiologia , Nefrite/metabolismo , Nefrite/fisiopatologia , Vasodilatação , Função Ventricular Esquerda , Remodelação Ventricular
14.
J Cardiothorac Surg ; 15(1): 34, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041642

RESUMO

BACKGROUND: This study aims to compare the effects of storage solutions commonly used in coronary artery bypass grafting on the vascular reactivity in vein graft interposed in arterial position in syngeneic rats. METHODS: Twenty-seven male Lewis rats were sacrified to sample a vein graft implanted 6 weeks ago into abdominal aorta position. The vein grafts were inferior venae cavae initially pretreated with heparinized saline solution (HS) or autologous heparinized blood (AHB) or our referent solution, GALA. The endothelial functionality, the in situ Reactive Oxygen Species (ROS) levels and the histological characteristics were conducted from segments of arterialized vein graft. RESULTS: At 6 weeks, graft thrombosis occurred respectively in 22% of AHB group, 62.5% in the HS group and 82.5% in the GALA group. In each group, significative intimal hyperplasia was observed. After 6 weeks, an endothelium-remodeling layer associated with an increase of wall thickness was observed in each group. Endothelium-dependent tone was reduced in the vein graft regardless of the group. No difference was observed concerning the ROS in vein graft between the different groups. In distal aortic sections, ROS levels were increased in HS and GALA groups. CONCLUSIONS: Storage solutions used in this experimental model of vein graft implanted in arterial position cause graft injury and a complete disappearance of vascular reactivity. GALA solution did not reduce intimal risk hyperplasia when the vein graft was exposed to arterial flow in a rat model.


Assuntos
Aorta Abdominal/cirurgia , Ponte de Artéria Coronária , Endotélio Vascular/efeitos dos fármacos , Soluções para Preservação de Órgãos/farmacologia , Túnica Íntima/patologia , Veia Cava Inferior/transplante , Animais , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Sangue , Modelos Animais de Doenças , Endotélio Vascular/patologia , Heparina/administração & dosagem , Heparina/uso terapêutico , Hiperplasia , Masculino , Soluções para Preservação de Órgãos/administração & dosagem , Soluções para Preservação de Órgãos/uso terapêutico , Ratos , Ratos Endogâmicos Lew , Espécies Reativas de Oxigênio/análise , Solução Salina/administração & dosagem , Solução Salina/uso terapêutico , Túnica Íntima/efeitos dos fármacos , Veia Cava Inferior/efeitos dos fármacos
15.
Microvasc Res ; 122: 13-21, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30399363

RESUMO

BACKGROUND: Forearm cutaneous blood flux (CBF) measurement with post-occlusive reactive hyperemia (PORH) is uncomfortable and may not be devoid of risks. We aimed to investigate post-compression reactive hyperemia (PCRH) with a custom-made indenter that was designed to be easily used routinely by inexperienced observers. METHODS: Medical students evaluated PCRH with 1- to 4-min pressure applications of 16 to 34 kPa and PORH with 3-min forearm cuff occlusion using laser speckle contrast imaging in 15 healthy volunteers. Participants were asked to quantify their discomfort with a visual analogue scale (VAS) of 10 cm. Total ischemia (ISCH) was quantified by the product of CBF during ischemia and ischemia duration (min). We subtracted the CBF changes in the skin from a reference ipsilateral (PCRH) or contralateral (PORH) non-stimulated area. RESULTS: The average VAS was 1.0 for PCRH vs. 6.0 for PORH (p < 0.001). A strong linear relationship between ISCH and peak PCRH (r2 = 0.915, p < 0.001) was noted. Peak PORH values (63.9 laser perfusion units (LPU)) were significantly lower than all values of the 3-min PCRH (72.6 LPU), including the one obtained with 16 kPa. CONCLUSION: Inexperienced observers could test microvascular reactivity with PCRH without inducing the discomfort that is typically experienced with PORH. Further, PCRH elicits a higher peak response to ischemia compared with PORH. This extremely simple method could influence a broad spectrum of routine cutaneous microcirculation investigations, especially when a painful approach is particularly inadequate or if the patient is fragile. CLINICAL TRIAL REGISTRATION: NCT02861924.


