RESUMO
Intrauterine growth restriction (IUGR) can induce deleterious changes in the modulatory ability of the vascular endothelium, contributing to an increased risk of developing cardiovascular diseases in the long term. However, the mechanisms involved are not fully understood. Emerging evidence has suggested the potential role of endothelial progenitor cells (EPCs) in vascular health and repair. Therefore, we aimed to evaluate the effects of IUGR on vascular reactivity and EPCs derived from the peripheral blood (PB) and bone marrow (BM) in vitro. Pregnant Wistar rats were fed an ad libitum diet (control group) or 50% of the ad libitum diet (restricted group) throughout gestation. We determined vascular reactivity, nitric oxide (NO) concentration, and endothelial nitric oxide synthase (eNOS) protein expression by evaluating the thoracic aorta of adult male offspring from both groups (aged: 19-20 weeks). Moreover, the amount, functional capacity, and senescence of EPCs were assessed in vitro. Our results indicated that IUGR reduced vasodilation via acetylcholine in aorta rings, decreased NO levels, and increased eNOS phosphorylation at Thr495. The amount of EPCs was similar between both groups; however, IUGR decreased the functional capacity of EPCs from the PB and BM. Furthermore, the senescence process was accelerated in BM-derived EPCs from IUGR rats. In summary, our findings demonstrated the deleterious changes in EPCs from IUGR rats, such as reduced EPC function and accelerated senescence in vitro. These findings may contribute towards elucidating the possible mechanisms involved in endothelial dysfunction induced by fetal programming.
Assuntos
Células Progenitoras Endoteliais/patologia , Endotélio Vascular/patologia , Retardo do Crescimento Fetal/fisiopatologia , Estresse Oxidativo , Vasodilatação , Animais , Feminino , Masculino , Óxido Nítrico/metabolismo , Gravidez , Ratos , Ratos WistarRESUMO
It has been demonstrated that intrauterine growth restriction (IUGR) can program increase cardiometabolic risk. There are also evidences of the correlation between IUGR with low-grade inflammation and, thus can contribute to development of several cardiometabolic comorbidities. Therefore, we investigated the influence of IUGR on circulating mitochondrial DNA (mtDNA)/Toll-like receptor 9 (TLR9) and TNF-α expression in adult offspring. Considering that the aerobic training has anti-inflammatory actions, we also investigated whether aerobic training would improve these inflammatory factors. Pregnant Wistar rats received ad libitum or 50% of ad libitum diet throughout gestation. At 8 weeks of age, male offspring from both groups were randomly assigned to control, trained control, restricted and trained restricted. Aerobic training protocol was performed on a treadmill and after that, we evaluated circulating mtDNA, cardiac protein expression of TLR9, plasma and cardiac TNF-α levels, and left ventricle (LV) mass. We found that IUGR promoted an increase in the circulating mtDNA, TLR9 expression and plasma TNF-α levels. Further, our results revealed that aerobic training can restore mtDNA/TLR9 content and plasma levels of TNF-α among restricted rats. The cardiac TNF-α content and LV mass were not influenced either by IUGR or aerobic training. In conclusion, IUGR can program mtDNA/TLR9 content, which may lead to high levels of TNF-α. However, aerobic training was able to normalize these alterations. These findings evidenced that the association of IUGR and aerobic training seems to exert an important interaction effect regarding pro-inflammatory condition and, aerobic training may be used as a strategy to reduce deleterious adaptations in IUGR offspring.
