RESUMEN
OBJECTIVE: To evaluate whether active immunization producing ß1- or ß3-antibodies (ß1-ABs and ß3-ABs) detected in sera of patients with dilated cardiomyopathies has deleterious effects on vascular reactivity in Lewis rat thoracic aorta (TA) and small mesenteric arteries (SMA). DESIGN AND METHOD: Lewis rats were immunized for 6months with peptidic sequences corresponding to the second extracellular loop of ß1- and ß3-adrenoceptors (ARs). During the immunization, systolic blood pressure (SBP) was monitored using the tail cuff method. The vascular reactivity of immunized rats was assessed by ex vivo studies on SMA and TA using various ß-AR agonists, phenylephrine and KCl. RESULTS: The immunizations producing functional ß1-ABs and ß3-ABs did not affect the SBP. However, in TA from ß1-AR-immunized rats, the relaxations mediated by dobutamine and salbutamol were significantly impaired in comparison with adjuvant rats whereas nebivolol-induced relaxation was not modified. Moreover, phenylephrine and KCl-mediated contractions were enhanced in these rats. In contrast, immunization with ß3-AR peptide led to the increase of relaxations induced by dobutamine in TA but did not change those induced by salbutamol and nebivolol. Surprisingly, in SMA from both rats immunized with ß1- or ß3-peptides, relaxations induced by the various ß-agonists were not changed whereas phenylephrine and KCl-mediated contractions were impaired. CONCLUSIONS: Our study shows that ß1- and ß3-ABs can affect vascular reactivity. ß1-ABs would have a pathogenic action whereas ß3-ABs would have a beneficial effect on aorta reactivity.
Asunto(s)
Autoanticuerpos/inmunología , Receptores Adrenérgicos beta 1/inmunología , Receptores Adrenérgicos beta 3/inmunología , Vacunación/métodos , Agonistas Adrenérgicos beta/farmacología , Animales , Aorta Torácica/inmunología , Aorta Torácica/metabolismo , Masculino , Arterias Mesentéricas/inmunología , Arterias Mesentéricas/metabolismo , Péptidos/administración & dosificación , Péptidos/inmunología , Fenilefrina/farmacología , Cloruro de Potasio/farmacología , Ratas , Ratas Endogámicas Lew , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
Resistance arteries play a key role in the control of local blood flow. They undergo outward remodeling in response to a chronic increase in blood flow as seen in collateral artery growth in ischemic disorders. We have previously shown that mesenteric artery outward remodeling depends on the endothelial estrogen receptor alpha. As outward arterial remodeling is associated with improved endothelium-dependent dilation, we hypothesized that estrogens might also play a role in flow-mediated improvement of endothelium-dependent dilation. Local increase in blood flow in first order mesenteric arteries was obtained after ligation of adjacent arteries in three-month old ovariectomized female rats treated with 17-beta-estradiol (OVX+E2) or vehicle (OVX). After 2 weeks, diameter was equivalent in high flow (HF) than in normal flow (NF) arteries with a greater wall to lumen ratio in HF vessels in OVX rats. Acetylcholine-mediated relaxation was lower in HF than in NF vessels. eNOS and caveolin-1 expression level was equivalent in HF and NF arteries. By contrast, arterial diameter was 30% greater in HF than in NF arteries and the wall to lumen ratio was not changed in OVX+E2 rats. Acetylcholine-mediated relaxation was higher in HF than in NF arteries. The expression level of eNOS was higher and that of caveolin-1 was lower in HF than in NF arteries. Acetylcholine (NO-dependent)-mediated relaxation was partly inhibited by the NO-synthesis blocker L-NAME in OVX rats whereas L-NAME blocked totally the relaxation in OVX+E2 rats. Endothelium-independent relaxation (sodium nitroprusside) was equivalent in OXV and OVX+E2 rats. Similarly, serotonin- and phenylephrine-mediated contractions were higher in HF than in NF arteries in both OVX and OVX+E2 rats in association with high ratio of phosphorylated ERK1/2 to ERK1/2. Thus, we demonstrated the essential role of endogenous E2 in flow-mediated improvement of endothelium (NO)-mediated dilatation in rat mesenteric arteries.