Assuntos
Técnicas de Diagnóstico Cardiovascular/instrumentação , Isquemia/fisiopatologia , Fluxometria por Laser-Doppler , Microcirculação , Dor/prevenção & controle , Pele/irrigação sanguínea , Velocidade do Fluxo Sanguíneo , Técnicas de Diagnóstico Cardiovascular/efeitos adversos , Desenho de Equipamento , Feminino , Antebraço , Voluntários Saudáveis , Humanos , Hiperemia/fisiopatologia , Masculino , Dor/diagnóstico , Dor/etiologia , Medição da Dor , Valor Preditivo dos Testes , Pressão , Fluxo Sanguíneo Regional , Estudantes de Medicina , Fatores de Tempo , Adulto Jovem
16.
PLoS One ; 13(11): e0206814, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30399161

RESUMO

BACKGROUND: Antiphospholipid syndrome is associated with endothelial dysfunction, which leads to thrombosis and early atheroma. Given that hydroxychloroquine has anti-thrombotic properties in lupus, we hypothesized that it could reduce endothelial dysfunction in an animal model of antiphospholipid syndrome. We evaluated the effect of hydroxychloroquine in preventing endothelial dysfunction in a mouse model of antiphospholipid syndrome. METHODS: Antiphospholipid syndrome was induced by an injection of monoclonal anti-beta-2-GPI antibodies. Vascular reactivity was evaluated in mesenteric resistance arteries isolated from mice 3 weeks (APL3W) after receiving a single injection of anti-beta-2-GPI antibodies and after 3 weeks of daily oral hydroxychloroquine treatment (HCQ3W) compared to control mice (CT3W). We evaluated endothelial dysfunction by measuring acetylcholine-mediated vasodilation. A pharmacological approach was used to evaluate NO synthase uncoupling (tetrahydrobiopterin) and the generation of reactive oxygen species (Tempol). RESULTS: Impaired acetylcholine-mediated dilation was evidenced in mice 3 weeks after anti-beta-2-GPI antibodies injection compared to CT3W, by reduced maximal dilation (p<0.0001) and sensitivity (pKd) (p = 0.01) to acetylcholine. Hydroxychloroquine improved acetylcholine-dependent dilation, on pKd (p = 0.02) but not maximal capacity compared to untreated mice. The addition of tetrahydrobiopterin (p = 0.02) and/or Tempol (p = 0.0008) improved acetylcholine-mediated dilation in APL3W but not in HCQ3W. CONCLUSIONS: We demonstrated that endothelial dysfunction in mouse resistance arteries persisted at 3 weeks after a single injection of monoclonal anti-beta-2-GPI antibodies, and that hydroxychloroquine improved endothelium-dependent dilation at 3 weeks, through improvement of NO synthase coupling and oxidative stress reduction.


Assuntos
Síndrome Antifosfolipídica/tratamento farmacológico , Endotélio/efeitos dos fármacos , Hidroxicloroquina/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Animais , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Anti-Idiotípicos/toxicidade , Síndrome Antifosfolipídica/induzido quimicamente , Síndrome Antifosfolipídica/patologia , Modelos Animais de Doenças , Endotélio/patologia , Humanos , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/patologia , Camundongos , Trombose/tratamento farmacológico , Trombose/imunologia , Trombose/patologia , Vasodilatação/efeitos dos fármacos , beta 2-Glicoproteína I/administração & dosagem , beta 2-Glicoproteína I/toxicidade
17.
Autoimmun Rev ; 17(12): 1153-1168, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30316994

RESUMO

The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%-21% at 5 years in thrombotic APS and 20-28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4-16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.


