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Am J Physiol Heart Circ Physiol 287: H2106-H2114, 2004. First published July 1, 2004; doi:10.1152/ajpheart.00290.2004
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Gene deletion of dopamine {beta}-hydroxylase and {alpha}1-adrenoceptors demonstrates involvement of catecholamines in vascular remodeling

Hua Zhang,1 Susanna Cotecchia,2 Steven A. Thomas,3 Akito Tanoue,4 Gozoh Tsujimoto,4 and James E. Faber1

1Department of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599-7545; 2Institut de Pharmacologie et Toxicologie, Université de Lausanne, CH-1005 Lausanne, Switzerland; 3Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104; and 4Department of Molecular and Cellular Pharmacology, National Children's Medical Research Center, Tokyo 606-8501, Japan

Submitted 25 March 2004 ; accepted in final form 25 June 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
In vitro studies have shown that stimulation of {alpha}1-adrenoceptors (ARs) directly induces proliferation, hypertrophy, and migration of arterial smooth muscle cells and adventitial fibroblasts. In vivo studies confirmed these findings and showed that catecholamine trophic activity becomes excessive after experimental balloon injury and contributes to neointimal growth, adventitial thickening, and lumen loss. However, past studies have been limited by selectivity of pharmacological agents. The aim of this study, in which mice devoid of norepinephrine and epinephrine synthesis [dopamine {beta}-hydroxylase (DBH–/–)] or deficient in {alpha}1-AR subtypes expressed in murine carotid ({alpha}1B-AR–/– and {alpha}1D-AR–/–) were used, was to test the hypothesis that catecholamines contribute to wall hypertrophy after injury. At 3 wk after injury of wild-type mice, lumen area and carotid circumference increased significantly, and hypertrophy of media and adventitia was in excess of that needed to restore circumferential wall stress to normal. In DBH–/– and {alpha}1B-AR–/– mice, increases in lumen area, circumference, and hypertrophy of the media and adventitia were reduced by 50–91%, resulting in restoration of wall tension to nearly normal (DBH–/–) or normal ({alpha}1B-AR–/–). In contrast, in {alpha}1D-AR–/– mice, increases in lumen area, circumference, and wall hypertrophy were unaffected and wall thickening remained in excess of that required to return tension to normal. When examined 5 days after injury, proliferation and leukocyte infiltration were inhibited in DBH–/– mice. These studies suggest that the trophic effects of catecholamines are mediated primarily by {alpha}1B-ARs in mouse carotid and contribute to hypertrophic growth after vascular injury.

adrenergic receptors; knockout; smooth muscle; adventitia; growth; injury

ELEVATED SYMPATHETIC NERVOUS system activity and plasma catecholamines have traditionally been regarded as risk factors for vascular disease (18). For example, progressive elevation of plasma norepinephrine (NE) with aging is positively correlated with hypertension, wall hypertrophy, severity of arteriosclerosis, and heart failure (9, 17, 18, 23). Chronic NE infusion induces wall hypertrophy and initiates or worsens atherosclerosis, whereas non-subtype-specific {alpha}1-adrenoceptor (AR) antagonists lessen these conditions (9, 17, 21–23, 26, 30). {alpha}1-AR antagonists also reduce neointimal formation in animal studies (15, 20, 31, 40). It has been unclear whether these effects derive from a direct trophic action of catecholamines or are secondary to alterations in arterial pressure and wall tension, because increased arterial pressure is assumed to directly promote vascular wall hypertrophy and is a primary risk factor for vascular disease.

