Vascular remodeling in experimental hypertension

The basic hemodynamic abnormality in hypertension is an increased peripheral resistance that is due mainly to a decreased vascular lumen derived from structural changes in the small arteries wall, named (as a whole) vascular remodeling. The vascular wall is an active, flexible, and integrated organ made up of cellular (endothelial cells, smooth muscle cells, adventitia cells, and fibroblasts) and noncellular (extracellular matrix) components, which in a dynamic way change shape or number, or reorganize in response to physiological and pathological stimuli, maintaining the integrity of the vessel wall in physiological conditions or participating in the vascular changes in cardiovascular diseases such as hypertension. Research focused on new signaling pathways and molecules that can participate in the mechanisms of vascular remodeling has provided evidence showing that vascular structure is not only affected by blood pressure, but also by mechanisms that are independent of the increased pressure. This review will provide an overview of the evidence, explaining some of the pathophysiologic mechanisms participating in the development of the vascular remodeling, in experimental models of hypertension, with special reference to the findings in spontaneously hypertensive rats as a model of essential hypertension, and in fructose-fed rats as a model of secondary hypertension, in the context of the metabolic syndrome. The understanding of the mechanisms producing the vascular alterations will allow the development of novel pharmacological tools for vascular protection in hypertensive disease.Fil: Risler, Norma Raquel. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Cruzado, Montserrat C.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Miatello, Roberto Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin

Fisiología del músculo liso vascular

Capas de células musculares lisas conforman las paredes de numerosos órganos y tubos en el organismo, incluyendo los vasos sanguíneos. Las células musculares lisas vasculares carecen del patrón estriado en bandas que se observa en el músculo cardíaco y el esquelético. Reciben inervación neural del sistema nervioso autónomo. El fenotipo contráctil del músculo liso está regulado por hormonas, capaces de actuar mediante mecanismos autocrinos o paracrinos, así como señales físicas y químicas locales. Las CMLV pueden desarrollar contracciones tónicas y fásicas en respuesta a cambios en la carga o longitud. Independientemente del estímulo, estas células utilizan la interacción actina-miosina para desarrollar la fuerza, donde iones de calcio son responsables del inicio de la contracción. Este capítulo repasa conceptos sobre los mecanismos de regulación de las respuestas integradas de contracción y relajación, así como de la regulación de la estructura vascular.Fil: Renna, Nicolas Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Miatello, Roberto Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin

Fisiopatología del remodelado vascular en la hipertensión arterial

El estrechamiento aterosclerótico de la luz arterial no es simplemente el resultado de la ampliación de lesiones ateroscleróticas. Las arterias, en lugar de realizar un remodelado estrechando la luz arterial, realizan una serie de cambios, como el aumento del diámetro exterior, para permitir la preservación del flujo arterial. Esta capacidad de adaptación es fundamental en la mayoría de las enfermedades arteriales. Enfermedades como la hipertensión arterial pueden considerarse como fracasos de la pared arterial para mantener un tamaño de luz adecuado como para permitir el flujo normal de sangre. Recientemente se ha sugerido que la incapacidad de los vasos de remodelar de manera correcta es una forma de "insuficiencia vascular", similar a la insuficiencia cardíaca para el corazón.Fil: Renna, Nicolas Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Miatello, Roberto Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin

Effects of Methotrexate on IL-6alphar, VCAM-1 and NF Kappa B Expression in a Rat Model of Metabolic Syndrome

Background: In this study, we used Methotrexate (Mtx) to examine the role of immunomodulation on the activation of IL-6 and VCAM-1, which could generate a microenvironment that supports cardiovascular remodelling.Methods: Male WKY and SHR rats were separated into five groups: Control, FFR: WKY rats receiving a 10% (w/v) fructose solution during all 12 weeks, SHR, FFHR: SHR receiving a 10% (w/v) fructose solution during all 12 weeks and FFHR+Mtx (0,3 mg/kg intraperitoneal one injection per day week for 6 weeks) (n = 8 per group). Metabolic variables and systolic blood pressure were measured. Cardiac and vascular remodelling was also evaluated. To assess this, IL-6R and VCAM-1 immunostaining techniques were used.Results: The FFHR experimental model developed metabolic syndrome, vascular and cardiac remodelling, and vascular inflammation because of increased expression of IL-6 and VCAM-1. Chronic treatment with Mtx completely or partiality reversed the variables studied.Conclusions: The results demonstrated an impact on immunomodulation after mtx treatment, which included a reduction in vascular inflammation and a favourable reduction in metabolic and structural parameters.Fil: Renna, Nicolas Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Ramirez, Jésica M.. Universidad Nacional de Cuyo. Instituto de Genética; ArgentinaFil: García, Rodrigo Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Diez, Emiliano Raúl. Universidad Nacional de Cuyo. Instituto de Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Miatello, Roberto Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Instituto de Genética; Argentin

