Vascular Thrombin Receptor Regulation in Hypertensive Rats

Capers, Quinn; Laursen, Jørn Bech; Fukui, Toshiki; Rajagopalan, Sanjay; Mori, Ichiro; Lou, Pingping; Freeman, Bruce Α.; Berrington, William R.; Griendling, Kathy K.; Harrison, David G.; Runge, Marschall S.; Alexander, R. Wayne; Taylor, W. Robert

doi:10.1161/01.res.80.6.838

Cited by 41 publications

(26 citation statements)

References 33 publications

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“…11 Although there was a trend for the CCR2-deficient animals to exhibit a slightly greater hypertensive response, there was no statistically significantly difference in the peak blood pressure response between the wild-type and the CCR2-deficient animals (20Ϯ8% versus 33Ϯ13% increase, Pϭ0.38).…”

Section: Resultsmentioning

confidence: 89%

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CC Chemokine Receptor 2 Is Required for Macrophage Infiltration and Vascular Hypertrophy in Angiotensin II–Induced Hypertension

et al. 2000

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Abstract-Recent studies have identified the presence of macrophages in the arterial wall of hypertensive animals and suggested that as is the case in atherosclerosis, macrophage products may be important mediators of the adaptive response of the arterial wall. In support of this, we have previously shown that the expression of monocyte chemoattractant protein-1 is upregulated in the arteries of hypertensive animals. We hypothesized that macrophage recruitment is a critical step in the pathogenesis of hypertension. To obtain insights into this potential mechanism, we made use of mice deficient in the CC chemokine receptor 2 (CCR2), the receptor for monocyte chemoattractant protein-1. Hypertension was induced with the subcutaneous administration of angiotensin II (0.75 mg ⅐ kg Ϫ1 ⅐ d Ϫ1) for 7 days. Using in situ hybridization with a probe for c-fms to identify macrophages, we found that hypertension-induced macrophage infiltration of the arterial wall was virtually eliminated in CCR2-deficient mice. In addition, vascular hypertrophy was reduced by Ϸ65% compared with wild-type animals. These data demonstrate that CCR2 is essential for the recruitment of macrophages into the arterial wall in the setting of hypertension. Furthermore, the decreased hypertrophic response suggests that vascular hypertrophy occurs in part as a consequence of macrophage infiltration. In angiotensin II-induced hypertension, CCR2-mediated responses are critical to the process of macrophage recruitment and vascular hypertrophy and may represent one mechanism by which at least some forms of hypertension may lead to the development of atherosclerosis. (Hypertension. 2000;36:360-363.) Key Words: proteins Ⅲ angiotensin II Ⅲ hypertrophy Ⅲ macrophages I t is becoming increasingly apparent that hypertension, like atherosclerosis, is associated with the presence of an inflammatory response in the arterial wall. 1,2 The initial phase of this inflammatory response is characterized by the accumulation of macrophages in the arterial wall. [3][4][5] The importance of this macrophage infiltration in the development of hypertensive vasculopathy remains unknown. Furthermore, the precise factors that control macrophage recruitment into the vascular wall have not been determined.We recently demonstrated that the expression of monocyte chemoattractant protein-1 (MCP-1) is upregulated at both the message and protein level in aortic tissues of hypertensive animals. 4 This response was seen in animals made hypertensive with the infusion of either angiotensin II or norepinephrine. MCP-1 is a potent macrophage chemoattractant that has been previously implicated in the development of atherosclerosis. 6 -9 We hypothesized that in at least some forms of hypertension, MCP-1 upregulation and subsequent macrophage infiltration may represent a key step in the development of vascular hypertrophy. Implicit in this hypothesis is the assumption that vascular hypertrophy is dependent to a significant degree on the production of growth factors by resident macrophages.To gain ...

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Section: Resultsmentioning

confidence: 89%

“…4,11 Briefly, mice were anesthetized with ketamine (80 mg/kg IP) and xylazine (10 mg/kg IP). With sterile technique, osmotic minipumps that contained sufficient angiotensin II to deliver a dose of 0.75 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 were placed in the subcutaneous space over the abdomen.…”

Section: Angiotensin II Model Of Hypertensionmentioning

confidence: 99%

CC Chemokine Receptor 2 Is Required for Macrophage Infiltration and Vascular Hypertrophy in Angiotensin II–Induced Hypertension

et al. 2000

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“…Angiotensin II also upregulates thrombin receptor expression in the aortic tissues of rats via a redox-sensitive mechanism. 36 This appears to occur via the generation of reactive oxygen species and is independent of the pressor effects of angiotensin II. Angiotensin also upregulates expression of monocyte chemoattractant protein-1 (MCP-1) in cultured vascular smooth muscle cells, 37 which may occur through a redox-sensitive pathway.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II–Induced Hypertension Accelerates the Development of Atherosclerosis in ApoE-Deficient Mice