Recent studies, however, demonstrate that NE has direct trophic actions on smooth muscle cells (SMCs) and adventitial fibroblasts (AFBs). In cell culture, NE induces proliferation, hypertrophy, and migration of SMCs and AFBs, and different AR subtypes contribute to these processes (10, 14, 46, 48). Direct trophic actions of NE have also been reported in the intact rat aorta and carotid artery in vitro and in vivo (12, 47). Contraction of these arteries is mediated almost entirely by {alpha}1D-ARs (8, 9). However, medial SMCs of rat aorta and carotid also express {alpha}1A-AR and {alpha}1B-AR, and, surprisingly, AFBs in these vessels express all three {alpha}1-AR subtypes (14). Treatment of rat aorta with NE in organ culture caused proliferation that was strongly augmented after balloon injury and appeared, on the basis of pharmacological antagonists, to be mediated by {alpha}1A-ARs in the media and {alpha}1B-ARs in the adventitia (47). Similarly, chronic in vivo perivascular suffusion of NE worsened neointimal growth, collagen deposition, and lumen loss after balloon injury of rat carotid artery (12). Moreover, chronic suffusion of an {alpha}1A-AR antagonist inhibited restenosis, whereas antagonists for {alpha}1D-, {alpha}2-, and {beta}-ARs (which are also present in carotid media and adventitia) were without effect (12). This is in agreement with lack of contribution of {alpha}2- and {beta}-ARs to NE-mediated hypertrophy and proliferation of SMCs and AFBs in aorta organ culture (47) or SMC culture (46). Consistent with these studies, chronic intravenous administration of an {alpha}1A-AR antagonist, which had no hemodynamic effects, caused dose-dependent inhibition of neointimal growth and lumen loss in the balloon-injured rat carotid artery (37). Recently, it was reported that {alpha}1-AR-mediated trophic activity in SMCs in cell and organ culture is dependent on stimulation of the vascular NAD(P)H oxidase, followed by transactivation of epidermal growth factor receptors and subsequent stimulation of p42/44 MAPKs (2).

These findings suggest that catecholamines may constitute direct risk factors for worsening vascular hypertrophy and intimal lesion formation. However, this hypothesis requires examination via nonpharmacological methods to address limitations posed by specificity of {alpha}1-AR antagonists. It is also important to examine species other than the rat and to use different models of injury and disease to ascertain the generality of vascular adrenergic trophic action. In the present study, we examined a carotid injury model (33) that induces hypertrophic outward (i.e., positive) remodeling in normal mice or mice genetically deficient in NE and epinephrine synthesis [dopamine {beta}-hydroxylase (DBH) "knockout" (KO) mice] (38) or in the two {alpha}1-AR subtypes expressed (6, 32) in the murine carotid artery ({alpha}1B- and {alpha}1D-AR KO mice).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Genetic strains. Three strains of mice with approximately equal numbers of males and females were used (except {alpha}1B-AR KO and wild types, which were all male). Age and body weight at the beginning versus the end of the 3-wk study were as follows: 4–5 mo old and 28 ± 1 vs. 27 ± 1 g for DBH–/– mice (n = 8) and 31 ± 2 vs. 29 ± 1 g for heterozygote ("control") DBH+/– littermates (n = 12), which have normal levels of plasma and tissue catecholamines (38); 6–7 mo old and 36 ± 1 vs. 34 ± 1 g for {alpha}1B-AR–/– mice (n = 6) and 38 ± 2 vs. 36 ± 2 g for wild-type (control) {alpha}1B-AR+/+ littermates (n = 5); 5–6 mo old and 31 ± 1 vs. 31 ± 1 g for {alpha}1D-AR–/– mice (n = 9) and 32 ± 1 vs. 28 ± 1 g for wild-type (control) {alpha}1D-AR+/+ littermates (n = 10). DBH–/– and DBH+/– mice for the 5-day study were 4 to 4.5 mo old with body weights similar to those reported above. The generation of these strains is described elsewhere (6, 36, 38). Briefly, control and KO mice were constructed on the 129Sv and C57BL/6 genetic background. DBH mice were congenics crossed for >50 generations. For the {alpha}1B- and {alpha}1D-AR strains, mice from different litters were randomly intercrossed beyond the F4 generation within the same strain to obtain the control and KO mice. Control mice were derived from the initial intercrosses between the heterozygotes and bred in parallel with the KO progeny. Control and KO mice for each of the three genetic targets were from at least two litters to exclude the possibility that differences might result from the clustering within one litter of other genetic changes different from the targeted deletion. To control for differences in genetic background among the three KO models, separate sham-injury groups were studied for all three strains. Procedures were conducted according to the Animal Care and Use Committee of the University of North Carolina at Chapel Hill in accordance with National Institutes of Health guidelines.

