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1Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina; 2Department of Molecular and Cellular Pharmacology, National Research Institute for Child Health and Development, Tokyo; 3Department of Genomic Drug Discovery Science, Kyoto University, Kyoto, Japan; and 4Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania
Submitted 8 February 2005 ; accepted in final form 22 March 2005
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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1-adrenoceptors (ARs) induces proliferation, hypertrophy, and migration of vascular smooth muscle cells and adventitial fibroblasts in cell and organ culture. In vivo studies have confirmed this direct trophic action and found that endogenous catecholamines contribute to neointimal formation and wall hypertrophy induced by mechanical injury. In murine carotid artery, these effects are mediated by 1B-ARs, whereas 1D-ARs mediate contraction and 1A-ARs are not expressed. Herein, we examined whether catecholamines also contribute to arterial wall growth in a noninjury model, i.e., flow-mediated remodeling. In wild-type mice or mice deficient in norepinephrine and epinephrine synthesis [dopamine 
-hydroxylase knockout (DBH-KO)], all distal branches of the left carotid artery (LC) except the thyroid artery were ligated to reduce flow in the LC and increase flow in the right carotid artery (RC). Twenty-one days later, negative hypertrophic remodeling of the LC [i.e., –20% (decrease) in lumen area, –2% in circumference of the external elastic lamina (CEEL), +98% (increase) in thickness of the intima media, and +71% in thickness for adventitia; P < 0.01 vs. sham ligation] and positive eutrophic remodeling of the RC [+23% in lumen area, +11% in CEEL; P < 0.01 vs. sham ligation] were inhibited in DBH-KO mice [LC: +10% intima media and +3% adventitia; RC: +9% lumen area and +3% CEEL]. This inhibition was associated with reduced proliferation in the RC and reduced apoptosis and leukocyte accumulation in the RC and LC when examined 5 days after ligation. Carotid remodeling in 1D-AR-knockout mice evidenced little or no inhibition, which suggests dependence on 1B-ARs. These findings suggest that catecholamine-induced trophic activity contributes to both flow-mediated negative remodeling and adaptive positive arterial remodeling.
dopamine -hydroxylase; carotid; -adrenoceptor; apoptosis; leukocyte accumulation; restenosis
1-adrenoceptor (AR) antagonists reduces these conditions (14, 17–19, 23, 24, 29) as well as neointimal formation after balloon injury (11, 16, 25, 36).
Although these actions may derive in part from the effects of catecholamines to raise and of catecholamine blockade to lower arterial pressure, recent studies demonstrate that NE, like the other G protein-coupled receptor agonists, angiotensin II, and endothelin-1, has direct vascular trophic actions. NE induces proliferation, hypertrophy, and migration of smooth muscle cells (SMCs) and adventitial fibroblasts studied in cell and vessel organ culture, and different 1-AR subtypes mediate these effects (40, 42, 43). For example, although contraction of aorta and carotid artery in rat is mediated by 1D-ARs (8), prolonged NE treatment in organ culture causes proliferation that is strongly augmented after balloon injury and mediated by 1A-ARs in the media and 1B-ARs in the adventitia (42). Likewise, chronic local elevation of NE in rat carotid artery in vivo caused decreases in the lumen area and circumference of the external elastic laminus (EEL; Ref. 9).
Evidence that endogenous catecholamines contribute to vascular growth after injury comes from in vivo studies demonstrating that chronic local increase in wall NE augmented neointimal growth and lumen loss after balloon injury of rat carotid artery (9). Furthermore, 1A-AR blockade inhibited restenosis, whereas antagonists for 1D-, 2-, and -ARs were without effect (9), which is in agreement with studies in organ culture (42). Similarly, chronic intravenous administration of 1A-AR antagonists at concentrations that had no effect on arterial pressure, heart rate, or peripheral vascular resistance caused dose-dependent inhibition of neointimal growth and lumen loss in balloon-injured rat carotid artery (33). These findings have been confirmed using mutant mice devoid of either catecholamine synthesis or individual 1-AR subtypes (44); however, whereas trophic effects of catecholamines were mediated by 1A-ARs in rat carotid artery (9, 33, 42), 1B-ARs mediated these effects in mouse carotid artery (44) that lacks expression of 1A-ARs (27). Recent studies have found that 1-AR-mediated trophic activity in SMCs and adventitial fibroblasts is dependent on stimulation of vascular NAD(P)H oxidase, transactivation of EGF receptors, and activation of mitogen-activated protein kinases (1, 41). Thus trophic 1-AR subtypes activate signaling pathways that overlap in part with other G protein-coupled receptors that stimulate SMC growth.
