(Hypertension. 2000;36:360.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
CC Chemokine Receptor 2 Is Required for Macrophage Infiltration and Vascular Hypertrophy in Angiotensin II–Induced Hypertension
From the Department of Medicine (W.R.T.), Cardiology Division, Atlanta VA Medical Center, and Emory University School of Medicine (E.B., J.N.W., H.D., M.H., W.R.T.), Atlanta, Ga; and Department of Pathology (N.M., W.A.K., T.C.D.), University of North Carolina, Chapel Hill, NC.
Correspondence to W. Robert Taylor, MD, PhD, Cardiology Division, Emory University School of Medicine, 1639 Pierce Dr, Suite WMB 319, Atlanta, GA 30322. E-mail wtaylor{at}emory.edu
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Abstract |
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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 · kg-1 · d-1) 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
65% 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.
Key Words: proteins • angiotensin II • hypertrophy • macrophages
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Introduction |
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It 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 7 8 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 further insights into the potential contributions of monocytic inflammatory responses to hypertensive vascular changes in angiotensin II–induced hypertension, we made use of mice deficient in the CC chemokine receptor 2 (CCR2).10 The only known agonist for this receptor is MCP-1. This model provides the opportunity to determine the functional importance of angiotensin II–induced macrophage recruitment into the arterial wall. We hypothesized that when angiotensin II–mediated hypertension is induced in CCR2-deficient mice, there would be a marked reduction in macrophage accumulation in the arterial wall as well as a decrease in vascular hypertrophy.
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Methods |
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Animals
Mice deficient in CCR2 were generated as described previously.10 The animals were the progeny of breeder pairs that had been back crossed into the C57BL/6 line for 8 generations to ensure genetic homogeneity. All animals used in the present study were male progeny derived from homozygous breeding pairs. Animals were used at 4 to 8 weeks of age. C57BL/6 wild-type animals were used as control animals and were age and sex matched for all experiments. Six animals were included in each experimental group.
Angiotensin II Model of Hypertension
Hypertension was induced through the use of continuous
angiotensin II infusion delivered via an osmotic minipump
(Alzet) as previously described.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
· kg-1 · d-1
were placed in the subcutaneous space over the abdomen. Blood pressures
were measured with a computerized, noninvasive tail-cuff system (BP
2000; Visitech Systems).12
Microscopic Analysis
Animals were killed with CO2 inhalation.
The thorax was opened, a 21-gauge needle was placed into the left
ventricle, and the inferior vena cava was severed. The
animals were then perfused with normal saline at 100 mm Hg until
the perfusate was clear. The entire animal was pressure fixed
at 100 mm Hg with 4% formalin, and the aorta was removed en bloc
and embedded in paraffin. Individual sections were made of the proximal
third of the descending thoracic aorta.
For morphometric analysis of vascular hypertrophy, sections were stained with hematoxylin and eosin. Three serial sections from the proximal descending thoracic aorta of each animal were photographed and stored in a digital format. Arterial wall thickness was then measured in a blinded fashion with NIH Image software.
To identify macrophages in an accurate and specific manner, in situ hybridizations for c-fms, the monocyte colony-stimulating factor receptor, were carried out as described previously.13 The number of macrophages in the intima, media, and adventitia were counted in a blinded fashion. A cell was counted as a macrophage if it was mononuclear in appearance and there were at least 4 silver grains localized over that cell.
Statistical Analysis
All results are expressed as mean±SEM. Comparisons between
groups were made with a Student’s t test.
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Results |
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Angiotensin II treatment resulted in a uniform increase in systolic blood pressure of treated animals; the mean blood pressures are shown in the Table. Previous studies from our laboratory have demonstrated that 7 days of angiotensin II infusion results in a maximal blood pressure response.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 (20±8% versus 33±13% increase, P=0.38).
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In situ hybridization for c-fms, which encodes the monocyte colony-stimulating factor receptor, was used to identify vascular macrophages in a specific and sensitive manner that would allow for the quantification and localization of the site of infiltration. Essentially no macrophages were seen in the aortic wall of wild-type animals under control conditions. In contrast, when wild-type animals were made hypertensive with angiotensin II infusions, macrophages were readily identified throughout the arterial wall (Figures 1A and 1B). In the wild-type animals treated with angiotensin II, the majority of c-fms–positive cells were seen in the adventitia. Mean data that document this distribution are presented in Figure 2.
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In the CCR2-deficient animals, there was a marked decrease in the accumulation of macrophages in animals treated with angiotensin II. A representative example of an aortic cross section is shown in Figure 1C, and mean data are shown in Figure 2. Compared with wild-type animals, angiotensin II–induced macrophage infiltration was reduced by >90% in CCR2-deficient animals.
To assess the role of macrophage infiltration in vascular hypertrophy, the thickness of the proximal descending aorta was measured in wild-type and CCR2-deficient animals under control conditions and after the development of angiotensin II–induced hypertension. Representative histological sections stained with hematoxylin and eosin for morphometric analysis are shown in Figure 3. There is marked vascular hypertrophy in the wild-type animals. In contrast, the CCR2-deficient mice exhibited a highly significant reduction in hypertrophy. Mean data are summarized in Figure 4.
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Discussion |
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The study data demonstrate that in an angiotensin II model of experimental hypertension, the CCR2 receptor is necessary for the accumulation of macrophages and the subsequent development of vascular hypertrophy. We have previously shown that MCP-1 expression is upregulated in the aortic tissues of hypertensive animals.4 Currently, the only identified ligand for the CCR2 receptor is MCP-1. Thus, the present study demonstrates the potential functional importance of MCP-1 as a chemoattractant for macrophages in vivo. In animals that lack CCR2, the recruitment of macrophages into the arterial wall of hypertensive animals was almost completely eliminated. Furthermore, we demonstrated that in these animals, vascular hypertrophy was markedly reduced. Taken together, these findings demonstrate the presence of CCR2 is an absolute requirement for macrophage infiltration and subsequent vascular hypertrophy in an angiotensin II model of hypertension. They also raise the possibility that MCP-1 is the critical chemoattractant for macrophages in angiotensin II–induced hypertension.
The mechanisms responsible for the upregulation of MCP-1 expression in experimental hypertension are likely complex and involve several different signaling pathways.14 15 Angiotensin II has been directly implicated in the expression of MCP-1 in vascular cells.16 In addition, mechanical strain directly induces the expression of MCP-1 in cultured vascular cells.4 15 17 Thus, it is possible that both mechanical and humoral factors may be important in the regulation of MCP-1 in vivo.18 Studies performed by Ollenserhaw et al19 have shown that in an aortic coarctation model of hypertension (which is characterized by activation of the renin-angiotensin system), vascular hypertrophy occurs above the level of the coarctation (where wall strain is increased) but not below the level of the coarctation despite the fact the 2 regions are in the same humoral milieu. Similarly, we have shown that MCP-1 expression is upregulated in both an angiotensin II model and a norepinephrine model of hypertension.4 It appears that even though both angiotensin II and wall strain may result in the upregulation of MCP-1 expression in vivo, the mechanoregulation of MCP-1 may be of greater importance under these experimental conditions.18
The finding that macrophage recruitment represents a necessary requirement for the development of vascular hypertrophy provides strong support for the hypothesis that the vascular pathology of angiotensin II–induced hypertension, like atherosclerosis, occurs in part as the result of the development of an inflammatory state in the vascular wall.1 20 21 22 23 This hypothesis is also supported by the earlier observations that inflammatory cells are present in the arterial wall of hypertensive animals,3 4 5 as well as more recent observations that reactive oxygen species play a critical role in the hypertensive response.24 Perhaps more important, the commonality of disease mechanisms of hypertension and atherosclerosis suggests a potential mechanism by which hypertension can accelerate the development of atherosclerosis. This is further supported by the recent observations that in 2 different murine models of atherosclerosis, MCP-1 is essential to the development of atherosclerotic lesions.25 26
It is important to point out that the overall process of macrophage infiltration of the arterial wall is only part of a much larger process. Monocyte infiltration of the arterial wall is a complex process and involves several sequential steps, including chemotaxis, adhesion, infiltration, sustenance, and possibly proliferation. In additional, there are likely additional mediators of each step of this process (eg, adhesion molecules). Therefore, although a CCR2 agonist may be necessary for macrophage recruitment, it is likely that it is only 1 component of a far more complex process.
In summary, we used a CCR2-deficient animal model to demonstrate the critical contribution of macrophage recruitment to vascular hypertrophy in angiotensin II–induced hypertension. These results also raise the possibility that CCR2-mediated chemotaxis may be 1 mechanism whereby hypertension contributes to the development of atherosclerosis.
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Acknowledgments |
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This work was supported by grants from the Veterans Administration and the National Institutes of Health (grants HL-58000 and HL-62820).
Received March 8, 2000; first decision March 27, 2000; accepted April 3, 2000.
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References |
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