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Velocidad del Flujo Sanguíneo/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Estradiol/farmacología , Estrógenos/farmacología , Arterias Mesentéricas/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Animales , Western Blotting , Caveolina 1/genética , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Femenino , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa de Tipo III/genética , Nitroprusiato/farmacología , Ovariectomía , Ratas Wistar , Remodelación Vascular/efectos de los fármacos , Resistencia Vascular/efectos de los fármacosRESUMEN
In resistance arteries, a chronic increase in blood flow induces hypertrophic outward remodeling. This flow-mediated remodeling (FMR) is absent in male rats aged 10 mo and more. As FMR depends on estrogens in 3-mo-old female rats, we hypothesized that it might be preserved in 12-mo-old female rats. Blood flow was increased in vivo in mesenteric resistance arteries after ligation of the side arteries in 3- and 12-mo-old male and female rats. After 2 wk, high-flow (HF) and normal-flow (NF) arteries were isolated for in vitro analysis. Arterial diameter and cross-sectional area increased in HF arteries compared with NF arteries in 3-mo-old male and female rats. In 12-mo-old rats, diameter increased only in female rats. Endothelial nitric oxide synthase expression and endothelium-mediated relaxation were higher in HF arteries than in NF arteries in all groups. ERK1/2 phosphorylation, NADPH oxidase subunit expression levels, and arterial contractility to KCl and to phenylephrine were greater in HF vessels than in NF vessels in 12-mo-old male rats only. Ovariectomy in 12-mo-old female rats induced a similar pattern with an increased contractility without diameter increase in HF arteries. Treatment of 12-mo-old male rats and ovariectomized female rats with hydralazine, the antioxidant tempol, or the angiotensin II type 1 receptor blocker candesartan restored HF remodeling and normalized arterial contractility in HF vessels. Thus, we found that FMR of resistance arteries remains efficient in 12-mo-old female rats compared with age-matched male rats. A balance between estrogens and vascular contractility might preserve FMR in mature female rats.
Asunto(s)
Estrógenos/metabolismo , Arterias Mesentéricas/fisiología , Remodelación Vascular , Resistencia Vascular , Factores de Edad , Animales , Bencimidazoles/farmacología , Compuestos de Bifenilo , Óxidos N-Cíclicos/farmacología , Estrógenos/farmacología , Femenino , Hidralazina/farmacología , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/crecimiento & desarrollo , Arterias Mesentéricas/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , NADPH Oxidasas/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas , Ratas Wistar , Marcadores de Spin , Tetrazoles/farmacología , Vasoconstricción , Vasoconstrictores/farmacología , Vasodilatación , Vasodilatadores/farmacologíaRESUMEN
OBJECTIVE: Pseudoxanthoma elasticum is an inherited metabolic disorder resulting from ABCC6 gene mutations. It is characterized by progressive calcification and fragmentation of elastic fibers in the skin, retina, and the arterial wall. Despite calcium accumulation in the arteries of patients with pseudoxanthoma elasticum, functional consequences remain unknown. In the present study, we investigated arterial structure and function in Abcc6(-/-) mice, a model of the human disease. APPROACH AND RESULTS: Arterial calcium accumulation was evaluated using alizarin red stain and atomic absorption spectrometry. Expression of genes involved in osteochondrogenic differentiation was measured by polymerase chain reaction. Elastic arterial properties were evaluated by carotid echotracking. Vascular reactivity was evaluated using wire and pressure myography and remodeling using histomorphometry. Arterial calcium accumulation was 1.5- to 2-fold higher in Abcc6(-/-) than in wild-type mice. Calcium accumulated locally leading to punctuate pattern. Old Abcc6(-/-) arteries expressed markers of both osteogenic (Runx2, osteopontin) and chondrogenic lineage (Sox9, type II collagen). Abcc6(-/-) arteries displayed slight increase in arterial stiffness and vasoconstrictor tone in vitro tended to be higher in response to phenylephrine and thromboxane A2. Pressure-induced (myogenic) tone was significantly higher in Abcc6(-/-) arteries than in wild type. Arterial blood pressure was not significantly changed in Abcc6(-/-), despite higher variability. CONCLUSIONS: Scattered arterial calcium depositions are probably a result of osteochondrogenic transdifferentiation of vascular cells. Lower elasticity and increased myogenic tone without major changes in agonist-dependent contraction evidenced in aged Abcc6(-/-) mice suggest a reduced control of local blood flow, which in turn may alter vascular homeostasis in the long term.