Role of Insulin Resistance in Vascular Inflammation

Cardiovascular diseases (CVDs) such as ischemic heart disease (IHD), stroke, and peripheral artery disease (PAS) are the leading causes of mortality and morbidity around the world; about 30% of global deaths and 10% of global disease burden a year are due to CVDs. In this chapter, we will analyze the classic concepts of vascular remodeling, to later expand the concepts and physiopathological mechanisms of vascular inflammation. The role of immunomodulation from IL-6R alpha and the JAK/STAT3 intracellular cascade, will be proposed as an activator of vascular remodeling mechanisms. In addition, the role of new drugs such as LCZ696 and immunomodulators involved in the local inflammatory response will also be analyzed. The concept of remodeling and vascular inflammation, which a decade ago was only important at the level of basic research, step-by-step has proven crucial in the appearance of atherosclerosis, called subclinical atherosclerosis. Even though much progress has been made in the treatment and discovery of pathophysiological mechanisms, it has not been possible to reduce of cardiovascular risk, this is perhaps, it the decade in which we can advance in this

Efecto del poscondicionamiento isquémico sobre las arritmias de reperfusión en un modelo de hipertrofia miocárdica

Introducción El poscondicionamiento isquémico (PCI) es una estrategia cardioprotectora con propiedades antiarrítmicas. La hipertrofia cardíaca secundaria a hipertensión arterial se aumenta el riesgo de sufrir arritmias y, además, reduce la respuesta a algunos tratamientos. Objetivo Determinar si el efecto antiarrítmico del PCI se mantenía en corazones hipertróficos. Métodos Los corazones aislados de ratas Wistar Kyoto (WKY) y de ratas espontáneamente hipertensas (SHR) de la misma edad, fueron perfundidos según la técnica de Langendorff y sometidos a 15 min de isquemia regional. Al momento de la reperfusión se dividieron en: a) WKY, b) WKY-PCI, c) SHR, d) SHR-PCI (n=13 por grupo). El PCI consistió en 3 ciclos de 30 seg de reperfusión y 30 seg de isquemia. Se clasificaron las arritmias ventriculares observadas en el ECG. Se estimó la hipertrofia por el peso cardíaco relativo. Resultados La hipertensión arterial en las ratas SHR provocó hipertrofia miocárdica. Todos los corazones sufrieron una alta incidencia de fibrilación ventricular (SHR 92.3% y WKY 77%, ns). El PCI restituyó el ritmo sinusal en los corazones de las ratas normotensas (WKY-PCI 61,5% vs WKY 23,1%, p=0,0236 por test del χ2) y en los de las SHR (SHR-PCI 69,2% vs SHR 15,4%, p=0,0016 test del χ2). Conclusión El PCI es capaz de restituir a ritmo sinusal la mayoría de los corazones que presentaron arritmias ventriculares de reperfusión y el efecto antiarrítmico se mantiene en corazones hipertróficos provenientes de ratas SHR.Introduction: ischemic postconditioning (IPC) is a protective strategy against reperfusion injury with antiarrhythmic properties. Cardiac hypertrophy secondary to hypertension increases the risk of arrhythmias and also reduces the response to some treatments. Objective: to determine whether the antiarrhythmic effect of IPC was maintained in hypertrophic hearts. Methods: isolated rat hearts from Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) of the same age, were perfused according to Langendorff technique and subjected to 15 min regional ischemia. At the moment of reperfusion, hearts were divided into: a) WKY, b) WKY-IPC, c) SHR, d) SHR-IPC (each group, n= 13). The IPC consisted of 3 cycles of 30 s of reperfusion and 30 s of ischemia at the onset of reperfusion. Ventricular arrhythmias were diagnosed using ECG records. Hypertrophy was estimated by relative heart weight. Results: hypertension in SHR induce myocardial hypertrophy. All hearts underwent a high incidence of ventricular fibrillation (SHR 92,3% and WKY 77%, ns). IPC restored sinus rhythm in the hearts of normotensive rats (WKY-PCI 61,5% versus WKY 23,1%, p = 0,0236 by C2 test) and in those from SHR (SHR-PCI 69% versus SHR 15,4%, p = 0,0016 C2 test). Conclusion: IPC is able to restore sinus rhythm from most of the hearts that developed reperfusion ventricular arrhythmias and the antiarrhythmic effect remains in hypertrophic hearts from SHR rats.Fil: Diez, Emiliano Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Prado, Natalia Jorgelina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo; ArgentinaFil: Ponce Zumino, Amira Zulma. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Miatello, Roberto Miguel. Universidad Nacional de Cuyo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin

Garlic and Onion Attenuates Vascular Inflammation and Oxidative Stress in Fructose-Fed Rats

This study evaluates the antioxidant and the anti-inflammatory properties of garlic (G) and onion (O) in fructose-fed rats (FFR). Thirty-day-old male Wistar rats were assigned to control (C), F (10% fructose in drinking water), F+T (tempol 1 mM as control antioxidant), F+G, and F+O. Aqueous G and O extracts were administered orally in doses of 150 and 400 mg/kg/d respectively, and along with tempol, were given during the last 8 weeks of a 14-week period. At the end of the study, FFR had developed insulin resistance, aortic NADPH oxidase activity, increased SBP, plasma TBARS and vascular cell adhesion molecule-1 (VCAM-1) expression in mesenteric arteries, and a decrease in heart endothelial nitric oxide synthase (eNOS). Garlic and onion administration to F rats reduced oxidative stress, increased eNOS activity, and also attenuated VCAM-1 expression. These results provide new evidence showing the anti-inflammatory and antioxidant effect of these vegetables

Vascular smooth muscle cell NAD(P)H oxidase activity during the development of hypertension: Effect of angiotensin II and role of insulinlike growth factor-1 receptor transactivation

We investigated whether angiotensin II (Ang II)-induced reactive oxygen species (ROS) generation is altered in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) during the phases of prehypertension, developing hypertension, and established hypertension and assessed the putative role of insulinlike growth factor-1 receptor (IGF-1R) in Ang II-mediated actions. The VSMCs from SHR and Wistar-Kyoto rats (WKY) aged 4 (prehypertensive), 9 (developing hypertension), and 16 (established hypertension) weeks were studied. The ROS production and NAD(P)H oxidase activation were determined by fluorescence and chemiluminescence, respectively. The role of IGF-1R was assessed with the selective inhibitor AG1024. The ROS bioavailability was manipulated with Tiron (10-5 mol/L) and diphenylene iodonium (DPI) (10-6 mol/L). Angiotensin II dose dependently increased ROS production in WKY and SHR at all ages. The Ang II-induced responses were greater in SHR versus WKY at 9 and 16 weeks (P < .05). The Ang II-stimulated ROS increase was greater in 9- and 16-week-old SHR versus 4-week SHR (P < .05). These effects were reduced by AG 1024. Basal NAD(P)H oxidase activity was higher in VSMCs from 9-week-old SHR versus 4-week-old rats (P < .05). Angiotensin II induced a significant increase in oxidase activity in VSMCs from 9- and 16-week-old SHR (P < .001), without influencing responses in cells from 4-week-old SHR. Pretreatment of 9- and 16-week-old SHR cells with AG1024 reduced Ang II-mediated NAD(P)H oxidase activation (P < .05). Basal and Ang II-induced NAD(P)H-driven ROS generation are enhanced in VSMCs from SHR during development of hypertension, but not in cells from prehypertensive rats. Transactivation of IGF-1R by Ang II may be important in vascular oxidative excess in the development of hypertension in SHR.Fil: Cruzado, Montserrat Cecilia. Universidad Nacional de Cuyo; Argentina. Universidad de Mendoza; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Risler, Norma Raquel. Universidad Nacional de Cuyo; ArgentinaFil: Miatello, Roberto Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Yao, Guoying. Institut de Recherches Cliniques de Montréal; CanadáFil: Schiffrin, Ernesto L.. Institut de Recherches Cliniques de Montréal; CanadáFil: Touyz, Rhian M.. Institut de Recherches Cliniques de Montréal; Canad

