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Mulvany, Michael J.; Baumbach, Gary L.; Aalkjær, Christian; Heagerty, Anthony M.; Korsgaard, Niels; Schiffrin, Ernesto L.; Heistad, Don D.

doi:10.1097/00004872-199715040-00002

Cited by 71 publications

(100 citation statements)

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“…16 In addition, resistance vessels from essential hypertensive patients and SHRs show inward eutrophic remodeling, that is, increased media:lumen ratio without changes in the amount of material. 17,18 Chronic treatment with GW0742 strongly reduced the vascular remodeling in mesenteric arteries, suggesting that this may contribute to reduce blood pressure. The lack of inhibitory effects of GW0742 in cardiac hypertrophy despite the reduction of blood pressure may be explained by insufficient time of low systolic blood pressure to induce morphological regression and induction of rapid cardiac growth, as described previously in mice with either GW0742 or another PPAR␤ agonist GW501516, 19 which counterbalances the effects of reduced blood pressure and Ang II pathway activity.…”

Section: Discussionmentioning

confidence: 99%

Antihypertensive Effects of Peroxisome Proliferator-Activated Receptor-β Activation in Spontaneously Hypertensive Rats

Zarzuelo

Jiménez²,

Galindo³

et al. 2011

Hypertension

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Abstract-Activation of nuclear hormone receptor peroxisome proliferator-activated receptor ␤/␦ (PPAR␤) has been shown to improve insulin resistance and plasma high-density lipoprotein levels, but nothing is known about its effects in genetic hypertension. We studied whether the PPAR␤ agonist GW0742 might exert antihypertensive effects in spontaneously hypertensive rats (SHRs). The rats were divided into 4 groups, Wistar Kyoto rat-control, Wistar Kyoto rat-treated (GW0742, 5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 by oral gavage), SHR-control, and SHR-treated, and followed for 5 weeks. GW0742 induced a progressive reduction in systolic arterial blood pressure and heart rate in SHRs and reduced the mesenteric arterial remodeling, the increased aortic vasoconstriction to angiotensin II, and the endothelial dysfunction characteristic of SHRs. These effects were accompanied by a significant increase in endothelial NO synthase activity attributed to upregulated endothelial NO synthase and downregulated caveolin 1 protein expression. Moreover, GW0742 inhibited vascular superoxide production, downregulated p22 phox and p47 phox proteins, decreased both basal and angiotensin II-stimulated NADPH oxidase activity, inhibited extracellular-regulated kinase 1/2 activation, and reduced the expression of the proinflammatory and proatherogenic genes, interleukin 1␤, interleukin 6, or intercellular adhesion molecule 1. None of these effects were observed in Wistar Kyoto rats. PPAR␤ activation, both in vitro and in vivo, increased the expression of the regulators of G protein-coupled signaling proteins RGS4 and RGS5, which negatively modulated the vascular actions of angiotensin II. PPAR␤ activation exerted antihypertensive effects, restored the vascular structure and function, and reduced the oxidative, proinflammatory, and proatherogenic status of SHRs. We propose PPAR␤ as a new therapeutic target in hypertension. T he peroxisome proliferator-activated receptors (PPARs) PPAR␣, PPAR␤/␦, and PPAR␥ are members of the nuclear hormone receptor superfamily. PPARs were initially believed to regulate genes involved only in lipid and glucose metabolism. 1 However, in recent years, evidence suggests that activation of PPAR␣ or PPAR␥ may exert cardiovascular protection beyond their metabolic effects. 2 In fact, PPAR␣ or PPAR␥ agonists exert antihypertensive effects in both human and animal models with or without metabolic disorders. [3][4][5][6] The mechanisms underlying the beneficial effects of PPARs beyond glucose and lipid metabolism may relate to their anti-inflammatory and antioxidant actions. 5 Thus, activation of both PPAR␣ or PPAR␥ antagonizes angiotensin II (Ang II) actions, including the activation of NADPH oxidase and the generation of reactive oxygen species, as well as the increase in proinflammatory mediators and adhesion molecules in blood vessels. 5,6 Activation of PPAR␤/␦ (PPAR␤) also exhibits antiinflammatory properties in the vessel wall by inhibiting the expression of vascular cell adhesion molecule 1 and monocyte chemoattractant prote...