These findings demonstrate that catecholamines have direct trophic actions that are amplified when growth of vascular wall cells is already activated by injury and repair. However, it is not known whether adrenergic trophic activity also contributes to growth in arteries undergoing adaptive restructuring or in models of growth of vascular wall cells not involving injury. The present study examined this hypothesis during flow-mediated remodeling of carotid artery in mice with germline deletion of the dopamine -hydroxylase gene to render them devoid of catecholamine synthesis. Mice deficient in 1D-ARs were also examined as controls for arterial pressure and possible 1D-AR contribution to growth. Positive outward remodeling of arteries, induced by increased shear stress, is essential for tissue growth during embryonic development through adulthood (22). It also permits structural adaptations of the vasculature in the adult and, within limits, protects against the progression toward lumen narrowing in arterial pathologies such as atherosclerosis, restenosis, and hypertensive wall hypertrophy (3, 35, 39). On the other hand, excessive proliferation of vascular SMCs caused by low or disturbed shear stress is an early initiating disturbance in atheroma formation. Thus understanding how these physiological and pathological types of growth and remodeling are regulated is a topic of significant interest. In the carotid artery model of flow-mediated remodeling, chronic reduction in flow in the left carotid artery causes excessive medial and adventitial proliferation and negative hypertrophic remodeling, while concomitant increased flow in the right carotid artery causes positive eutrophic remodeling (20, 28, 30). Therefore, a trophic response induced by a pathological-like stimulus in the left carotid artery can be simultaneously studied with a physiological stimulus in the right carotid artery that causes an adaptive growth process.
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MATERIALS AND METHODS |
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-hydroxylase-knockout (DBH–/–) mice were 4–5 mo old, 27 ± 1 g (n = 20) and heterozygous (DBH+/–) "control" littermates were 31 ± 1 g (n = 26); and 1D-AR–/– mice were 5–6 mo old, 33 ± 1 g (n = 13) and wild-type (1D-AR+/+) control littermates were 31 ± 1 g (n = 15). DBH–/– and DBH+/– mice for the 5-day study were 4–4.5 mo old and had similar weights as above. Body weights at 5 or 21 days after surgery did not differ from the above values. Approximately equal numbers of males and females were used in all studies. DBH+/– mice have normal levels of plasma and tissue adrenergic catecholamines, whereas in knockout mice these are undetectable (34). Generation of these germline-deletion mutants, which are on the C57BL/6 x 129Sv background, has been described elsewhere (32, 34). Wild-type and knockout mice were studied in at least two litters to exclude the possibility that differences might result from the clustering within one litter of unpredicted genetic differences. Also, separate age-matched, sham-ligation groups were studied for both knockout types to control for differences in genetic background. Procedures were conducted per the Institutional Animal Care and Use Committee of the University of North Carolina at Chapel Hill in accordance with National Institutes of Health guidelines. All analyses were conducted by observers blinded to animal phenotype.
Carotid artery flow model.
Mice were anesthetized with ketamine (100 mg/kg im) and xylazine (15 mg/kg im) and received atropine (54 µg/kg sc) and subsequent antibiotic (50 mg/kg im cephazolin), analgesic (10 mg/kg im pentazocine), and topical nitrofurazolidone after wound closure. Sterile technique and x100 magnification were used to delicately isolate 
0.5-mm lengths of the left external carotid artery distal to the thyroid artery and the left internal carotid/occipital artery pair; this was followed by ligation with 7-0 suture. Tissue was not disturbed proximal to these points. This ligation model, which leaves thyroid artery flow intact, produces a persistent 85% reduction in left carotid artery flow and 75% increase in right carotid artery flow for at least 4 wk (20, 28, 30). The sham procedure consisted of vessel isolation and ligature placement without ligation.