Quercetin attenuates adipose hypertrophy, in part through activation of adipogenesis in rats fed a high-fat diet

An impaired capacity of adipose tissue expansion leads to adipocyte hypertrophy, inflammation and insulin resistance (IR) under positive energy balance. We previously showed that a grape pomace extract, rich in flavonoids including quercetin (Q), attenuates adipose hypertrophy. This study investigated whether dietary Q supplementation promotes adipogenesis in the epididymal white adipose tissue (eWAT) of rats consuming a high-fat diet, characterizing key adipogenic regulators in 3T3-L1 pre-adipocytes. Consumption of a high-fat diet for 6 weeks caused IR, increased plasma TNFα concentrations, eWAT weight, adipocyte size and the eWAT/brown adipose tissue (BAT) ratio. These changes were accompanied by decreased levels of proteins involved in angiogenesis, VEGF-A and its receptor 2 (VEGF-R2), and of two central adipogenic regulators, i.e. PPARγ and C/EBPα, and proteins involved in mature adipocyte formation, i.e. fatty acid synthase (FAS) and adiponectin. Q significantly reduced adipocyte size and enhanced angiogenesis and adipogenesis without changes in eWAT weight and attenuated systemic IR and inflammation. In addition, high-fat diet consumption increased eWAT hypoxia inducible factor-1 alpha (HIF-1α) levels and those of proteins involved in adipose inflammation (TLR-4, CD68, MCP-1, JNK) and activation of endoplasmic reticulum (ER) stress, i.e. ATF-6 and XBP-1. Q mitigated all these events. Q and quercetin 3-glucoronide prevented TNFα-mediated downregulation of adipogenesis during 3T3-L1 pre-adipocytes early differentiation. Together, Q capacity to promote a healthy adipose expansion enhancing angiogenesis and adipogenesis may contribute to reduced adipose hypertrophy, inflammation and IR. Consumption of diets rich in Q could be useful to counteract the adverse effects of high-fat diet-induced adipose dysfunction.Fil: Perdicaro, Diahann Jeanette. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Rodriguez Lanzi, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Gambarte Tudela, Julian Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Miatello, Roberto Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Oteiza, Patricia Isabel. University of California. Departments of Nutrition and Environmental Toxicology; Estados UnidosFil: Vazquez, Marcela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina; Argentin

(-)-Epicatechin mitigates high-fructose-associated insulin resistance by modulating redox signaling and endoplasmic reticulum stress

We investigated the capacity of dietary (-)-epicatechin (EC) to mitigate insulin resistance through the modulation of redox-regulated mechanisms in a rat model of metabolic syndrome (MetS). Adolescent rats were fed a regular chow diet without or with high fructose (HFr) (10% (w/v)) in drinking water for 8 weeks, and a group of HFr-fed rats was supplemented with EC in the diet. HFr-fed rats developed insulin resistance which was mitigated by EC supplementation. Accordingly, the activation of components of the insulin signaling cascade (insulin receptor (IR), IRS-1, Akt and ERK1/2) was impaired, while negative regulators (PKC, IKK, JNK and PTP1B) were upregulated in the liver and adipose tissue of HFr rats. These alterations were partially or totally prevented by EC supplementation. In addition, EC inhibited events which contribute to insulin resistance: HFr-associated increased expression and activity of NADPH oxidase , activation of redox-sensitive signals , expression of NF-kB-regulated pro-inflammatory cytokines and chemokines, and some sub-arms of endoplasmic reticulum stress signaling. Collectively, these findings indicate that EC supplementation can mitigate HFr-induced insulin resistance and are relevant to define interventions that can prevent/mitigate MetS-associated insulin resistance.Fil: Bettaieb, Ahmed. University of California at Davis; Estados UnidosFil: Vazquez, Marcela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Rodriguez Lanzi, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Miatello, Roberto Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Haj, Fawaz G.. University of California at Davis; Estados UnidosFil: Fraga, César Guillermo. University of California at Davis; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Oteiza, Patricia Isabel. University of California at Davis; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin