Vascular Endothelin-B Receptor System In Vivo Plays a Favorable Inhibitory Role in Vascular Remodeling After Injury Revealed by Endothelin-B Receptor–Knockout Mice

Murakoshi, Nobuyuki; Miyauchi, Takashi; Kakinuma, Yoshihiko; Ohuchi, Tomohiro; Goto, Katsutoshi; Yanagisawa, Masashi; Yamaguchi, Iwao

doi:10.1161/01.cir.0000032004.56585.2a

Cited by 85 publications

(82 citation statements)

References 40 publications

(43 reference statements)

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“…This hypothesis was based on previous studies showing that ET-1 stimulates collagen accumulation in aortic and mesenteric vessels in type 1 diabetes and that pharmacological or genetic manipulation of ET B receptors results in augmented intimal remodeling in a carotid injury model (3,4,8,20). This study was designed to examine structural changes in resistance arteries of control and diabetic animals chronically treated with an ET A or ET B receptor antagonist and also to evaluate potential mechanisms of altered matrix dynamics in the microvasculature in diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…More importantly, the relative role(s) of ET receptor subtypes in mediating vascular remodeling in diabetes was unclear. Murakoshi et al (8) reported that inhibition of the ET B receptor system in a knockout mouse model or pharmacological blockade by an ET B antagonist led to enhanced intimal hyperplasia observed in carotid arteries after injury induced by ligation, suggesting that blockade of the receptor subtype may be detrimental. Thus, this study compared the effects of selective ET A versus ET B antagonism on vascular remodeling in diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…This duality of function of ETB B receptors underscores the importance of binding and function of both ET receptor subtypes. Especially given that inhibition of the ETB BB receptor system in a knockout mouse model or pharmacological blockade by an ETB BB antagonist leads to enhanced intimal hyperplasia observed in carotid arteries after injury induced by ligation, suggesting a vasculoprotective effect (8), the question remains whether ET B receptors contribute to or balance detrimental effects of ET A receptor activation in diabetic vascular remodeling.…”

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

et al. 2007

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OBJECTIVE-Vascular remodeling, characterized by extracellular matrix deposition and increased media-to-lumen (M/l) ratio, contributes to the development of microvascular complications in diabetes. Matrix metalloproteinases (MMPs) play an important role in the regulation of extracellular matrix (ECM) turnover and vascular remodeling. Vasoactive factor endothelin (ET)-1 not only causes potent vasoconstriction but also exerts profibrotic and proliferative effects that change vessel architecture, which makes it a likely candidate for a key role in vascular complications of diabetes. Thus, this study investigated the regulation of MMP activity of resistance arteries under mild-to-moderate diabetes conditions, as seen in type 2 diabetes, and the relative role of ET receptors in this process. C ardiovascular complications contribute to the increased morbidity and mortality in type 2 diabetes. Pathological changes in vascular function and structure underlie these complications. Vasoactive factor endothelin (ET)-1 not only causes potent vasoconstriction but also exerts profibrotic and proliferative effects that change vessel architecture, which make it a likely candidate for a key role in vascular complications of diabetes. A significant correlation has been observed between plasma ET-1 levels and diabetes complications (1,2). ET A receptor antagonism prevents mesenteric vascular hypertrophy in type 1 diabetes (3). Fukuda et al. (4) reported that blockade of ET-1 action inhibits aortic extracellular matrix (ECM) deposition. We showed that ET-1 levels are elevated and that an ET A antagonist prevents ECM deposition and MMP activation in middle cerebral arteries but not in the kidney of Goto-Kakizaki (GK) rats-a nonobese type 2 diabetes model (5,6). ET-1 mediates its diverse effects via distinct G protein-coupled receptor subtypes ETB AB and ETB BB . While these past studies indicate the involvement of the ET A receptor subtype in mediating detrimental effects of ET-1, the role of ET B receptors in diabetes-induced changes in the vasculature remains unknown. ETB AB receptors, localized mainly on vascular smooth muscle cells (VSMCs), are responsible for the vasocontractile and proliferative response to ET-1 (7). Endothelial ETB B receptors mediate vasodilatation, whereas VSMC ET B receptors can also lead to vasoconstriction in certain vascular beds (7). This duality of function of ETB B receptors underscores the importance of binding and function of both ET receptor subtypes. Especially given that inhibition of the ETB BB receptor system in a knockout mouse model or pharmacological blockade by an ETB BB antagonist leads to enhanced intimal hyperplasia observed in carotid arteries after injury induced by ligation, suggesting a vasculoprotective effect (8), the question remains whether ET B receptors contribute to or balance detrimental effects of ET A receptor activation in diabetic vascular remodeling. RESEARCH DESIGN AND METHODS-VesselVascular ECM displays a very dynamic equilibrium where there is constant synthesis, degra...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2007