Histology and morphometry. Procedures described below are similar to those used previously (44). At 5 or 21 days after the surgical procedure, the vasculature was fixed by transcardial perfusion at 100 mmHg with 25 ml of phosphate-buffered solution (PBS) followed by 100 ml of 4% paraformaldehyde in PBS. The trachea, left and right carotid arteries, and surrounding tissue were removed en bloc. After postfixation for 24 h in 4% paraformaldehyde in PBS at 4°C, the central 5-mm section was embedded in paraffin. Sections (5 µm) were cut every 300 µm through the central-most 2.5-mm length, and eight sections were mounted to a slide; additional slides were prepared in the same way by serially sectioning at these eight intervals along the vessel. In the 5- and 21-day studies, slides with adjacent serial sections were stained with Masson's trichrome for morphometry and hematoxylin-eosin for cell density and morphology. In the 5-day study, slides of adjacent sections were also subjected to immunohistochemistry for Ki67 (1:25 dilution of clone TEC-3; M7249; DAKO), CD45 (1:200 dilution of clone 30-F11; BD PharMingen), and cleaved caspase-3 (1:200 dilution of clone Asp175; Cell Signaling Technology) according to the manufacturers' instructions, and were visualized with horseradish peroxidase-conjugated secondary antibodies and Vector ABC reagents (Burlingame, VT). Assays were benchmarked against the following mouse tissues as positive controls: normal intestine, intestine from gamma-irradiated mouse, postweaning mammary gland, and spleen, as well as esophagus, trachea, and lymph glands also present on the en bloc carotid sections. Negative controls (no primary antibody or substitution with IgG-isotype control antibody) were performed in each assay.
For morphometry, three sections, each separated by 600 µm, were selected by an observer who was unaware of the treatment groups. Areas were determined as follows (Scion Image software; National Institutes of Health): lumen area = (lumen circumference)2/4
, intima media area = area between the lumen and EEL, circumference = length of EEL, and adventitial area = area of the dense collagen-containing layer between the EEL and loose perivascular connective tissue. Thickness of intima media was calculated as [(circumference of EEL ÷ 2) – (circumference of lumen ÷ 2)]; thickness of adventitia was calculated similarly using the circumference of the EEL and the outer edge of the dense adventitia. Thicknesses were obtained because wall areas change secondary to changes in vessel circumference; thus increased or decreased area may not equate with hypertrophy or atrophy of vessel wall layers.
In the 5-day study, the following parameters were obtained for the intimal (lumenal surface of the intima), medial, and adventitial layers of each animal: for cell density, all cell nuclei in the entire layer of the vessel were counted at x400 magnification in two sections that were separated by at least 300 µm and stained with hematoxylin-eosin; values were then averaged. For proliferation, apoptosis, and leukocyte accumulation, all cells in the entire layer that were immunohistochemically positive for the particular marker were counted at x200 magnification in seven sections, each of which was separated by 300 µm.
Data are means ± SE for n number of vessels (one left and right carotid artery per animal). Unless otherwise indicated, differences were subjected to unpaired t-tests or ANOVA and subsequent Bonferroni correction for multiple comparisons. Significance was set at P < 0.05.
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RESULTS |
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1D-AR–/– mice and their controls, as is described below; Fig. 1). In a previous study (44), we found that these same knockout mice and their wild-type controls also did not form a neointima in response to injury from overdistension and endothelial denudation of the carotid artery. The extent of neointimal formation has been shown to vary widely among different mouse background strains with minimal formation in the strains used herein (see Ref. 44 for references).
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Flow-mediated remodeling in mice devoid of 1D-ARs.
Mouse carotid artery expresses 1D- and 1B-ARs, but 1A-ARs have not been detected (8, 27, 44). In this vessel, 1D-ARs mediate contraction (8), whereas adrenergic trophic effects are mediated by 1B-ARs with a possible small contribution by 1D-ARs (7, 44). Thus mice with targeted deletion of 1D-ARs would be expected to show little or no deficit in flow-mediated remodeling. To test this hypothesis, 1D-AR-deficient and wild-type mice were examined. Lumen loss and hypertrophy of adventitia in left carotid artery 3 wk after ligation were similar in both groups (Fig. 4). Hypertrophy of intima media in 1D-AR–/– mice was less than in control animals (Fig. 4), although it still more than doubled in thickness as it did in the DBH wild-type mice (see Fig. 3). In right carotid artery, increases in lumen area and circumference of the EEL were not inhibited in 1D-AR–/– mice (Fig. 4). Baseline vessel dimensions in the sham surgery groups did not differ between control and knockout mice (Fig. 4, open bars) and are similar to values reported previously for these mice at the same age (44). An anomalous decrease in adventitial thickness in right carotid artery occurred in control animals after ligation (Fig. 4). Like the decrease in adventitial thickness that also occurred in right carotid artery after ligation in DBH–/– mice (see Fig. 3), we do not know whether these data reflect the greater variability in measuring adventitial thickness; the data analysis in this study was conducted "blinded," and no values were excluded as outliers. Sex-related differences were not evident in sham or ligated groups in the DBH and 1D-AR experiments.