Carotid injury model. Mice were anesthetized with ketamine (100 mg/kg im) and xylazine (15 mg/kg im) and received atropine (54 µg/kg sc) and antibiotic (cephazolin, 50 mg/kg im). Care was taken to avoid tissue and nerve damage. The omohyoideus muscle overlying the common carotid artery was not disturbed, and the artery was not exposed. Instead, with use of sterile technique, microforceps, and x100 magnification, dissection was limited to exposure of the left external carotid artery just proximal to the lingual artery to permit ligation with 7-0 suture. No tissue dissection was done below the bifurcation of the occipital artery, except for exposure of the ventral surface of the left common carotid artery for a distance of 1 mm posterior to the omohyoideus. An atraumatic vascular microclip was placed on the common carotid at this point and on 1-mm exposures of the internal carotid and occipital arteries. A 30-gauge stainless steel cannula was advanced into an external carotid arteriotomy. The common carotid segment was perfused with PBS to remove blood. The cannula was then sealed against the external carotid with a ligature, and pressure (2.5 atm; Indeflator) was applied to the carotid segment for 30 s. After deflation, a 30-gauge needle hole was made in the ventral common carotid wall caudal to the omohyoideus. The vessel was covered with PBS, and 60 ml of air were perfused through the segment with a syringe pump for 3 min to cause drying and subsequent denudation of endothelial cells (33). After removal of the vascular clips, blood flow was restored and the needle hole was gently clotted with a cotton-tipped applicator. Heparin was administered (63 U/kg im and 113 U/kg sc), the wound was closed and treated with nitrofurazone, and pentazocine (10 mg/kg im) was given for analgesia.

Histology and morphometry. After 5 or 21 days, the vasculature was perfusion fixed at 100 mmHg with 25 ml of PBS and then with 100 ml of 4% paraformaldehyde in PBS. The trachea, left and right carotids, and surrounding tissue were removed en bloc. After fixation 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 centralmost 2.5-mm length and mounted eight sections to a slide; additional slides were prepared in the same way by serial sectioning at these eight intervals along the vessel. In the 21-day study, two slides with adjacent (serial) sections were stained with Masson's trichrome (morphometry) and hematoxylin-eosin (cell density and morphology). In the 5-day study, five slides with adjacent sections were stained with cyano-Masson's-elastin (morphometry) and hematoxylin-eosin (cell density and morphology) or subjected to immunohistochemistry for Ki67 (clone TEC-3, Dako), CD45 (clone 30-F11, BD-PharMingen), and cleaved caspase-3 (clone Asp175, Cell Signaling Technology) according to the manufacturers' instructions. Assays were benchmarked against the following mouse tissues as positive controls: normal intestine, intestine from {gamma}-irradiated mouse, postweaning mammary gland, and spleen. Negative controls (no primary antibody or substitution with IgG isotype control antibody) were run in each assay.

For morphometry, three sections that were separated almost equally over the 2.5-mm vessel length were selected by an observer blind to the treatment groups. Areas were determined as follows (with Scion Image software, NIH): lumen area [(lumen circumference)2/4{pi}], intima-media area [area between lumen and external elastic laminus (EEL)], circumference (length of EEL), and adventitia area (area of dense collagen-containing layer between EEL and loose perivascular connective tissue). Thickness of the intima-media was calculated as follows: (circumference of EEL ÷ 2{pi}) – (circumference of lumen ÷ 2{pi}); thickness of the adventitia was calculated similarly using circumferences of EEL and the outer edge of the dense adventitia, respectively. Thicknesses were calculated because, in the absence of hypertrophy, wall areas change secondary to changes in vessel circumference. Thus increased area may not equate with hypertrophy.

In the 5-day study, the following parameters were obtained for the intimal layer (luminal surface of the intima), medial layer, and adventitial layer of each animal: For cell density, all cell nuclei in the entire layer were counted at x400 magnification in two sections that were separated by ≥300 µm and stained with hematoxylin and 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 that were separated by 300 µm.