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“…In support of a role of ET B receptors in blood pressure regulation it has been shown that ET B heterozygous (+/−) knockout mice are hypertensive, possibly due to unbalanced activation of ET A receptors by endogenous ET-1 [67]. Also, studies in ET B receptor-knockout mice have suggested that the vascular ET B receptors in vivo may play a favorable inhibitory role in vascular remodeling after injury [68]. ET B receptors are also abundant in tubular epithelium of the renal medulla.…”

Section: Functions Of Et/et Receptorsmentioning

confidence: 98%

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Hynynen

Khalil²

2006

PRC

107

105

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The discovery of endothelin two decades ago has now evolved into an intricate vascular endothelin (ET) system. Several ET isoforms, receptors, signaling pathways, agonists, antagonists, and clinical applications have been identified and documented in first-rate patents. The role of ET as one of the most potent endothelium-derived vasoconstricting factors is now complemented by a newly discovered role in vascular relaxation. ET synthesis is initiated by the transcription of ET genes in endothelial cells and the generation of the gene products preproET and big ET, which are further cleaved by specific ET converting enzymes into ET-1, -2, -3 and -4 isoforms. ET isoforms bind with different affinities to ET A and ET B2 receptors in vascular smooth muscle, and stimulate [Ca 2+ ] i , protein kinase C, mitogen-activated protein kinase and other signaling mechanisms of smooth muscle contraction, growth and proliferation. ET also binds to endothelial ET B1 receptors, which mediate the release of vasodilator substances such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor. Endothelial ET B1 receptors may also function in ET re-uptake and clearance. Although the effects of ET on vascular function and growth are well-recognized, the role of ET and its receptors in the regulation of blood pressure and in the pathogenesis of hypertension is not clearly established. Salt-dependent hypertension in experimental animals and some forms of moderate to severe hypertension in human may show elevated levels of plasma or vascular ET; however, other forms of hypertension show normal ET levels. The currently available ET receptor antagonists reduce blood pressure in some forms of experimental hypertension. Careful examination of recent patents may identify more effective and specific modulators of the vascular ET system for clinical use in human hypertension.

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“…17,18 The luminal, internal elastic lamina (IEL), and external elastic lamina areas were measured with Scion Image software (Scion Corp). Morphological parameters were calculated as described previously.…”

Section: Morphometric and Histological Examinationsmentioning

confidence: 99%

Ablation of MEK Kinase 1 Suppresses Intimal Hyperplasia by Impairing Smooth Muscle Cell Migration and Urokinase Plasminogen Activator Expression in a Mouse Blood-Flow Cessation Model

Minamino

Tsukamoto

et al. 2005

Circulation

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Background-Migration, proliferation, and matrix-degrading protease expression of smooth muscle cells (SMCs) are major features of intimal hyperplasia after vascular injury. Although MEK kinase 1 (MEKK1) has been shown to regulate cell migration and urokinase plasminogen activator (uPA) expression, the precise role of MEKK1 in this process remains unknown. Methods and Results-We triggered a vascular remodeling model by complete ligation of the right common carotid artery in wild-type (WT) and MEKK1-null (MEKK1 Ϫ/Ϫ ) mice. The intimal areas 28 days after ligation were significantly decreased in the ligated MEKK1 Ϫ/Ϫ arteries compared with WT arteries (28Ϯ8 versus 65Ϯ17 m 2 , PϽ0.05). There were no differences in the ratios of proliferating cell nuclear antigen (PCNA)-positive cells to total cells within the arterial wall between WT and MEKK1 Ϫ/Ϫ arteries. Proliferation capacity also did not differ between WT and MEKK1

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Vascular Endothelin-B Receptor System In Vivo Plays a Favorable Inhibitory Role in Vascular Remodeling After Injury Revealed by Endothelin-B Receptor–Knockout Mice

Abstract: Background-Two subtypes of endothelin (ET) receptors, ET

Cited by 85 publications

References 40 publications

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

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

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Ablation of MEK Kinase 1 Suppresses Intimal Hyperplasia by Impairing Smooth Muscle Cell Migration and Urokinase Plasminogen Activator Expression in a Mouse Blood-Flow Cessation Model

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