Assuntos
Cardiomegalia/prevenção & controle , DNA Mitocondrial/genética , Retardo do Crescimento Fetal/fisiopatologia , Condicionamento Físico Animal/métodos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Receptor Toll-Like 9/metabolismo , Adaptação Fisiológica , Animais , Animais Recém-Nascidos , Cardiomegalia/etiologia , DNA Mitocondrial/sangue , Feminino , Masculino , Gravidez , Ratos , Ratos WistarRESUMO
AIMS: Hypertension is associated with increased levels of circulating cytokines and recent studies have shown that innate immunity contributes to hypertension. The mechanisms which hypertension stimulates immune response remain unclear, but may involve formation of neo-antigens that activate the immune system. Toll like receptor 4 (TLR4) is an innate immune receptor that binds a wide spectrum of exogenous (lipopolysaccharide) and endogenous ligands. TLR4 signaling leads to activation of nuclear factor kappa B (NFκB) and transcription of genes involved in inflammatory response. We previously demonstrated that TLR4 blockade reduces blood pressure and the augmented vascular contractility in spontaneously hypertensive rats (SHR). Here we hypothesized that inhibition of TLR4 ameliorates the vascular inflammatory process by a NFκB signaling pathway. MAIN METHODS: SHR and Wistar rats were treated with anti-TLR4 antibody (1µg/day) or unspecific IgG for 15days (i.p.). KEY FINDINGS: Anti-TLR4 treatment decreased production of reactive oxygen species and expression of IL-6 cytokine in mesenteric resistance arteries from SHR, when compared with IgG-treated SHR. Anti-TLR4 treatment also abolished the increased vascular reactivity to noradrenaline observed in IgG-treated SHR, as described before, and inhibition of NFκB decreased noradrenaline responses only in IgG-treated SHR. Mesenteric arteries from SHR treated with anti-TLR4 displayed decreased expression of MyD88, but not TRIF, key molecules in TLR4 signaling. Phosphorylation of p38 and NF-κB p65 were decreased in arteries from anti-TLR4-treated SHR versus IgG-treated SHR. SIGNIFICANCE: Together, these results suggest that TLR4 is a key player in hypertension and vascular inflammatory process by a NFκB signaling pathway.
Assuntos
Anticorpos Monoclonais/farmacologia , Hipertensão/prevenção & controle , Inflamação/prevenção & controle , Artérias Mesentéricas/imunologia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Pressão Sanguínea/efeitos dos fármacos , Western Blotting , Células Cultivadas , Citocinas/metabolismo , Hipertensão/imunologia , Hipertensão/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismoRESUMO
Long-chain fatty acids are capable of inducing alterations in the homoeostasis of glucose-stimulated insulin secretion (GSIS), but the effect of medium-chain fatty acids (MCFA) is poorly elucidated. In the present study, we fed a normoenergetic MCFA diet to male rats from the age of 1 month to the age of 4 months in order to analyse the effect of MCFA on body growth, insulin sensitivity and GSIS. The 45% MCFA substitution of whole fatty acids in the normoenergetic diet impaired whole body growth and resulted in increased body adiposity and hyperinsulinaemia, and reduced insulin-mediated glucose uptake in skeletal muscle. In addition, the isolated pancreatic islets from the MCFA-fed rats showed impaired GSIS and reduced protein kinase Ba (AKT1) protein expression and extracellular signal-related kinase isoforms 1 and 2 (ERK(1/2)) phosphorylation, which were accompanied by increased cellular death. Furthermore, there was a mildly increased cholinergic sensitivity to GSIS. We discuss these findings in further detail, and advocate that they might have a role in the mechanistic pathway leading to the compensatory hyperinsulinaemic status found in this animal model.
Assuntos
Gorduras na Dieta/metabolismo , Ácidos Graxos/metabolismo , Resistência à Insulina/fisiologia , Ilhotas Pancreáticas/metabolismo , Receptor de Insulina/metabolismo , Triglicerídeos/sangue , Animais , Modelos Animais de Doenças , Ácidos Graxos/química , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Músculo Esquelético/metabolismo , Fosforilação/fisiologia , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Triglicerídeos/químicaRESUMO
Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.
Assuntos
Humanos , Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Obesidade/fisiopatologia , Hipertensão/etiologia , Resistência à Insulina/fisiologia , Obesidade/complicações , Fatores de Risco , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.