Values are means ± SE for the number of vessels (1 left and right carotid per animal) represented by n. Unless otherwise indicated, differences were subjected to unpaired t-tests or ANOVA, followed by Bonferroni's correction for multiple comparisons. Significance was set at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Hypertrophic positive remodeling in control strains. At 3 wk after injury, lumen area, thickness the of intima-media and adventitia, and circumference of the EEL ("circumference") were increased in the control strains (Figs. 1–4). These changes are similar to those previously reported (33); however, dimensions of the adventitia and thickness of the intima and media were not measured. Because circumference increased, we determined average thicknesses of the media and adventitia as a measure of hypertrophy. There were small differences in vessel dimensions before injury between the control strain for the {alpha}1B-AR KO animals and the other two strains (Figs. 2, 3, and 4), presumably due to differences in body weight ({alpha}1B > {alpha}1D {cong} DBH) and age ({alpha}1B > {alpha}1D > DBH; see MATERIALS AND METHODS for values). It is possible that modestly smaller carotid dimensions in the {alpha}1D-AR and DBH strains led to slightly greater injury. However, this did not result in greater remodeling; i.e., the amount of outward remodeling of lumen and circumference ({alpha}1B-AR+/+ > DBH+/– > {alpha}1D-AR+/+) varied directly with starting dimensions. However, adventitial hypertrophy was larger in the smaller vessel strains ({alpha}1D-AR+/+ and DBH+/–). This may extend from greater injury of a smaller carotid and, in turn, greater thickening of the adventitia. As well, the differences in thickening of the adventitia before injury ({alpha}1B-AR+/+ > {alpha}1D-AR+/+ {cong} DBH+/–) correlated inversely with the degree of adventitial hypertrophy after injury (P < 0.05). There were no significant changes in body weight over the 3-wk period for any of the six groups. Overall, the magnitude of hypertrophic outward remodeling was reasonably consistent among the three control strains.



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  		Fig. 1. Hypertrophic outward remodeling in carotid artery of uninjured, control [{alpha}1B-adrenoceptor (AR)+/+, top] mice and {alpha}1B-AR+/+ mice 21 days after injury (bottom). Injury increased lumen area, thickness of media and adventitia, and vessel (external elastic laminus) circumference. Intact vagus (top) and sympathetic nerves (top and bottom) are dark red circular structures adjacent to adventitia. Masson's trichrome. Scale bar, 100 µm.

 


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  		Fig. 4. Remodeling in carotid artery of control and {alpha}1D-AR–/– mice 21 days after injury. Increases in lumen area, circumference, and thickness of adventitia were not inhibited in {alpha}1D-AR–/– mice. For control, n = 10; for knockout, n = 9.

 


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  		Fig. 2. Remodeling in carotid artery of control and dopamine {beta}-hydroxylase–/– (DBH–/–) mice 21 days after injury. Increases in lumen area, circumference, and thickness of intima and media were inhibited in DBH–/– mice. For control, n = 12; for knockout, n = 8, where n represents number of vessels (1 per animal).

 


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  		Fig. 3. Remodeling in carotid artery of control and {alpha}1B-AR–/– mice 21 days after injury. Increases in lumen area, circumference, thickness of intima and media, and thickness of adventitia were inhibited in {alpha}1B-AR–/– mice. For control, n = 5; for knockout, n = 6.

 
Effect of DBH, {alpha}1B-AR, and {alpha}1D-AR gene deletion on hypertrophic positive remodeling. Injury-induced expansion of lumen area, circumference, and thickness of the intima and media in DBH–/– and {alpha}1B-AR–/– mice (and adventitia in {alpha}1B-AR–/– mice) were sharply attenuated when expressed as absolute values (Figs. 2 and 3) or as percentage of control (Fig. 5). Thickening of the intima-media and adventitia before injury tended to be greater in {alpha}1B-AR–/– than in {alpha}1B-AR+/+ mice (Fig. 3). These trends were not significant and were unrelated to body weight. In contrast to DBH–/– and {alpha}1B-AR–/– mice, expansion of lumen area, circumference, and thickening of the adventitia were unaffected in {alpha}1D-AR–/– mice (Figs. 4 and 5). However, absolute (Fig. 4) and normalized (Fig. 5) hypertrophy of the intima-media was attenuated.



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  		Fig. 5. Comparison of outward remodeling in carotid artery of 3 knockout strains, with data from Figs. 2–4 normalized to response of control strains. Expansion of lumen area and circumference of external elastic laminus (CEEL), thickening of intima and media, and thickening of adventitia were inhibited in DBH–/– and {alpha}1B-AR–/– mice, whereas only thickening of intima and media was attenuated in {alpha}1D-AR–/– mice.