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/deficiencia , Arterias/metabolismo , Calcio/metabolismo , Tejido Elástico/metabolismo , Seudoxantoma Elástico/metabolismo , Calcificación Vascular/metabolismo , Rigidez Vascular , Vasoconstricción , Transportadoras de Casetes de Unión a ATP/genética , Animales , Presión Arterial , Arterias/patología , Arterias/fisiopatología , Biomarcadores/metabolismo , Transdiferenciación Celular , Condrogénesis , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Modelos Animales de Enfermedad , Tejido Elástico/patología , Tejido Elástico/fisiopatología , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Osteogénesis , Osteopontina/genética , Osteopontina/metabolismo , Seudoxantoma Elástico/genética , Seudoxantoma Elástico/patología , Seudoxantoma Elástico/fisiopatología , ARN Mensajero/metabolismo , Flujo Sanguíneo Regional , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Calcificación Vascular/genética , Calcificación Vascular/patología , Calcificación Vascular/fisiopatologíaRESUMEN
Systemic and immune manifestations have been reported in patients with MDS. The correlation between immunological abnormalities and prognosis in myelodysplastic syndrome patients remains controversial. Most of the authors agree that the median survival in myelodysplastic syndrome is not related to the presence of systemic and immune manifestations, but only with the existence of a systemic vasculitis.
Asunto(s)
Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/mortalidad , Vasculitis Sistémica/complicaciones , Humanos , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/fisiopatología , Pronóstico , Vasculitis Sistémica/inmunologíaRESUMEN
OBJECTIVE: Flow- (shear stress-)mediated outward remodeling of resistance arteries is involved in collateral growth during postischemic revascularization. As this remodeling is especially important during pregnancy, we hypothesized that estrogens may be involved. A surgical model eliciting a local increase in blood flow in 1 mesenteric resistance artery was used in 3-month-old ovariectomized female rats either treated with 17-ß-estradiol (E2) or left untreated. METHODS AND RESULTS: After 14 days, arterial diameter was greater in high-flow arteries than in normal-flow vessels. An ovariectomy suppressed high-flow remodeling, while E2 restored it. High-flow remodeling was absent in mice lacking the estrogen receptor α but not estrogen receptor ß. The kinetics of inflammatory marker expression, macrophage infiltration, oxidative stress, and metaloproteinases expression were not altered by the absence of E2 after 2 and 4 days, that is, during remodeling. Nevertheless, E2 was required for the increase in endothelial nitric oxide synthase expression and activation at day 4 when diameter expansion occurs. Finally, the impact of E2 on the endothelium appeared crucial for high-flow remodeling, as this E2 action was abrogated in mice lacking endothelial NOS, as well as in Tie2-Cre(+) ERα(f/f) mice. CONCLUSIONS: We demonstrate the essential role of E2 and endothelial estrogen receptor α in flow-mediated remodeling of resistance arteries in vivo.
Asunto(s)
Células Endoteliales/metabolismo , Estradiol/administración & dosificación , Receptor alfa de Estrógeno/agonistas , Terapia de Reemplazo de Estrógeno , Arterias Mesentéricas/efectos de los fármacos , Resistencia Vascular/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Caveolina 1/metabolismo , Células Endoteliales/efectos de los fármacos , Receptor alfa de Estrógeno/deficiencia , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/deficiencia , Receptor beta de Estrógeno/genética , Femenino , Arterias Mesentéricas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico Sintasa de Tipo III/genética , Ovariectomía , Fosforilación , Ratas , Ratas Wistar , Flujo Sanguíneo Regional/efectos de los fármacos , Circulación Esplácnica/efectos de los fármacos , Factores de Tiempo , Vasodilatación/efectos de los fármacosRESUMEN
INTRODUCTION: Cryofibrinogenemia may be essential, or secondary to diseases such as neoplasia, infection, thrombosis, and collagen vascular diseases. In a previous study, we reported the occurrence of neoplasia in some essential cryofibrinogenemia patients after a short period of follow-up. PURPOSE: We performed a prospective multi-center 5-year follow-up study in essential cryofibrinogenemia patients (2005-2009). RESULTS: 23 patients with essential cryofibrinogenemia were included, mean age 59 years (range: 33-79), 14 males. After a mean follow-up period of 24 months, 11/23 (47%) of cases that were initially diagnosed as essential cryofibrinogenemia were found to have an underlying lymphoma (6 T lymphoma and 5 B lymphoma). CONCLUSION: This prospective study suggests that some cases of cryofibrinogenemia that are initially considered as essential, may have underlying lymphoma. Thus, we further suggest that regular follow-up should be performed in patients with essential cryofibrinogenemia.