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Proliferation values were determined for intima (i.e., cells touching the lumen), media, and adventitia of left and right carotid arteries 5 days after surgery. Intima values are for endothelial cells, because they are easily distinguished from adherent leukocytes by their small, flat nuclei, and because adherent leukocytes do not proliferate until after diapedesis. In the absence of double labeling for proliferation and markers for SMCs, fibroblasts, and leukocytes, it is not possible to know the cell identity of Ki67-positive nuclei based on morphology, because positive nuclei in 5-µm sections are often not sectioned at midpoint. However, because CD45-positive cells are rare in the media at the time examined (see Fig. 3), most of proliferating medial cells are thus SMCs. Proliferation was significantly inhibited only in the right carotid adventitia of DBH–/– mice. In these same mice, CD45-positive cells were reduced in the adventitia of left carotid artery and almost reached significant reduction in right carotid artery (Fig. 5). Thus it is possible that lower numbers of proliferating cells in the adventitia of DBH–/– mice reflect reduction in both adventitial fibroblasts and CD45-positive cells. Nevertheless, the large inhibition of medial and adventitial growth in DBH–/– mice at 21 days after surgery (see Fig. 3) in the context of similar cell densities and no stimulation of apoptosis in DBH–/– mice examined at day 5 (see Fig. 5) suggests that significant reduction of SMC and adventitial fibroblast proliferation over the time course examined underlies the strong inhibitory effect of catecholamine absence on inward hypertrophic remodeling in DBH–/– mice.
There were no differences in morphometric measures for left or right carotid arteries between control and DBH–/– mice examined 5 days after surgery (data not shown); this is consistent with the data in Fig. 2, which demonstrate that remodeling requires >5 days to become evident. Perfusion fixation at 100 mmHg, which is commonly used by others, was used because it is close to values reported for resting awake mice of various strains including C57BL/6 mice (e.g., Ref. 31), and because we wanted to use a uniform pressure. Although mean arterial pressure is 14% lower in DBH–/– (31) and 8% lower in 1D-AR–/– mice (32) than in their wild-type controls, this difference between the two genetic strains is small. Moreover, in the present study, lumen diameter and circumference of left and right carotid arteries in both knockout mouse groups after sham surgery were not significantly different from their wild-type controls (see Figs. 3 and 4). Thus perfusion fixation at a slightly higher pressure did not cause dilation of the carotid artery.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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1D-ARs. This suggests that flow was reduced by similar amounts in the two genotypes and that adrenergic trophic mechanisms do not influence adaptive changes in lumen diameter to reduced flow. However, hypertrophy of the intima media and adventitia was sharply reduced in DBH–/– mice, whereas 1D-AR–/– mice evidenced a much smaller inhibition in growth of intima media and no inhibition in adventitial hypertrophy. Positive outward remodeling of right carotid lumen area and circumference in response to increased flow were reduced by 54 and 71% in mice lacking catecholamine synthesis and were no longer significant. In contrast, outward remodeling was fully preserved in 1D-AR–/– mice. Although the small degree of outward remodeling characteristic of the carotid artery (20, 28, 30) together with the baseline differences and statistical variance we encountered reduce the veracity of our conclusions regarding outward remodeling in DBH–/– mice (Fig. 3), similar baseline differences were also obtained with 1D-AR–/– mice (see Fig. 4). Inhibition of remodeling in DBH–/– mice was associated with reduced leukocyte accumulation, proliferation, and apoptosis in one or more of the vessel layers of left and right carotid arteries. This inhibition of flow-mediated remodeling is most likely due to the absence of trophic actions of catecholamines and other growth and remodeling mechanisms that interact with them. The minimal effect on remodeling of right or left carotid artery in 1D-AR–/– mice but strong inhibition in DBH–/– mice together with the absence of expression of 1A-ARs in mouse carotid artery (27) suggest that these trophic effects of catecholamines may be mediated primarily by 1B-ARs. These results are consistent with previous evidence that NE signals contraction through 1D-ARs and growth through 1B-ARs in this vessel (8, 27, 44). The present findings agree with other studies of carotid artery in rat and mouse and of aorta in rat, which found that catecholamines exert trophic actions on