 
In uninjured groups, lumen area and circumference were larger in {alpha}1D-AR–/– than in wild-type mice (Fig. 4). This may reflect ~8% lower arterial pressure than in wild-type mice because of a reduction in peripheral and cerebrovascular resistance (35, 36). In contrast, mean arterial pressure is unchanged in DBH–/– and {alpha}1B-AR–/– mice (6, 7, 41). Compensatory reflex increases in cardiac output and carotid flow velocity in {alpha}1D-AR–/– mice would favor flow-mediated outward remodeling, which may explain the larger lumen area and circumference. However, the magnitude of the baseline differences in lumen area and circumference remained evident after injury and thus does not invalidate the conclusion that outward hypertrophic remodeling was little altered in the {alpha}1D-AR–/– mice. No gender-related differences were evident in control dimensions or in the response to injury between the {alpha}1D-AR and DBH groups (only male {alpha}1B-AR+/+ and {alpha}1B-AR–/– mice were available for study).

Circumferential wall tension. Hypertrophic outward remodeling in control groups caused a decrease in estimated wall tension (Tw; Table 1). This suggests that thickening of the wall of the media and adventitia at day 21 exceeded that required to maintain Tw in the face of increased vessel circumference. This excess hypertrophy was lessened in the DBH–/– mice and eliminated in the {alpha}1B-AR–/– mice. However, it was unaffected in the {alpha}1D-AR–/– mice. In agreement with previous reports (5), Tw in uninjured carotid for the three strains varied directly with age and body weight. Tw was lower in {alpha}1B-AR+/+ and {alpha}1B-AR–/– mice. This is evident in their thicker media and adventitia (Figs. 2– 4). This difference may arise because the {alpha}1B-AR mice were slightly older and heavier than the other two strains, and all were males (see MATERIALS AND METHODS).


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  		Table 1. Circumferential wall stress (105 x dyn/cm2) in right (uninjured) and left (injured) carotid 21 days after injury

 
Proliferation, apoptosis, and leukocyte infiltration. At 21 days after injury, there were no significant differences in cell density or in the infrequently present leukocytes in intima-media and adventitia in control and KO mice. This is likely because proliferation and apoptosis of SMCs and AFBs, as well as infiltration of leukocytes, occur earlier after injury. Therefore, DBH–/– and control mice were studied 5 days after injury. In control mice, injury caused an increase in thickness of intima-media and adventitia, and lumen area declined. These hypertrophic effects were inhibited in DBH–/– mice, and lumen area increased (Fig. 6). In control mice 5 days after injury, cell density was little affected, presumably because of simultaneous increases in proliferation and apoptosis, and leukocyte accumulation was evident (Fig. 7). Proliferation and leukocyte infiltration were inhibited in DBH–/– mice (Fig. 7).



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  		Fig. 6. Wall hypertrophy 5 days after injury is inhibited in DBH knockout mice. For control, n = 4; for knockout, n = 5.

 


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  		Fig. 7. Proliferation and leukocyte infiltration 5 days after injury were inhibited in DBH knockout mice, whereas cell density and apoptosis were largely unaffected. Number of cells positive for proliferation, apoptosis, and leukocyte antigen in each layer were normalized to cell density of each layer. Key shown for proliferation index applies to leukocyte index and apoptosis index as well. For control, n = 4; for knockout, n = 5.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The major findings of this study were that hypertrophic outward remodeling was significantly attenuated in DBH–/– and {alpha}1B-AR–/– mice. This was in association with inhibition of proliferation in the media and accumulation of leukocytes in the intima of DBH–/– mice, in which these mechanisms were examined. In contrast, increases in lumen area, circumference, and thickening of the adventitia were unaffected in {alpha}1D-AR–/– mice. These results complement our previous in vivo and ex vivo studies in the rat (12, 37, 47) by using a different species, injury model, and genetic, rather than pharmacological, approach. Thus they strengthen the generality of our hypothesis that catecholamines exert direct trophic actions on arteries that are augmented by injury and that may contribute to vascular hypertrophic diseases.

Little or no neointima developed in our injury model. This is in agreement with reports, using the same background strain of mice, that minimal if any neointima forms in flow-mediated positive remodeling (34) and mechanical injury of the carotid (43). However, a small neointima was reported in one study in which the injury model was the same as that used here (33). Differences in neointimal formation could relate to age (4–7 mo in our study vs. ≤4 mo in Ref. 33) or differences in surgical methods. During injury, Simon et al. (33) dissected and isolated the portion of the common carotid artery that would later be removed for histological analysis. In contrast, our injury procedure did not disturb the portion of the common carotid and overlying omohyoideus that were later removed en bloc for histology. A number of studies have demonstrated that injury of the adventitia induces neointimal formation.