2001

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Background-Angiotensin II may contribute to the development and progression of atherosclerotic lesions because of its growth and proinflammatory effects. We sought to determine whether angiotensin II-induced hypertension would augment and accelerate the development of atherosclerotic lesions in apoE-deficient mice. Methods and Results-Angiotensin II (0.7 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 SC) was administered to apoE-deficient mice via osmotic minipumps. The animals were placed on either standard chow or an atherogenic diet. After 8 weeks, the mean atherosclerotic lesion area in the descending thoracic and abdominal aortas of animals on a standard chow diet was 0.4Ϯ0.1% compared with 5.2Ϯ1.2% in those animals maintained on an atherogenic diet (PϽ0.0001). In angiotensin II-treated animals on standard chow, the mean lesion area was increased to 11.0Ϯ2.3%, which was further increased to 69.9Ϯ9.4% (PϽ0.0001) in angiotensin II-treated animals on an atherogenic diet. Similar findings were obtained when tissues from the ascending aorta were analyzed. At 8 weeks in mice receiving a standard chow diet, angiotensin II dramatically increased the atherosclerotic lesion area by 840Ϯ83 m 2 (PϽ0.0001). Animals on a high-fat diet had a similar marked increase in lesion area in response to angiotensin II (217Ϯ19 m 2 , PϽ0.0001). In contrast, when hypertension was induced with norepinephrine, only a modest effect on the atherosclerotic lesion area was observed. Conclusions-Angiotensin II-induced hypertension specifically increased the development of atherosclerosis in apoE knockout mice. This response was seen in animals receiving either standard chow or an atherogenic diet. These studies demonstrate the profound effect of angiotensin II on the development of atherosclerosis.

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“…Table 3 suggests other intriguing possibilities for therapeutic agents. For example, angiotensin II may play a critical role in the upregulation of PAR1 in the hypertension model, 105 thus suggesting angiotensin II receptor antagonists could be a therapeutic agent. Oxidative stress is suggested to be involved in the upregulation of PAR1 induced by the cyclin strain, whereas the scavengers of free radials and inhibitors of NAD(P)H oxidase, have been shown to inhibit the upregulation of PAR1.…”

Section: The Possibility Of Pars As Therapeutic Targets For Vascular mentioning

confidence: 99%

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

Hirano

2007

ATVB

136

121

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Abstract-Proteinase-activated receptors (PARs) belong to a family of G protein-coupled receptors, thus mediating the cellular effects of proteinases. In the vascular system, thrombin and other proteinases in the coagulation-fibrinolysis system are considered to be the physiologically relevant agonists, whereas PARs are among the most important mechanisms mediating the interaction between the coagulation-fibrinolysis system and the vascular wall. Under physiological conditions, PARs are mainly expressed in endothelial cells, and participate in the regulation of vascular tone, mostly by inducing endothelium-dependent relaxation. PARs in endothelial cells are also suggested to contribute to a proinflammatory phenotypic conversion and an increase in the permeability of vascular lesions. In smooth muscle cells, PARs mediate contraction, migration, proliferation, hypertrophy, and production of the extracellular matrix, thereby contributing to the development of vascular lesions and the pathophysiology of such vascular diseases as atherosclerosis. However, the expression of PARs in the smooth muscle of normal arteries is limited. The upregulation of PARs in the smooth muscle is thus considered to be a key step for PARs to participate in the pathogenesis of vascular lesions. Elucidating the molecular mechanism regulating the PARs expression is therefore important to develop new strategies for the prevention and treatment of vascular diseases. (Arterioscler Thromb Vasc Biol. 2007;27:27-36.)

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Vascular Thrombin Receptor Regulation in Hypertensive Rats

Cited by 41 publications

References 33 publications

CC Chemokine Receptor 2 Is Required for Macrophage Infiltration and Vascular Hypertrophy in Angiotensin II–Induced Hypertension

CC Chemokine Receptor 2 Is Required for Macrophage Infiltration and Vascular Hypertrophy in Angiotensin II–Induced Hypertension

Angiotensin II–Induced Hypertension Accelerates the Development of Atherosclerosis in ApoE-Deficient Mice

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

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