Asunto(s)
Crioglobulinemia/etiología , Linfoma/complicaciones , Adulto , Anciano , Crioglobulinemia/diagnóstico , Crioglobulinemia/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Estudios ProspectivosRESUMEN
OBJECTIVE: The presence of systemic and/or immune manifestations in myelodysplasia has been currently reported. The influence of these manifestations on the natural outcome of myelodysplastic syndrome has to be considered. We present a multicenter retrospective study (2002-2009) of patients with myelodysplastic syndrome disclosing systemic and/or immune manifestations. METHODS: Forty-six patients with myelodysplasia presenting with systemic and/or immune manifestations were compared in terms of survival with 189 patients with myelodysplasia lacking these features. RESULTS: The clinical picture in these cases consisted of fever (13%), arthralgia or arthritis (13%), and cutaneous manifestations (67%). Four cases of systemic vasculitis have been reported in our series, and they have a worse prognosis. Immune anomalies were recorded in 29% of the cases, and the presence of cryoglobulins was also associated with a worse prognosis. CONCLUSION: A difference in survival between patients with myelodysplastic syndrome with systemic manifestations and patients lacking these manifestations has been observed in the presence of systemic vasculitis and/or cryoglobulins.
Asunto(s)
Crioglobulinas/inmunología , Síndromes Mielodisplásicos/inmunología , Vasculitis Sistémica/complicaciones , Anciano , Anciano de 80 o más Años , Artralgia/complicaciones , Artralgia/inmunología , Artritis/complicaciones , Artritis/inmunología , Femenino , Fiebre/complicaciones , Fiebre/inmunología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/complicaciones , Estudios Retrospectivos , Vasculitis Sistémica/inmunologíaRESUMEN
The role of complement activation on the cerebral vasculature after cardiopulmonary bypass (CPB) is unclear. The goal of the study was to assess whether heparin-coated CPB reduces complement activation, and influences cerebral blood flow velocities (CBFV). Twenty-four patients undergoing coronary surgery were randomly allocated to non-coated (NC-group) or heparin-coated (HC-group) CPB. Complement activation was assessed by measuring sC5b-9. Transcranial Doppler (TCD) was performed on middle cerebral arteries before and after CPB. Systolic (SV), diastolic (DV) and mean (MV) CBFV were measured. Significant increase of sC5b-9 (p=0.003) was observed in the NC-group and CBFV increased after CPB (SV by 27%, p=0.05; DV by 40%, p=0.06; MV by 33%, p=0.04) whereas no changes were detected in the HC-group. TCD values were higher in the NC-group than in the HC-group (SV, p=0.04; DV, p=0.03; MV, p=0.03) although cardiac index, systemic vascular resistance, haematocrit and pCO(2) were similar. Postoperative SV, DV and MV were significantly correlated with sC5b-9 (r=0.583, p=0.009; r=0.581, p=0.009; r=0.598, p=0.007, respectively). Increased CBFV after CPB are correlated to the level of complement activation and may be controlled by heparin-coated circuits.
Asunto(s)
Encéfalo/irrigación sanguínea , Encéfalo/fisiopatología , Puente Cardiopulmonar/métodos , Activación de Complemento/efectos de los fármacos , Heparina/farmacología , Anciano , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Encéfalo/inmunología , Humanos , Persona de Mediana Edad , Ultrasonografía Doppler TranscranealRESUMEN
Anti-Ku antibodies are reported in various connective tissue diseases and the Ku complex can be responsible for a very strong autoimmune answer in autoimmune disease. Nowadays, anti-Ku antibodies are detected by ELISA, counterimmunoelectrophoresis (CIE), immunoblot (IB) and new highly performant techniques. Although the prevalence of anti-Ku antibodies is not homogenous, depending on several features such as disease type, genetic and geographical clustering, and also method of detection, they could be found in 55% overlap PM/systemic sclerosis patients. Moreover, anti-Ku antibodies are not associated with a particular clinical outcome, and especially with cancer related to myositis.