Potential secondary effects in the KO strains merit consideration. Differences in resting arterial pressure do not explain our results. Compared with wild-type strains, arterial pressure is reportedly unaltered in DBH–/– and {alpha}1B-AR–/– mice (6, 7, 41) but is ~8% lower in {alpha}1D-AR–/– mice (35, 36). This is consistent with evidence that {alpha}1D-ARs are primarily responsible for the adrenergic component of baseline and reflex increases in peripheral resistance and arterial pressure and that heart function is normal in {alpha}1D-AR–/– mice ({alpha}1D-ARs are not expressed in rat or mouse heart) (35, 36). Pressure-dependent wall stress is widely assumed to have a direct trophic influence on thickness of the arterial media. Thus lower pressure in the {alpha}1D-AR–/– mice may contribute to the partial attenuation of injury-induced medial hypertrophy in this strain (and the larger lumen and circumference of the EEL; see RESULTS). Several studies support this explanation: Our previous results examining rat carotid and aorta showed that {alpha}1A- and {alpha}1B-ARs, but not {alpha}1D-ARs, mediate NE's trophic actions (12, 37, 47). Two of these studies used locally delivered pharmacological antagonists and found no trophic contribution of {alpha}2- or {beta}-ARs (12, 47). This finding is consistent with the {alpha}1-AR subtypes that mediate NE activation of MAPK pathways in expression cell lines (16, 19, 29) and bovine alveolar artery (42). Nevertheless, our data do not rule out the possibility that {alpha}1D-ARs might mediate a small portion of NE's trophic action on SMCs.

Similar to resting arterial pressure, predicted differences among the KO strains in the magnitude of pressure fluctuations during behavior also do not account for our results. Evidence suggests that {alpha}1B-ARs mediate only a small amount of NE's contractile activity in arteries of rats and mice (6, 8, 10). Similarly, {alpha}1B-AR–/– mice exhibit slightly smaller pressor responses to high levels of catecholamine infusion (6). This suggests that {alpha}1B-ARs may mediate a minor component of the increase in arterial pressure during sympathoexcitation in mice. Thus it is likely that during nonresting states all three KO strains studied here, but especially the DBH–/– and {alpha}1D-AR–/– mice, exhibit larger declines and smaller increases in arterial pressure than their controls. However, inhibition of outward remodeling was not comparable in these two strains but, instead, was prominent in DBH–/– and absent in {alpha}1D-AR–/– mice.

The present findings are consistent with our previous studies suggesting that specific {alpha}1-AR subtypes in a vessel may serve trophic functions. Medial SMCs and AFBs of rat carotid and aorta express all three {alpha}1-AR subtypes (14). Other vessels express multiple ARs but often with species differences (10). For example, {alpha}1D- and {alpha}1B-ARs are present in mouse aorta and carotid (6, 8, 10, 35, 36), but {alpha}1A-ARs have not been detected (8, 32). Catecholamine constriction of carotid and aorta in mice and rats is mediated by the {alpha}1D-AR, with a minor component mediated by the {alpha}1B-AR in the mouse (and possibly rat) vessels (8, 10, 35, 36). However, in balloon-injured rat aorta in organ culture, {alpha}1A- and {alpha}1B-ARs mediated NE proliferation of SMCs and AFBs, respectively, whereas blockade of {alpha}1D-ARs was without effect (47). Similarly, the {alpha}1A-AR, but not the {alpha}1D-AR, appears to mediate the effect of endogenous and exogenous NE to worsen restenosis of rat carotid after balloon injury (12, 37). The apparent lack of {alpha}1A-AR expression in the mouse carotid (8, 32) may account for the present results showing that {alpha}1B-ARs are trophic in mouse carotid, whereas {alpha}1A-ARs serve this role in the rat. It is unlikely that injury induces {alpha}1A-AR expression in mouse carotid, with subsequent contribution to the trophic effects reported here, for the following reasons. First, injury does not increase but, instead, reduces expression of {alpha}1A-ARs in media and adventitia of rat carotid and aorta by 40–80% below control levels when measured 4 and 21 days after injury (13). Second, in the present study, the hypertrophic response to injury was inhibited to a similar extent in {alpha}1B-AR–/– and DBH–/– mice yet was little affected in {alpha}1D-AR–/– mice. Thus {alpha}1B-ARs appear to account for most, if not all, of the trophic contribution of catecholamines in mouse carotid.