cells of the media and adventitia that are strongly augmented by injury (7, 33, 42, 44). The present results extend this concept of augmented catecholamine growth-promoting actions to include not only injury-induced remodeling but also hypertrophic negative remodeling in response to reduced shear stress. This model has features in common with the intimal proliferation that occurs in regions of arteries with low and/or disturbed shear stress that characterizes the early stage of atheroma formation. Such growth factor-like activity of catecholamines, possibly through augmented leukocyte accumulation and proliferation and migration of SMCs (processes that are already activated at sites of early lesion formation), may underlie previous reports that plasma catecholamine levels associate with progression or worsening of atherosclerosis (14, 19, 23, 24, 29). Our results also extend adrenergic trophic activity to physiological (adaptive) positive remodeling in response to maintained high shear stress. This finding is similar to a previous study (13) showing that flow-mediated positive remodeling of small canine mesenteric arteries was prevented by surgical denervation of the perivascular sympathetic nerves at a location remote from the site of positive remodeling. Thus with remodeling inhibited, shear stress remained increased to a similar extent at all time points examined during 8 wk after ligation.
The 1D-AR-knockout mice were studied to gain insight into the responsible 1-AR subtype and also as a control for the possibility that reduced arterial pressure in DBH–/– mice might account for the observed inhibition of remodeling. In conscious, unrestrained mice, arterial pressure is lower by a similar amount (8% in 1D-AR–/– and 14% in DBH–/– mice; Refs. 31, 32) and is unaffected in 1B-AR–/– mice (5, 7, 15b, 37). This is consistent with evidence that 1D-ARs (and 1A-ARs in certain beds) but not 1B-ARs mediate adrenergic contribution to normal vascular resistance in mice (5, 15b, 32, 37). If lower arterial pressure in DBH–/– mice were responsible for the inhibition of flow-mediated remodeling observed herein, a similar inhibition should have occurred in the 1D-AR–/– mice. However, in contrast with the strong inhibition in DBH–/– mice, remodeling of both carotid arteries was unaffected in 1D-AR–/– mice with the exception of a partial reduction of intimal medial thickening in the left carotid artery (see Fig. 4). Nevertheless, because of this partial inhibition, it is not possible for us to rule out a contribution of reduced arterial pressure to the observed inhibition of intima media hypertrophy in the left carotid artery. It is not likely that this partial inhibition of intima media thickening in the 1D-AR–/– mice is due to a greater reduction in flow and shear stress in the left carotid artery caused by lower arterial pressure in the DBH–/– group, because lower arterial pressure and thus shear stress would favor increased leukocyte adhesion and negative remodeling to restore tangential wall stress and shear stress toward normal rather than the reduced leukocyte accumulation and remodeling that were observed. Instead, the partial reduction in intima media thickening in left carotid artery of 1D-AR–/– mice may reflect the reduced pressure itself on proliferation of SMCs. This conclusion is supported by other evidence that 1D-ARs do not signal direct trophic effects in rat and mouse aorta or carotid artery (9, 33, 42, 44) or activation of mitogen-activated protein kinase pathways in cultured cells (12, 38).
Our findings are consistent with previous studies indicating that the 1B-AR subtype mediates the trophic activity of catecholamines in mouse carotid artery. The vessel expresses both 1B- and 1D-ARs, whereas expression of the third 1-AR receptor, the 1A-AR, has not been detected (8, 27, 44). We previously found that the 1B-AR mediates virtually all of the contribution of endogenous catecholamines to medial and adventitial hypertrophy and positive remodeling of mouse carotid artery after injury caused by angioplasty-like overdistension and endothelial damage (44). In that study, hypertrophy and remodeling were inhibited to similar degrees in both DBH–/– and 1B-AR–/– mice, whereas virtually no inhibition was observed in 1D-AR–/– mice. Moreover, as in the present study, carotid arteries of DBH–/– mice examined 5 days after injury had reduced proliferation and leukocyte accumulation (44). Vecchione et al. (37) also reported evidence that 1B-ARs mediate catecholamine trophic actions. Chronic increase in plasma phenylephrine to levels without detectable effects on arterial pressure caused medial thickening in murine arteries that was inhibited in 1B-AR–/– mice. The 2- and -ARs do not contribute to catecholamine trophic effects in the carotid artery or aorta of rat (9, 42), although this has not yet been confirmed for mice.