Asunto(s)
Antígenos Nucleares/inmunología , Autoanticuerpos/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades del Tejido Conjuntivo/inmunología , Proteínas de Unión al ADN/inmunología , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/genética , Enfermedades del Tejido Conjuntivo/diagnóstico , Enfermedades del Tejido Conjuntivo/epidemiología , Enfermedades del Tejido Conjuntivo/genética , Proteína Quinasa Activada por ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Autoantígeno Ku , Proteínas Nucleares/metabolismo , Prevalencia , Grupos Raciales , Factores de RiesgoRESUMEN
OBJECTIVE: Notch3, a member of the evolutionary conserved Notch receptor family, is primarily expressed in vascular smooth muscle cells. Genetic studies in human and mice revealed a critical role for Notch3 in the structural integrity of distal resistance arteries by regulating arterial differentiation and postnatal maturation. METHODS AND RESULTS: We investigated the role of Notch3 in vascular tone in small resistance vessels (tail and cerebral arteries) and large (carotid) arteries isolated from Notch3-deficient mice using arteriography. Passive diameter and compliance were unaltered in mutant arteries. Similarly, contractions to phenylephrine, KCl, angiotensin II, and thromboxane A2 as well as dilation to acetylcholine or sodium nitroprusside were unaffected. However, Notch3 deficiency induced a dramatic reduction in pressure-induced myogenic tone associated with a higher flow (shear stress)-mediated dilation in tail and cerebral resistance arteries only. Furthermore, RhoA activity and myosin light chain phosphorylation, measured in pressurized tail arteries, were significantly reduced in Notch3KO mice. Additionally, myogenic tone inhibition by the Rho kinase inhibitor Y27632 was attenuated in mutant tail arteries. CONCLUSIONS: Notch3 plays an important role in the control of vascular mechano-transduction, by modulating the RhoA/Rho kinase pathway, with opposite effects on myogenic tone and flow-mediated dilation in the resistance circulation.
Asunto(s)
Arterias/fisiología , Arterias Cerebrales/fisiología , Receptores Notch/fisiología , Resistencia Vascular/fisiología , Acetilcolina/farmacología , Amidas/farmacología , Animales , Arterias/efectos de los fármacos , Arterias/patología , Arterias/fisiopatología , Arterias Cerebrales/efectos de los fármacos , Arterias Cerebrales/patología , Arterias Cerebrales/fisiopatología , Inhibidores Enzimáticos/farmacología , Masculino , Ratones , Ratones Noqueados , Fenilefrina/farmacología , Piridinas/farmacología , Receptor Notch3 , Receptores Notch/deficiencia , Receptores Notch/genética , Cola (estructura animal)/irrigación sanguínea , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/genética , Vasoconstricción/efectos de los fármacos , Vasoconstricción/genética , Vasoconstricción/fisiología , Vasodilatación/efectos de los fármacos , Vasodilatación/genética , Vasodilatación/fisiología , Proteínas de Unión al GTP rho/metabolismo , Quinasas Asociadas a rho/antagonistas & inhibidores , Proteína de Unión al GTP rhoARESUMEN
Pre-capillary arteries are often called resistance arteries as they are responsible for a large proportion of peripheral vascular resistance. Resistance arteries possess a permanent vasoconstrictor tone providing the capacity to further contract or dilate. This property allows an efficient control of local blood flow, and this tone is called the "vasodilation reserve". Physiologically, this basal tone is also the functional limit between resistance and large compliance arteries. Microvascular tone is controlled by the metabolic needs of the surrounding tissue, the nervous system, local and circulating hormonal systems and mechanical factors. Pressure and flow are the main mechanical factors influencing microvascular tone. Increases in blood pressure induce a contraction called myogenic tone whereas increases in blood flow induce a rise in shear stress triggering dilation (flow-mediated dilation). Myogenic tone can be considered as a background tone preparing the contractile apparatus to contract more if agonists are produced, or less if the endothelium generates vasodilators. Such a basal tone allows a rapid and efficient control of vascular tone and local blood flow. The role of myogenic tone in pathological situations is not yet clearly known. Nevertheless, in hypertension or diabetes a blunted myogenic responsiveness in renal pre-glomerular arterioles may account for the pressure-induced damages in glomeruli. On the other hand, an increased myogenic tone may participate in the occurrence of vasospasm.