In addition to arterial pressure, other reported phenotypic differences in KO strains also do not appear to explain our results. In DBH–/– mice, increased vagal tone results in a slightly reduced heart rate (7), whereas circulating leukocytes (1), cardiac weight, {beta}-AR density, and Gi and Gs protein levels in heart (7) are unchanged. Cardiac contractility is increased in association with reduced levels and activity of {beta}-AR kinase-1 ({beta}-ARK-1) and increased proportion of {beta}-ARs in the high-affinity state (7). These effects are expected from the absence of endogenous agonist. However, increased pulse pressure from reduced heart rate and augmented contractility would favor greater, rather than less, vascular hypertrophy. Reduced {beta}-ARK-1 would also promote enhanced signaling via trophic agonists (e.g., angiotensin and endothelin), acting on {beta}-ARK-1-dependent G protein-coupled receptors. Thus the inhibition that we observed for DBH–/– mice cannot be due to generalized reduced sensitivity to the trophic activity of such agonists; in fact, the opposite is favored.

The source of NE mediating the trophic contribution to the injury response could be perivascular nerves and/or plasma (including epinephrine). Although the common carotid artery is innervated with adrenergic nerves in many species (e.g., rabbit and guinea pig), no studies have examined innervation density, per se, of the mouse common carotid artery. The mouse external carotid has a dense adrenergic plexus (27), and the common carotid artery expresses tyrosine hydroxylase, a marker for sympathetic adrenergic nerves (25).

In {alpha}1B-AR–/– mice, heart rate and weight are unchanged, and there is no compensatory upregulation of expression of other {alpha}1-, {alpha}2-, or {beta}-ARs or altered vascular contractile responsiveness to angiotensin or vasopressin (6). Similarly, in {alpha}1D-AR–/– mice, other {alpha}1-ARs are not upregulated, heart rate and contractility are unaffected, and aortic contraction and pressor responses to angiotensin and vasopressin are unaltered (36). Notwithstanding the secondary phenotypic considerations discussed above, it is impossible when using genetically altered mice to exclude the possibility that an unknown phenotypic effect might have influenced the results.

Vecchione et al. (41) reported that infusion of phenylephrine (0.07 µg·kg–1·min–1) for 3 wk was accompanied by inward eutrophic remodeling of mesenteric resistance arteries and that this effect was absent in {alpha}1B-AR–/– mice. Because an increase in mean arterial pressure was not detected during infusion, the authors concluded that the remodeling was due to a direct trophic effect of phenylephrine mediated by the {alpha}1B-AR. Using a similar design (11), we also found changes in structure of the uninjured rat carotid artery: infusion of NE (0.25 µg·kg–1· min–1 iv, n = 10) for 4 wk vs. ascorbated Ringer solution (n = 10) had no effect on arterial pressure or heart rate, as determined daily in unanesthetized, unrestrained rats in their home cage. NE increased medial and adventitial area by 25% (P < 0.001) and 31% (P < 0.05), respectively, and increased lumen area and circumference by 15% and 5% (P < 0.05), respectively. Both of these studies agree with our previous findings (12, 47) of a direct trophic effect of prolonged catecholamine elevation on normal arteries. However, both studies recorded arterial pressure for only a limited interval (e.g., our measures were taken after rats were at rest for ≥30 min). Hence, they do not rule out the possibility that catecholamine infusion causes greater increases in baseline arterial pressure or greater pressure variability during wakeful activities. Such increases could, by the direct trophic effect of pressure, contribute to the reported findings (11, 41). It is known that increased arterial pressure variability accompanies infusion of catecholamines at low levels in conscious rats (24) and is a hallmark in patients with pheochromocytoma (28). Therefore, without continuous measurement of phasic arterial pressure over a 24-h interval in unrestrained animals, it remains uncertain whether structural changes in uninjured arteries induced by systemic administration of low levels of catecholamines are direct, i.e., independent of altered mechanical loading of the vascular wall.