The factors involved in flow-mediated negative and positive remodeling are complex and only partly understood (reviewed in Refs. 21, 22, 26) in part because of the difficulty in investigating cellular mechanisms in vivo. It is clear from both in vivo and in vitro studies that activation of endothelial cells and expression of adhesion molecules are key early responses to a sustained decrease or increase in shear stress, which results in leukocyte recruitment to the vascular wall. Growth factors (e.g., FGF-2, PDGF, and heparin-binding EGF), cytokines, and autacoids (e.g., nitric oxide and reactive oxygen species) released by activated endothelial cells, recruited macrophages, neutrophils, and T lymphocytes, as well as SMCs and fibroblasts responding to these factors, direct the ensuing matrix changes, proliferation, apoptosis, cell reorientation, and migration of vascular wall cells that are required for remodeling. In the present study, leukocyte accumulation, proliferation, and apoptosis increased many fold in the eutrophically remodeling right carotid and to an even greater extent in the hypertrophically remodeling left carotid artery of control mice examined 5 days after ligation. DBH–/– mice had reduced leukocyte accumulation in adventitia of left carotid artery and in intima of right carotid artery, reduced proliferation in adventitia of right carotid artery, and reduced apoptosis in media and adventitia of both vessels. Although little is known about how trophic 1-ARs amplify these events during remodeling, stimulation of 1-ARs induces protein synthesis, proliferation, apoptosis, migration, and matrix changes in SMCs and adventitial fibroblasts studied in cell culture, organ culture, and in vivo (1, 9, 33, 40, 41–44). Moreover, these same events are recruited during repair after arterial injury, and as observed in flow remodeling in the present study, inhibition of catecholamine production reduced proliferation, apoptosis, and leukocyte accumulation in association with reduced neointimal formation and lumen loss (44).
The proliferative and hypertrophic effects of 1-AR stimulation are mediated in SMCs both in cell culture and in the intact artery wall by a signaling pathway that includes, sequentially, the following: stimulation of vascular NAD(P)H oxidase, formation of reactive oxygen species, shedding of heparin-binding EGF, transactivation of EGF receptors, and activation of mitogen-activated protein kinases (1, 41). Many of the growth factors and cytokines that are released by activated leukocytes and vascular wall cells have been implicated in arterial growth and remodeling signal through pathways employing one or more of these same autocrine/paracrine and intracellular effectors. Thus it is possible that stimulation of trophic 1-ARs synergizes with or amplifies signaling by one or more of the factors and pathways involved. It is not known whether this occurs at normal NE levels in the arterial wall or only at increased levels. Interestingly, NE content increases in the arterial wall during neointimal formation and repair after balloon injury (4) possibly by injury-induced neurite outgrowth and enhanced NE release (2, 6). Whether this occurs during flow remodeling has not been examined. It is known that at least during wall hypertrophy after balloon injury, expression of 1-ARs is not increased (10). It will be important in future studies to determine how the trophic signals occurring during flow-mediated remodeling augment the growth-promoting effects of catecholamines or vice versa.
Our previous evidence that 1-AR stimulation by endogenous wall NE worsens the hypertrophic response to injury and that the trophic effect of NE becomes strongly amplified during injury suggests that catecholamines cause growth responses during repair and remodeling to become excessive (9, 33, 42). This is consistent with a recent study demonstrating that wall thickening during positive remodeling induced by injury was in excess of that required to return wall stress of the dilated artery to normal (44). The observation in the present study that lumen narrowing in left carotid artery proceeded unaffected in the absence of catecholamines (see Fig. 3) suggests that catecholamines may promote a period of excessive wall thickening during negative remodeling (see Figs. 1 and 2). This could prolong or prevent reduction of wall thickness to a value appropriate for rebalancing tangential wall stress after negative remodeling. According to this hypothesis, inhibition of catecholamine activity in DBH–/– mice lessened the magnitude of wall hypertrophy and/or permitted it to occur and resolve earlier during negative remodeling, which resulted in the results obtained for left carotid artery shown in Fig. 3.
