Evidence for Vasculoprotective Effects of ETB Receptors in Resistance Artery Remodeling in Diabetes

Self Cite

Structure and function of the cerebrovasculature is critical for ischemic stroke outcome. We showed that diabetes causes cerebrovascular remodeling by activation of the endothelin A (ET A ) receptors. The goal of this study was to test the hypotheses that vasculoprotective endothelial ET B receptors are decreased and pharmacological inhibition of the ET B receptor augments vascular remodeling of middle cerebral arteries (MCAs) in type 2 diabetes. MCA structure, matrix metalloprotease (MMP) activity, and matrix proteins as well as ET A and ET B receptor profiles were assessed in control Wistar and diabetic Goto-Kakizaki rats treated with vehicle, the ET B receptor antagonist (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-[(2,6-diethylphenyl)amino]-2-oxoethyl]-2-(4-propoxyphenyl)pyrrolidine-3-carboxylic acid (A192621) (30 mg/kg/day), or the dual ET receptor antagonist bosentan (100 mg/kg/day) for 4 weeks. Diabetes increased vascular smooth muscle (VSM) ET A and ET B receptors; the increase was prevented by chronic bosentan treatment. MCA wall thickness was increased in diabetes, and this was associated with increased MMP-2 activity and collagen deposition but reduced MMP-13 activity. Because of up-regulation of VSM ET receptors in diabetes, selective ET B receptor antagonism with A192621 blunts this response, and combined ET A and ET B receptor blockade with bosentan completely prevents this response. On the other hand, A192621 treatment augmented remodeling in control animals, indicating a physiological protective role for this receptor subtype. Attenuation of changes in ET receptor profile with bosentan treatment suggests that ET-1 has a positive feedback on the expression of its receptors in the cerebrovasculature. These results emphasize that ET receptor antagonism may yield different results in healthy and diseased states.

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endothelial Endothelin B Receptor-Mediated Prevention of Cerebrovascular Remodeling Is Attenuated in Diabetes Because of Up-Regulation of Smooth Muscle Endothelin Receptors

Kelly-Cobbs¹,

Harris²,

Elgebaly³

et al. 2010

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“…We have shown re-cently that vascular remodeling also occurs in GK rats, and endothelin (ET)-1, a potent vasoconstrictor with profibrotic properties, mediates this effect. In this model, there is an up-regulation of the matrix metalloproteinase (MMP) system in both the systemic and cerebral circulations, contributing to vascular remodeling (Harris et al, 2005;Sachidanandam et al, 2007). The MMPs are a family of zinc-dependent enzymes that are extensively involved in vascular remodeling by regulating extracellular matrix (ECM) turnover in a very complex manner (Nagase and Woessner, 1999).…”

mentioning

confidence: 99%

Differential Effects of Diet-Induced Dyslipidemia and Hyperglycemia on Mesenteric Resistance Artery Structure and Function in Type 2 Diabetes