The inhibition of remodeling in DBH–/– and {alpha}1B-AR–/– mice was stronger than the ~50% inhibition obtained with {alpha}1-AR antagonists in the balloon-injured rat carotid artery (12, 37). Besides differences in species and injury models, this could reflect incomplete {alpha}1-AR blockade in the previous studies, where higher concentrations of antagonists could not be used without loss of antagonist specificity. In contrast, use of KO mice in the present study eliminated {alpha}1B-ARs and NE and epinephrine synthesis (6, 7, 38). The strong inhibition of remodeling obtained in the present study suggests that even basal sympathetic activity contributes to wall growth after injury. Although additional studies are required to identify the mechanisms for this, including the interesting report that balloon injury increases wall catecholamine levels (4), some speculation can be offered (Fig. 8). Dilatation immediately follows overdistension injury (45). This likely reflects injury and death of SMCs and AFBs, inflammation, loss of smooth muscle tone, and proteolytic weakening of the extracellular matrix. The resultant increase in wall stress, together with the aforementioned conditions, would be expected to recruit mediators of proliferation, hypertrophy, apoptosis, and matrix reorganization that underlie the subsequent outward remodeling and wall hypertrophy. Our previous studies found that {alpha}1-AR stimulation by endogenous wall NE worsens the hypertrophic response to balloon injury (12, 37) and that balloon injury causes the trophic effect of NE to become excessive (47). These results suggest that {alpha}1-AR stimulation causes hypertrophy to become excessive in the injured vessel because of increased release of NE from perivascular nerves (4) and/or increased trophic responsiveness of vascular wall cells (47) to nerve-released or circulating catecholamines. This is consistent with the present evidence that wall thickening in wild-type mice was in excess of that required to return wall stress of the enlarged artery to normal (Table 1). Excessive hypertrophy and fibrosis could delay or prevent resolution (i.e., reversal) of the hypertrophic positive remodeling after repair is complete. Accordingly, interference with the trophic actions of NE in DBH–/– and {alpha}1B-AR–/– mice lessened excessive hypertrophy, thus permitting return to normal wall dimensions after repair. These findings likely depend on the effect of {alpha}1-AR stimulation to induce SMC and AFB proliferation, hypertrophy, migration, and collagen accumulation (12, 14, 37, 46–48), as well as to possibly augment responses to other growth factors released by injury. However, the mechanism whereby injury amplifies the trophic effect of NE (47) remains to be determined.



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  		Fig. 8. Model of proposed adrenergic participation in hypertrophic outward remodeling. Injury induces growth factors/mediators that act on smooth muscle cells and adventitial fibroblasts to cause wall hypertrophy through the indicated mechanisms. Hypertrophy favors reduced lumen area and increased shear stress. Increased shear stress promotes outward remodeling, which favors a return of lumen diameter and shear stress toward normal. Results of the present study suggest that wall norepinephrine (NE) derived from sympathetic nervous system (SNS) activity, acting through predominantly {alpha}1-ARs ({alpha}1B-ARs in the mouse carotid), causes hypertrophy in excess of that necessary to restore geometric wall stress to normal (Table 1). Relative values for wall thickness and lumen diameter for days 5 and 21 ({bullet}) are from Figs. 5 and 6 for DBH wild-type (WT) and knockout (KO) groups. WT curves suggest that, in the presence of injury, adrenergic trophic actions cause excessive wall growth, which results in delay or possible (?) prevention of subsequent reversal of hypertrophic outward remodeling. KO curves suggest that blockade of adrenergic trophic activity lessens excessive wall growth. This may promote repair and earlier reversal of hypertrophic outward remodeling.

 
Although positive remodeling at sites of human atheromas reduces lumen loss during atheroma development, its recent association with plaque instability has led to the suggestion that positive remodeling may result from worsening inflammation in the vascular wall (3, 39, 44). Thus it is important to understand the underlying mechanisms that promote and limit positive remodeling. Our results suggest that catecholamines participate in the progression of injury-induced positive remodeling and the accompanying medial and adventitial hypertrophy.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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REFERENCES
 
This study was supported by National Heart, Lung, and Blood Institute Grant HL-62584 (J. E. Faber).


   ACKNOWLEDGMENTS
 
We thank Kirk McNaughton for histology.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. E. Faber, Dept. of Cell and Molecular Physiology, 6309 MBRB, Univ. of North Carolina, Chapel Hill, NC 27599-7545 (E-mail: jefaber{at}med.unc.edu)

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.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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