Assuntos
Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Obesidade/fisiopatologia , Humanos , Hipertensão/etiologia , Resistência à Insulina/fisiologia , Obesidade/complicações , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco , Sistema Nervoso Simpático/fisiopatologiaRESUMO
AIMS: Inflammation may have an important role in the beginning and in the progress of cardiovascular diseases. Testosterone exerts important effects on vascular function, which is altered in arterial hypertension. Thus, the aim of this study was to evaluate the influence of endogenous testosterone on leukocyte behavior in post-capillary venules of the mesenteric bed of spontaneously hypertensive rats (SHR). MAIN METHODS: 18 week-old intact SHR, castrated SHR and normotensive rats (intact Wistar) were used. Blood pressure was measured by tail plethysmography and serum testosterone levels by ELISA. Leukocyte rolling, adhesion and migration were evaluated in vivo in situ by intravital microscopy. KEY FINDINGS: Castration significantly reduced blood pressure and reversed the increased leukocyte rolling and adhesion observed in SHRs. Leukocyte counts and other hemodynamic parameters did not differ among groups. SHRs displayed increased protein expression of P-selectin and ICAM-1 in mesenteric venules when compared to intact Wistar. Castration of SHRs restored the protein expression of the cell adhesion molecules. SIGNIFICANCE: The findings of the present study demonstrate the critical role of endogenous testosterone mediating the effects of hypertension increasing leukocyte-endothelial cell interaction. Increased expression of cell adhesion molecules contribute to the effects of endogenous testosterone promoting increased leukocyte rolling and adhesion in SHRs.
Assuntos
Comunicação Celular , Células Endoteliais/citologia , Hipertensão/imunologia , Leucócitos/citologia , Ratos Endogâmicos SHR/imunologia , Testosterona/imunologia , Animais , Adesão Celular , Células Endoteliais/imunologia , Hemodinâmica , Hipertensão/genética , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/imunologia , Migração e Rolagem de Leucócitos , Leucócitos/imunologia , Masculino , Orquiectomia , Selectina-P/genética , Selectina-P/imunologia , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos SHR/genética , Ratos Wistar , Vênulas/citologiaRESUMO
AIMS: Metformin is an insulin sensitizing agent with beneficial effects in diabetic patients on glycemic levels and in the cardiovascular system. We examined whether the metabolic changes and the vascular dysfunction in monosodium glutamate-induced obese non-diabetic (MSG) rats might be improved by metformin. MAIN METHODS: 16 week-old MSG rats were treated with metformin for 15 days and compared with age-matched untreated MSG and non-obese non-diabetic rats (control). Blood pressure, insulin sensitivity, vascular reactivity and prostanoid release in the perfused mesenteric arteriolar bed as well as nitric oxide production and reactive oxygen species generation in isolated mesenteric arteries were analyzed. KEY FINDINGS: 18-week-old MSG rats displayed higher Lee index, fat accumulation, dyslipidemia, insulin resistance and hyperinsulinemia. Metformin treatment improved these alterations. The norepinephrine-induced response, increased in the mesenteric arteriolar bed from MSG rats, was corrected by metformin. Indomethacin corrected the enhanced contractile response in MSG rats but did not affect metformin effects. The sensitivity to acetylcholine, reduced in MSG rats, was also corrected by metformin. Indomethacin corrected the reduced sensitivity to acetylcholine in MSG rats but did not affect metformin effects. The sensitivity to sodium nitroprusside was increased in preparations from metformin-treated rats. Metformin treatment restored both the reduced PGI2/TXA2 ratio and the increased reactive oxygen species generation in preparations from MSG rats. SIGNIFICANCE: Metformin improved the vascular function in MSG rats through reduction in reactive oxygen species generation, modulation of membrane hyperpolarization, correction of the unbalanced prostanoids release and increase in the sensitivity of the smooth muscle to nitric oxide.