Positive remodeling reduces lumen loss during atheroma development (3, 39). However, evidence suggests that positive remodeling may also indicate worsening inflammation in the vascular wall that possibly leads to plaque instability (35). In addition, reduced or disturbed shear stress is known to cause endothelial dysfunction, promote intimal hyperplasia, and favor formation of fatty streaks, i.e., events comprising the earliest stages of atheroma formation. Thus it is important to understand the mechanisms that regulate positive and negative remodeling. The present results suggest that trophic effects of catecholamines contribute to arterial remodeling.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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1b-adrenergic receptor. Proc Natl Acad Sci USA 94: 11589–11594, 1997.1B-adrenoceptors in mouse. Physiol Genomics 9: 85–91, 2002.1- and 2-adrenoceptors. Eur J Pharmacol 361: 1–15, 1998.[CrossRef][Web of Science][Medline]
1-Adrenoceptor stimulation directly induces growth of the injured vascular wall in vivo. Am J Physiol Heart Circ Physiol 283: H1577–H1587, 2002.-adrenoceptor subtype expression in neointima, media and adventitia (Abstract). FASEB J 13: A515, 1999.
1-Receptor antagonists urapidil and prazosin inhibit neointimal formation in rat carotid artery induced by balloon catheter injury. Basic Res Cardiol 86, Suppl 1: 75–81, 1991.
1-adrenergic receptor-induced contraction and extracellular signal-regulated kinase activation in the bovine inferior alveolar artery. J Pharmacol Exp Ther 303: 403–411, 2002.1-adrenoceptor subtypes regulating the vasopressor response have differential roles in blood pressure regulation. Mol Pharmacol 67: 912–922, 2005.1-adrenoceptor blockade on the development of hypertension in the spontaneously hypertensive rat. Eur J Pharmacol 211: 263–268, 1992.[CrossRef][Web of Science][Medline]
1-Adrenergic plus angiotensin receptor blockade reduces atherosclerosis in apolipoprotein E-deficient mice. Hypertension 32: 1044–1048, 1998.1A/C-adrenergic receptor subtype: the 1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure. Proc Natl Acad Sci USA 99: 9474–9479, 2002.1D-Adrenergic receptor directly regulates arterial blood pressure via vasoconstriction. J Clin Invest 109: 765–775, 2002.[CrossRef][Web of Science][Medline]
1A-adrenoceptor antagonist inhibits neointimal growth after balloon injury of rat carotid artery. Am J Physiol Heart Circ Physiol 284: H385–H392, 2003.-hydroxylase. J Neurochem 70: 2468–2476, 1998.[Web of Science][Medline]
1-adrenergic antagonist doxazosin. Br J Surg 79: 1285–1288, 1992.[Web of Science][Medline]
1b-adrenergic receptor defect in mice. Circulation 105: 1700–1707, 2002.1D-Adrenergic receptors and mitogen-activated protein kinase mediate increased protein synthesis by arterial smooth muscle. Mol Pharmacol 51: 764–775, 1997.1-adrenoceptor subtypes. Circ Res 89: 815–822, 2001.-adrenoceptors mediate migration of vascular smooth muscle cells and adventitial fibroblasts in vitro. Am J Physiol Heart Circ Physiol 282: H2364–H2370, 2002.-hydroxylase and 1-adrenoceptors demonstrates involvement of catecholamines in vascular remodeling. Am J Physiol Heart Circ Physiol 287: H2106–H2114, 2004.This article has been cited by other articles:
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 E. Ruiz, A. Gordillo-Moscoso, E. Padilla, S. Redondo, E. Rodriguez, F. Reguillo, A. M. Briones, C. van Breemen, E. Okon, and T. Tejerina Human vascular smooth muscle cells from diabetic patients are resistant to induced apoptosis due to high bcl-2 expression. Diabetes, May 1, 2006; 55(5): 1243 - 1251. [Abstract] [Full Text] [PDF]
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C.-F. Lam, T. E. Peterson, A. J. Croatt, K. A. Nath, and Z. S. Katusic Functional adaptation and remodeling of pulmonary artery in flow-induced pulmonary hypertension Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2334 - H2341. [Abstract] [Full Text] [PDF]
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D. Chalothorn, H. Zhang, J. A. Clayton, S. A. Thomas, and J. E. Faber Catecholamines augment collateral vessel growth and angiogenesis in hindlimb ischemia Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H947 - H959. [Abstract] [Full Text] [PDF]
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