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Section: Discussionmentioning

confidence: 99%

Antihypertensive Effects of Peroxisome Proliferator-Activated Receptor-β Activation in Spontaneously Hypertensive Rats

Zarzuelo

Jiménez²,

Galindo³

et al. 2011

Hypertension

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“…Representative studies showing time-frame of structural remodeling in resistance arteries and adventitia cross-sectional areas. For resistance vessels, the most widely used classification of macro-scale changes describing vascular remodeling was proposed by Mulvany et al (119). In their scheme, the basis for establishing the occurrence of remodeling is a change in the passive (fully relaxed) luminal diameter of vessels measured at a standard intravascular pressure.…”

Section: Small Artery Remodeling: Expanding Our Current Definitionsmentioning

confidence: 99%

The Plastic Nature of the Vascular Wall: A Continuum of Remodeling Events Contributing to Control of Arteriolar Diameter and Structure

2009

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The diameter of resistance arteries has a profound effect on the distribution of microvascular blood flow and the control of systemic blood pressure. Here, we review mechanisms that contribute to the regulation of resistance artery diameter, both acutely and chronically, their temporal characteristics, and their interdependence. Furthermore, we hypothesize the existence of a remodeling continuum that allows for the vascular wall to rapidly modify its structural characteristics, specifically through the re-positioning of vascular smooth muscle cells.Importantly, the concepts presented more closely link acute vasoregulatory responses with adaptive changes in vessel wall structure. These rapid structural adaptations provide resistance vessels the ability to maintain a desired diameter under presumed optimal energetic and mechanical conditions.1548-9213/09 8.00

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“…[1][2][3][4][5] It is reasonable to assume that each vessel segment reacts, through regulation of gene expression and cellular functions, to the local conditions and stimuli that it experiences, according to a common set of genetically determined responses or "rules." 6 Continuous dynamic reactions according to such rules can in principle lead to development of structures that are functionally adequate and capable of adaptation to changing conditions.…”

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confidence: 99%

Remodeling of Blood Vessels

2005

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Abstract-Vascular functions, including tissue perfusion and peripheral resistance, reflect continuous structural adaptation (remodeling) of blood vessels in response to several stimuli. Here, a theoretical model is presented that relates the structural and functional properties of microvascular networks to the adaptive responses of individual segments to hemodynamic and metabolic stimuli. All vessels are assumed to respond, according to a common set of adaptation rules, to changes in wall shear stress, circumferential wall stress, and tissue metabolic status (indicated by partial pressure of oxygen). An increase in vessel diameter with increasing wall shear stress and an increase in wall mass with increased circumferential stress are needed to ensure stable vascular adaptation. The model allows quantitative predictions of the effects of changes in systemic hemodynamic conditions or local adaptation characteristics on vessel structure and on peripheral resistance. Predicted effects of driving pressure on the ratio of wall thickness to vessel diameter are consistent with experimental observations. In addition, peripheral resistance increases by Ϸ65% for an increase in driving pressure from 50 to 150 mm Hg. Peripheral resistance is predicted to be markedly increased in response to a decrease in vascular sensitivity to wall shear stress, and to be decreased in response to increased tissue metabolic demand. This theoretical approach provides a framework for integrating available information on structural remodeling in the vascular system and predicting responses to changing conditions or altered vascular reactivity, as may occur in hypertension.

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Cited by 71 publications

References 1 publication

Antihypertensive Effects of Peroxisome Proliferator-Activated Receptor-β Activation in Spontaneously Hypertensive Rats

Antihypertensive Effects of Peroxisome Proliferator-Activated Receptor-β Activation in Spontaneously Hypertensive Rats

The Plastic Nature of the Vascular Wall: A Continuum of Remodeling Events Contributing to Control of Arteriolar Diameter and Structure

Remodeling of Blood Vessels

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