Assuntos
Síndrome Antifosfolipídica/complicações , Parto Obstétrico , Hidroxicloroquina/uso terapêutico , Trombose/prevenção & controle , Feminino , Humanos , Gravidez , Resultado da Gravidez , Prevenção Secundária , Trombose/etiologia
18.
J Am Heart Assoc ; 7(13)2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29959137

RESUMO

BACKGROUND: Although estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane-initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane-initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization. METHODS AND RESULTS: Using mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane-initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II-induced hypertension as well as to allow flow-mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow-mediated arteriolar remodeling. CONCLUSIONS: Altogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.


Assuntos
Doenças da Aorta/prevenção & controle , Artérias/metabolismo , Aterosclerose/prevenção & controle , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Receptor alfa de Estrogênio/metabolismo , Hipertensão/prevenção & controle , Animais , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Artérias/efeitos dos fármacos , Artérias/patologia , Artérias/fisiopatologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Pressão Sanguínea , Membrana Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Modelos Animais de Doenças , Estetrol/farmacologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/genética , Estrogênios/farmacologia , Feminino , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transdução de Sinais , Remodelação Vascular
19.
Autoimmun Rev ; 17(8): 739-745, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29885541

RESUMO

Primary antiphospholipid syndrome (PAPS) and antiphospholipid syndrome associated to lupus (SAPS) have several overlapping characteristics. As systemic manifestations are also reported in patients with PAPS, and as a subgroup of PAPS patients could evaluate to a SAPS, the differentiation between the two types of APS could be performed based on the clinical experience of the medical teams and is related to a variety of clinical, biological, histological and genetic features. Several data are available in the literature with respect to the identification of distinctive features between these two entities. However, there are some limitation in the interpretation of results issued from studies performed prior to updated Sydney criteria. Based on recent data, a certain number of features more frequent in one type of APS as compared to the other could be distinguished. The major differentiation between these two entities is genetical. New genetic data allowing the identification of specific subgroups of APS are ongoing.


Assuntos
Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/diagnóstico , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Humanos , Lúpus Eritematoso Sistêmico/imunologia
20.
Front Physiol ; 9: 350, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29670546

RESUMO

Aim/hypothesis:In utero exposure to maternal diabetes increases the risk of developing hypertension and cardiovascular disorders during adulthood. We have previously shown that this is associated with changes in vascular tone in favor of a vasoconstrictor profile, which is involved in the development of hypertension. This excessive constrictor tone has also a strong impact on vascular structure. Our objective was to study the impact of in utero exposure to maternal diabetes on vascular structure and remodeling induced by chronic changes in hemodynamic parameters. Methods and Results: We used an animal model of rats exposed in utero to maternal hyperglycemia (DMO), which developed hypertension at 6 months of age. At a pre-hypertensive stage (3 months of age), we observed deep structural modifications of the vascular wall without any hemodynamic perturbations. Indeed, in basal conditions, resistance arteries of DMO rats are smaller than those of control mother offspring (CMO) rats; in addition, large arteries like thoracic aorta of DMO rats have an increase of smooth muscle cell attachments to elastic lamellae. In an isolated perfused kidney, we also observed a leftward shift of the flow/pressure relationship, suggesting a rise in renal peripheral vascular resistance in DMO compared to CMO rats. In this context, we studied vascular remodeling in response to reduced blood flow by in vivo mesenteric arteries ligation. In DMO rats, inward remodeling induced by a chronic reduction in blood flow (1 or 3 weeks after ligation) did not occur by contrast to CMO rats in which arterial diameter decreased from 428 ± 17 µm to 331 ± 20 µm (at 125 mmHg, p = 0.001). In these animals, the transglutaminase 2 (TG2) pathway, essential for inward remodeling development in case of flow perturbations, was not activated in low-flow (LF) mesenteric arteries. Finally, in old hypertensive DMO rats (18 months of age), we were not able to detect a pressure-induced remodeling in thoracic aorta. Conclusions: Our results demonstrate for the first time that in utero exposure to maternal diabetes induces deep changes in the vascular structure. Indeed, the early narrowing of the microvasculature and the structural modifications of conductance arteries could be a pre-emptive adaptation to fetal programming of hypertension.

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