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Arterias/fisiología , Tono Muscular/fisiología , Músculo Liso Vascular/fisiología , Humanos , Microcirculación , Vasoconstricción/fisiología , Vasodilatadores/farmacologíaRESUMEN
Chronic heart failure (CHF) impairs endothelium-dependent, nitric oxide (NO)-mediated dilation. This decreased dilation may be partly secondary to the chronic decrease in blood flow, but this hypothesis has not yet been tested. Thus, we assessed whether a localized, chronic increase in blood flow in vivo reverses endothelial dysfunction of small arteries in rats with CHF. Two months after coronary artery ligation or sham surgery, second-order side branches of the superior mesenteric artery were ligated in order to obtain persistently elevated blood flow (HF) in the adjacent first-order side branch compared with normal vessels (NF). One month later, responses to acetylcholine and flow-mediated vasodilatation (FMD) were assessed in vitro in an arteriograph. Chronic heart failure induced a decrease in mesenteric blood flow (374 +/- 25 and 305 +/- 27 micro L/min for sham and CHF, respectively; P < 0.05). Neither CHF nor the chronic increase in flow affected the responses to acetylcholine. Chronic heart failure decreased FMD (maximal response in sham and control 34 +/- 6 and 13 +/- 4%, respectively; P < 0.05). Chronic increases in blood flow did not modify FMD in sham, but restored FMD in CHF rats (28 +/- 4%; P < 0.05 vs CHF NF). The restored response was abolished by an inhibitor of NO synthesis (N(G)-nitro-l-arginine). Chronic heart failure did not affect the abundance of mesenteric endothelial NO synthase (eNOS) mRNA. A chronic increase in flow significantly increased the abundance of eNOS mRNA in sham rats, but only moderately and non-significantly in CHF rats. Thus, endothelial dysfunction of small arteries in CHF appears to be largely the consequence of the chronic decrease in flow.
Asunto(s)
Endotelio Vascular/fisiología , Insuficiencia Cardíaca/fisiopatología , Circulación Esplácnica/fisiología , Vasodilatación/fisiología , Acetilcolina/farmacología , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Velocidad del Flujo Sanguíneo/fisiología , Enfermedad Crónica , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Ratas , Enfermedades Vasculares/fisiopatología , Vasodilatación/efectos de los fármacosRESUMEN
Angiotensin II exerts a potent role in the control of hemodynamic and renal homeostasis. Angiotensin II is also a local and biologically active mediator involved in both endothelial and smooth muscle cell function acting on 2 receptor subtypes: type 1 (AT(1)R) and type 2 (AT(2)R). Whereas the key role of AT(2)R in the development of the embryo has been extensively studied, the role of AT(2)R in the adult remains more questionable, especially in humans. In vitro studies in cultured cells and in isolated segments of aorta have shown that AT(2)R stimulation could lead to the production of vasoactive substances, among which NO is certainly the most cited, suggesting that acute AT(2)R stimulation will produce vasodilation. However, in different organs or in small arteries isolated from different type of tissues, other vasoactive substances may also mediate AT(2)R-dependent dilation. Sometimes, such as in large renal arteries, AT(2)R stimulation may lead to vasoconstriction, although it is not always seen. In isolated arteries submitted to physiological conditions of pressure and flow, AT(2)R stimulation may also have a role in shear stress-induced dilation through a endothelial production of NO. Thus, when acutely stimulated, the most probable response expected from AT(2)R stimulation will be a vasodilation. Therefore, in the perspective of a chronic AT(1)R blockade in patients, overstimulation of AT(2)R might be beneficial, given their potential vasodilator effect. Concerning the possible role of AT(2)R in cardiovascular remodeling, the situation is more controversial. In vitro AT(2)R stimulation clearly inhibits cardiac and vascular smooth muscle growth and proliferation, stimulates apoptosis, and promotes extra cellular matrix synthesis. In vivo, the situation might be less beneficial if not deleterious; indeed, if chronic AT(2)R overstimulation would lead to cardiovascular hypertrophy and fibrosis, then the long-term consequences of chronic AT(1)R blockade, and thus AT(2)R overstimulation, require more in-depth analysis.