Sachidanandam

Hutchinson

Elgebaly³

et al. 2008

Self Cite

Type 2 diabetes and dyslipidemia oftentimes present in combination. However, the relative roles of diabetes and diet-induced dyslipidemia in mediating changes in vascular structure, mechanics, and function are poorly understood. Our hypothesis was that addition of a high-fat diet would exacerbate small artery remodeling, compliance, and vascular dysfunction in type 2 diabetes. Vascular remodeling indices [media/lumen (M/L) ratio, collagen abundance and turnover, and matrix metalloproteinase dynamics], mechanical properties (vessel stiffness), and reactivity to pressure and vasoactive factors were measured in third-order mesenteric arteries in control Wistar and type 2 diabetic Goto-Kakizaki (GK) rats fed either a regular or high-fat diet. M/L ratios, total collagen, and myogenic tone were increased in diabetes. Addition of the high-fat diet altered collagen patterns (mature versus new collagen) in favor of matrix accumulation. Addition of a high-fat diet caused increased constriction to endothelin-1 (0.1-100 nM), showed impaired vasorelaxation to both acetylcholine (0.1 nM-1 M) and sodium nitroprusside (0.1 nM-1 M), and increased cardiovascular risk factors in diabetes. These results suggest that moderate elevations in blood glucose, as seen in our lean GK model of type 2 diabetes, promote resistance artery remodeling resulting in increased medial thickness, whereas addition of a high-fat diet contributes to diabetic vascular disease predominantly by impairing vascular reactivity in the time frame used for this study. Although differential in their vascular effects, both hyperglycemia and diet-induced dyslipidemia need to be targeted for effective prevention and treatment of diabetic vascular disease.It is estimated that over 23 million Americans are affected by type 2 diabetes. Obesity, insulin resistance, and hypertension often cluster along with type 2 diabetes, resulting in a condition known as metabolic syndrome or syndrome X, thus imposing an enormous task from a therapeutic standpoint (Muhammad, 2004). Although studies with obese Zucker rats (Frisbee, 2003;Stepp et al., 2004;Bouvet et al., 2007) and ob/ob mice (Schä fer et al., 2004) provide important evidence about complications of obesity, insulin resistance, hypertension, and prediabetes in the systemic microvasculature, the relative contributions of the individual components of metabolic syndrome to diabetes-associated complications cannot be dissected. Furthermore, effects of hyperglycemia and high-fat diet on the structure and mechanics of contractile medial layer are less understood. To define specific targets and develop therapeutic strategies to treat vascular complications, it is very important that the relative contributions of hyperglycemia and hyperlipidemia to vascular structure and function independent of atherosclerotic changes are well defined. The Goto-Kakizaki (GK) rat, being a spontaneous model of type 2 diabetes without the presence of comorbid complications, thus offers an excellent opportunity to study the individual role of...

“…In contrast, the selective ET A receptor blockade could attenuate this vascular remodeling in the same animals (Murakoshi et al, 2002). In addition, Sachidanandam et al (2007) reported that ET-1 contributes to the remodeling of mesenteric resistance arteries in diabetes via activation of ET A receptors, and ET B receptor-mediated action provides vasoprotective effects. Thereby, the blockade of ET B receptors may be harmful in vascular disease, and ET A receptor antagonists may be superior to ET A /ET B dual receptor antagonists in the treatment of vascular disease.…”

Section: Discussionmentioning

confidence: 95%

“…Murakoshi et al (2002) demonstrated that inhibition of ET B receptor system in a knockout mouse model or pharmacological blockade by a selective ET B receptor antagonist leads to the enhancement of vascular remodeling by the cessation of blood flow in the carotid artery. In addition, Sachidanandam et al (2007) reported that resistance artery remodeling in the diabetic rat is worsened by a selective ET B receptor antagonist, in contrast to the beneficial effect of a selective ET A receptor antagonist. These findings indicate that ET B receptor system plays a vasoprotective role in vascular remodeling.…”

mentioning

confidence: 99%

Inhibition of Endothelin ET_BReceptor System Aggravates Neointimal Hyperplasia after Balloon Injury of Rat Carotid Artery

Kitada¹,

Yui²,

Matsumoto³

et al. 2009

Endothelin-1 (ET)/ET A receptor system has been known to play an important role in the pathogenesis of neointimal hyperplasia after endothelial injury. However, the pathological role of endothelin ET B receptors on neointimal hyperplasia remains to be elucidated. In the present study, we investigated the pathological role of ET B receptors on neointimal hyperplasia in ballooninjured rat carotid arteries by pharmacological blockade with use of 2R- -104132), an ET A /ET B dual receptor antagonist. Moreover, the spotting-lethal rats, which carry a naturally occurring deletion in the endothelin ET B receptor gene, were used to examine the effects of genetic deficiency for this receptor subtype. Two weeks after balloon injury, the ratio of the neointimal to the medial area (neointima/media ratio) was determined. Treatment with A-192621 (30 mg/kg/day) for 2 weeks after injury significantly increased the neointima/media ratio in the injured artery. In contrast, ABT-627 (10 mg/kg/day) and J-104132 (10 mg/kg/day) markedly decreased the neointima/media ratio to the same extent. Furthermore, the neointima/media ratio in the injured artery of the ET B -deficient rat was significantly increased compared with that of the wild-type rat, and this increase was abolished by treatment with J-104132. These findings suggest that the inhibition of the ET B receptor system leads to an aggravation of neointimal hyperplasia after balloon injury, and the augmentation of ET A -mediated actions are responsible for the neointimal hyperplasia aggravated by the pharmacological blockade of ET B receptor or by its genetic deficiency. The antagonism of the ET A receptor system is essential for preventing restenosis after angioplasty.