Assuntos
Hipoglicemiantes/administração & dosagem , Artérias Mesentéricas/metabolismo , Metformina/administração & dosagem , Óxido Nítrico Sintase/metabolismo , Obesidade/tratamento farmacológico , Acetilcolina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Dislipidemias/tratamento farmacológico , Epoprostenol/metabolismo , Hiperinsulinismo/tratamento farmacológico , Indometacina/farmacologia , Insulina/sangue , Resistência à Insulina , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Óxido Nítrico/análise , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/análise , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Obesidade/induzido quimicamente , Obesidade/fisiopatologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Glutamato de Sódio/administração & dosagem , Tromboxano A2/metabolismoRESUMO
The endothelium plays a vital role in maintaining circulatory homeostasis by the release of relaxing and contracting factors. Any change in this balance may result in a process known as endothelial dysfunction that leads to impaired control of vascular tone and contributes to the pathogenesis of some cardiovascular and endocrine/metabolic diseases. Reduced endothelium-derived nitric oxide (NO) bioavailability and increased production of thromboxane A2, prostaglandin H2 and superoxide anion in conductance and resistance arteries are commonly associated with endothelial dysfunction in hypertensive, diabetic and obese animals, resulting in reduced endothelium-dependent vasodilatation and in increased vasoconstrictor responses. In addition, recent studies have demonstrated the role of enhanced overactivation of ß-adrenergic receptors inducing vascular cytokine production and endothelial NO synthase (eNOS) uncoupling that seem to be the mechanisms underlying endothelial dysfunction in hypertension, heart failure and in endocrine-metabolic disorders. However, some adaptive mechanisms can occur in the initial stages of hypertension, such as increased NO production by eNOS. The present review focuses on the role of NO bioavailability, eNOS uncoupling, cyclooxygenase-derived products and pro-inflammatory factors on the endothelial dysfunction that occurs in hypertension, sympathetic hyperactivity, diabetes mellitus, and obesity. These are cardiovascular and endocrine-metabolic diseases of high incidence and mortality around the world, especially in developing countries and endothelial dysfunction contributes to triggering, maintenance and worsening of these pathological situations.
Assuntos
Doenças Cardiovasculares/fisiopatologia , Doenças do Sistema Endócrino/fisiopatologia , Endotélio Vascular/fisiopatologia , Doenças Metabólicas/fisiopatologia , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Doenças do Sistema Endócrino/metabolismo , Endotélio Vascular/metabolismo , Fatores Relaxantes Dependentes do Endotélio/fisiologia , Humanos , Óxido Nítrico/biossíntese , Obesidade/metabolismo , Obesidade/fisiopatologia , RatosRESUMO
The endothelium plays a vital role in maintaining circulatory homeostasis by the release of relaxing and contracting factors. Any change in this balance may result in a process known as endothelial dysfunction that leads to impaired control of vascular tone and contributes to the pathogenesis of some cardiovascular and endocrine/metabolic diseases. Reduced endothelium-derived nitric oxide (NO) bioavailability and increased production of thromboxane A2, prostaglandin H2 and superoxide anion in conductance and resistance arteries are commonly associated with endothelial dysfunction in hypertensive, diabetic and obese animals, resulting in reduced endothelium-dependent vasodilatation and in increased vasoconstrictor responses. In addition, recent studies have demonstrated the role of enhanced overactivation ofβ-adrenergic receptors inducing vascular cytokine production and endothelial NO synthase (eNOS) uncoupling that seem to be the mechanisms underlying endothelial dysfunction in hypertension, heart failure and in endocrine-metabolic disorders. However, some adaptive mechanisms can occur in the initial stages of hypertension, such as increased NO production by eNOS. The present review focuses on the role of NO bioavailability, eNOS uncoupling, cyclooxygenase-derived products and pro-inflammatory factors on the endothelial dysfunction that occurs in hypertension, sympathetic hyperactivity, diabetes mellitus, and obesity. These are cardiovascular and endocrine-metabolic diseases of high incidence and mortality around the world, especially in developing countries and endothelial dysfunction contributes to triggering, maintenance and worsening of these pathological situations.
Assuntos
Animais , Humanos , Ratos , Doenças Cardiovasculares/fisiopatologia , Doenças do Sistema Endócrino/fisiopatologia , Endotélio Vascular/fisiopatologia , Doenças Metabólicas/fisiopatologia , Óxido Nítrico Sintase Tipo III/metabolismo , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Doenças do Sistema Endócrino/metabolismo , Endotélio Vascular/metabolismo , Fatores Relaxantes Dependentes do Endotélio/fisiologia , Óxido Nítrico/biossíntese , Obesidade/metabolismo , Obesidade/fisiopatologiaRESUMO
BACKGROUND AND AIM: given that obesity is an independent risk factor for the development of cardiovascular diseases we decided to investigate the mechanisms involved in microvascular dysfunction using a monosodium glutamate (MSG)-induced model of obesity, which allows us to work on both normotensive and normoglycemic conditions. METHODS AND RESULTS: Male offspring of Wistar rats received MSG from the second to the sixth day after birth. Sixteen-week-old MSG rats displayed higher Lee index, fat accumulation, dyslipidemia and insulin resistance, with no alteration in glycemia and blood pressure. The effect of norepinephrine (NE), which was increased in MSG rats, was potentiated by L-nitro arginine methyl ester (L-NAME) or tetraethylammonium (TEA) and was reversed by indomethacin and NS-398. Sensitivity to acetylcholine (ACh), which was reduced in MSG rats, was further impaired by L-NAME or TEA, and was corrected by indomethacin, NS-398 and tetrahydrobiopterin (BH4). MSG rats displayed increased endothelium-independent relaxation to sodium nitroprusside. A reduced prostacyclin/tromboxane ratio was found in the mesenteric beds of MSG rats. Mesenteric arterioles of MSG rats also displayed reduced nitric oxide (NO) production along with increased reactive oxygen species (ROS) generation; these were corrected by BH4 and either L-NAME or superoxide dismutase, respectively. The protein expression of eNOS and cyclooxygenase (COX)-2 was increased in mesenteric arterioles from MSG rats. CONCLUSION: Obesity/insulin resistance has a detrimental impact on vascular function. Reduced NO bioavailability and increased ROS generation from uncoupled eNOS and imbalanced release of COX products from COX-2 play a critical role in the development of these vascular alterations.
Assuntos
Animais Recém-Nascidos , Microvasos/fisiopatologia , Óxido Nítrico/fisiologia , Obesidade/induzido quimicamente , Prostaglandinas/fisiologia , Glutamato de Sódio/administração & dosagem , Animais , Arteríolas/enzimologia , Arteríolas/metabolismo , Ciclo-Oxigenase 2/análise , Masculino , Mesentério/irrigação sanguínea , Óxido Nítrico Sintase Tipo III/análise , Obesidade/fisiopatologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: We recently demonstrated that aldose reductase inhibition was effective in restoring the reduced migratory capacity of leukocytes in diabetic rats. To investigate the mechanism(s) involved in the restoring effect, we used minalrestat, an aldose reductase inhibitor. METHODS: In sodium pentobarbital-anesthetized (40 mg/kg, intraperitoneally) alloxan-diabetic or galactosemic male Wistar rats, the internal spermatic fascia was exteriorized, and the number of leukocytes rolling along the venular endothelium and the number of leukocytes sticking to the vascular wall after topical application of zymosan-activated plasma or leukotriene B(4) (1 ng/ml), as well as after the application of a local irritant stimulus (carrageenan, 100 microg), were determined using intravital microscopy. Data from animals that were treated with and those that were not treated with minalrestat (10 mg/kg/d by gavage) were compared. RESULTS: The reduced number of leukocytes rolling along the venular endothelium (by about 70%) and the number of adhered and migrated leukocytes in postcapillary venules (by 60%) were significantly restored to control values after minalrestat treatment. Total or differential leukocyte counts, venular blood flow velocity or wall shear rate were not altered by minalrestat treatment. The expression of ICAM-1 and P-selectin, cell adhesion molecules involved in the interaction of leukocyte-endothelium, reduced in diabetic rats was restored by minalrestat treatment. CONCLUSION: We conclude that an enhanced flux through the polyol pathway might be involved in the reduced expression of ICAM-1 and P-selectin contributing to the impaired leukocyte-endothelial interactions in diabetes mellitus and that aldose reductase inhibition restores the defect, restoring the reduced expression.