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Arterias/fisiología , Microcirculación/fisiología , Receptores de Angiotensina/fisiología , Animales , Circulación Sanguínea , Presión Sanguínea , Cardiomegalia/etiología , Fibrosis Endomiocárdica/etiología , Femenino , Humanos , Modelos Biológicos , Ratas , Receptor de Angiotensina Tipo 2 , Vasoconstricción , Vasodilatación , Sistema VasomotorRESUMEN
Experiments were designed to investigate endothelial function in the aorta of mice lacking the gene for the cytoskeleton protein vimentin (vim -/- ). Rings with and without endothelium from wild-type (vim +/+ ), heterozygous (vim +/- ), and homozygous (vim -/- ) mice were suspended in organ chambers to record of changes in isometric tension. During phenylephrine contraction, acetylcholine evoked comparable endothelium-dependent relaxations in the three groups. In the presence of Nomega-nitro-L-arginine, acetylcholine caused endothelium-dependent contractions, which were greater in vim -/- than in vim +/+ and vim +/- aortas. Indomethacin did not affect relaxation to acetylcholine in vim +/+ or in vim +/-, but it significantly increased the maximal response in vim -/- (67 +/- 7 vs. 102 +/- 4%). Response to acetylcholine in vim -/- aortas was not affected by cyclooxygenase type 2 inhibitor NS-398, the thromboxane receptor antagonist SQ-29,548, or superoxide dismutase. Relaxations to sodium nitroprusside were not different between vim +/+ and vim -/- mice and were not affected by cyclooxygenase inhibition. Cyclic guanosine monophosphate levels, which were increased to a comparable level by acetylcholine in vim +/+ and vim -/-, were augmented by indomethacin in vim -/- aortas but not in vim +/+ aortas. Expression of endothelial nitric oxide synthase was not different between vim +/+ and vim -/- preparations. These results suggest that despite comparable endothelium-dependent responses to acetylcholine, endothelial cells from vim -/- mice release a cyclooxygenase product that compensates the augmented contribution of nitric oxide.
Asunto(s)
Aorta/metabolismo , Arginina/fisiología , Óxido Nítrico/fisiología , Vimentina/deficiencia , Vimentina/genética , Acetilcolina/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , GMP Cíclico/biosíntesis , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Vasoconstricción/efectos de los fármacos , Vasoconstricción/genética , Vasodilatación/efectos de los fármacos , Vasodilatación/genética , Vasodilatadores/farmacologíaRESUMEN
This study investigated in vivo the putative angiogenic role of endothelin (ET)-1 in a model of ischemia-induced angiogenesis. Ischemia was produced by unilateral femoral artery occlusion in Wistar rats submitted to either chronic ET-1 infusion (2 nmol. kg(-1). min(-1)) or to a dual ET(A)/ET(B) receptor antagonist (bosentan, 100 mg. kg(-1). d(-1)) for 3 and 28 days. Arterial density was evaluated by microangiography and measurement of capillary and arteriolar density in hindlimb muscles. ET-1 infusion had no effect on ischemia-induced angiogenesis and was associated with a slight decrease in vascular endothelial growth factor (VEGF) content measured by Western blot analysis. Conversely, bosentan induced a marked increase in vessel density at 3 and 28 days (1.4-fold and 1.7-fold, respectively, compared with no treatment; P<0.05), which was associated with an increase in VEGF and endothelial NO synthase levels in ischemic legs (by 31+/-8% and 45+/-23%, respectively, at 3 days and by 65+/-13% and 55+/-15%, respectively, at 28 days; P<0.05 versus nontreated rats). At day 28, the proangiogenic effect of bosentan was abolished when NO synthesis inhibitor N(G)-nitro-L-arginine methyl ester (10 mg. kg(-1). d(-1)) or VEGF-neutralizing antibody (2.5 micro/kg twice a week) were coadministered with bosentan. Those results provide the first evidence of an early and sustained proangiogenic effect of endothelin antagonism associated with an upregulation of VEGF and endothelial NO synthase in vivo.
Asunto(s)
Factores de Crecimiento Endotelial/metabolismo , Antagonistas de los Receptores de Endotelina , Isquemia/sangre , Isquemia/metabolismo , Linfocinas/metabolismo , Neovascularización Fisiológica , Óxido Nítrico/metabolismo , Animales , Anticuerpos/farmacología , Bosentán , Capilares/diagnóstico por imagen , Capilares/fisiología , Factores de Crecimiento Endotelial/inmunología , Endotelina-1/farmacología , Inhibidores Enzimáticos/farmacología , Miembro Posterior/irrigación sanguínea , Miembro Posterior/diagnóstico por imagen , Isquemia/diagnóstico por imagen , Linfocinas/inmunología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa de Tipo III , Radiografía , Ratas , Ratas Wistar , Receptor de Endotelina A , Transducción de Señal , Sulfonamidas/farmacología , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
We have previously shown that angiotensin II (Ang II) and pressure increase extracellular signal-regulated kinase (ERK) 1/2 activity synergistically in intact, pressurized resistance arteries in vitro. However, the mechanisms by which pressure and Ang II activate ERK1/2 in intact resistance arteries remain to be determined. The purpose of the present study was to investigate the involvement of Rho-kinase and the actin filament network in Ang II- and pressure-induced ERK1/2 activation, as well as in the contractile response induced by Ang II. Mesenteric resistance arteries (200 to 300 microm) were isolated, mounted in an arteriograph, and stimulated by pressure, Ang II, or both. Activation of ERK1/2 was then measured by an in-gel assay. In mesenteric resistance arteries maintained at 70 mm Hg, Ang II (0.1 micromol/L) induced contraction (29+/-1.4% of phenylephrine, 10 micromol/L-induced contraction) and significantly increased ERK1/2 activity. Selective inhibition of Rho-kinase by Y-27632 (10 micromol/L) and selective disruption of the actin filament network by cytochalasin B (10 micromol/L) both decreased the Ang II-induced contraction by 78+/-1.2% and 87+/-1.9%, respectively, and significantly diminished ERK1/2 activity. In the absence of Ang II, increasing intraluminal pressure from 0 to 70 or 120 mm Hg increased ERK1/2 activity. ERK1/2 activity at 120 mm Hg was similar to that observed at 70 mm Hg in the presence of Ang II. Pressure-induced ERK1/2 activation was markedly attenuated by cytochalasin B but not by Y-27632. These results indicate that whereas pressure-induced ERK1/2 activation requires an intact actin filament network, but not Rho-kinase, the activation of ERK1/2 and the contraction induced by Ang II require both Rho-kinase and an intact actin filament network in isolated, intact mesenteric resistance arteries.
Asunto(s)
Citoesqueleto de Actina/fisiología , Músculo Liso Vascular/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Vasoconstricción/fisiología , Amidas/farmacología , Angiotensina II/farmacología , Animales , Citocalasina B/farmacología , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intracelular , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/fisiología , Músculo Liso Vascular/efectos de los fármacos , Piridinas/farmacología , Ratas , Transducción de Señal , Vasoconstricción/efectos de los fármacos , Quinasas Asociadas a rhoRESUMEN
BACKGROUND: Dystrophin has a key role in striated muscle mechanotransduction of physical forces. Although cytoskeletal elements play a major role in the mechanotransduction of pressure and flow in vascular cells, the role of dystrophin in vascular function has not yet been investigated. Thus, we studied endothelial and muscular responses of arteries isolated from mice lacking dystrophin (mdx mice). METHODS AND RESULTS: Carotid and mesenteric resistance arteries 120 micrometer in diameter were isolated and mounted in vitro in an arteriograph to control intraluminal pressure and flow. Blood pressure was not affected by the absence of dystrophin. Pressure-induced (myogenic), phenylephrine-induced, and KCl-induced forms of tone were unchanged. Flow (shear stress)-induced dilation in arteries isolated from mdx mice was decreased by 50% to 60%, whereas dilation to acetylcholine or sodium nitroprusside was unaffected. NG-nitro-L-arginine methyl ester-sensitive flow dilation was also decreased in arteries from mdx mice. Thus, the absence of dystrophin was associated with a defect in signal transduction of shear stress. Dystrophin was present in vascular endothelial and smooth muscle cells, as shown by immunolocalization, and localized at the level of the plasma membrane, as seen by confocal microscopy of perfused isolated arteries. CONCLUSIONS: -This is the first functional study of arteries lacking the gene for dystrophin. Vascular reactivity was normal, with the exception of flow-induced dilation. Thus, dystrophin could play a specific role in shear-stress mechanotransduction in arterial endothelial cells. Organ damage in such diseases as Duchenne dystrophy might be aggravated by such a defective arterial response to flow.