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Stress upregulates arterial matrix metalloproteinase expression and activity via endothelin A receptor activation

¹Clinical and Experimental Therapeutics Program, University of Georgia College of Pharmacy, Augusta 30912-3910; and ²Vascular Biology Center and ³Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912-3910

Submitted 12 February 2003 ; accepted in final form 1 July 2003

	ABSTRACT

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION DISCLOSURES REFERENCES

 
Degradation of the extracellular matrix proteins by matrix metalloproteinases (MMP) is an important regulatory step in the vascular remodeling process. Recent studies demonstrated that ET_A receptors regulate cardiac MMP activity and fibrosis in DOCA-salt hypertension. However, little is known about endothelin (ET)-1 regulation of vascular MMP activity in hypertension. Thus early changes in ET-1-mediated regulation of MMP activity were measured in borderline hypertensive rats that develop impaired vasorelaxation and hypertension with chronic exposure to stress. Experiments were performed after 10 days of exposure to the behavioral stressor, air-jet stress, but before the onset of stress-induced hypertension. Study groups were 1) control (n = 8); 2) air-jet stress for 10 days (n = 8); 3) control plus ET_A antagonist ABT-627 (n = 4), and 4) air-jet stress plus ET_A antagonist (n = 4). MMP activity in the thoracic aorta was assessed by gelatin zymography. MMP protein and tissue ET-1 levels were evaluated by immunohistochemistry, and ET receptor density was determined by immunoblotting. Exposure to stress caused a twofold increase in plasma ET-1 levels (P < 0.05), and there was increased ET-1 staining at the tissue level. Total MMP activity and expression of MMP-2 and MMP-9 were increased in the stress group. ET_A receptor antagonism prevented the increase in MMP expression and activation in the stress group. These results provide evidence that the MMP system is activated before the development of hypertension and ET-1 mediates these early events in vascular remodeling.

endothelin-1; ABT-627

The borderline hypertensive rat (BHR) is the first-generation offspring of a female SHR and a male Wistar-Kyoto rat and mimics a number of features common in the development of hypertension in African-Americans (29). First, the BHR becomes hypertensive with repeated exposure to behavioral stress (29). Second, high-salt diet causes the development of hypertension (3). Third, exposure to stress for 10 days alters vascular contraction and relaxation in BHRs (11, 13). Enhanced sympathetic nervous system activity and peripheral vascular structural changes leading to increased vascular resistance are believed to contribute to stress-induced hypertension. Whether there are changes in the vascular structure in early phases of stress is unknown. Furthermore, the effect of stress on ET-1 activation in this model is not well defined.

The present study was designed to determine behavioral stress-induced changes in vascular extracellular matrix proteins before the development of stress-induced hypertension in the BHR model. Because matrix MMPs regulate the turnover of structural proteins such as collagen and elastin in the extracellular matrix, this study focused on the expression and activity of vascular MMPs in response to stress. The second goal of the study was to investigate systemic and local ET-1 levels in response to stress and determine whether ET-1 contributes to changes in MMP expression and activation via the ET_A receptor.

	METHODS AND MATERIALS

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION DISCLOSURES REFERENCES

 
Blood pressure measurements and tissue collection. Female SHR and male Wistar-Kyoto rats were purchased from Taconic Farms (Germantown, NY) and bred at the Medical College of Georgia to obtain the first-generation offspring BHRs. Animal care and experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No 85-23, revised 1996). Male BHR were divided into two groups: control animals (n = 8) remained in their home cage for 10 days; stressed group (n = 8) was exposed to air-jet stress for 2 h/day for 10 days as previously described (10). Briefly, rats were placed in restrainers in sound-insulated chambers. Chronic stress consisted of pulses of compressed air directed toward the face from a 1/8-in. opening at the front of the restrainer. Animals were subjected to a random duration of pulses (5–120 s) and interpulse intervals (5–120 s) for 2 h/day for 10 days. The ET_A receptor antagonist ABT-627 was administered to additional control and stressed animals (n = 4 per group) in the drinking water (5 mg·kg^–1·day^–1) for 10 days. This dose has been shown to block ET receptors (26, 34). After the exposure to air-jet stress on day 10, rats were anesthetized with ketamine (50 mg/kg im) and acepromazine (16 mg/kg im). Under aseptic conditions, a cannula was placed in the femoral artery and was exteriorized at the nape of the neck. The cannula was flushed with heparinized saline (100 U/ml). After a 1-day recovery period, arterial pressure was measured with a Grass recorder in unrestrained rats in their home cage. On day 11, rats were anesthesized with pentobarbital sodium (50 mg/kg ip), heparin (500 U) was administered in the left ventricle, and aortas were removed. After being rinsed with saline, aortic samples were snap frozen in liquid nitrogen for zymography and immunoblotting. A segment of the aorta was fixed in 10% formalin.

MMP activity. MMP activity was determined with gelatin zymography of aortic homogenates. Frozen specimens were homogenized in extraction buffer (1:10, wt/vol) containing 0.15 M NaCl, 20 mM ZnCl₂, 1.5 mM NaN₃, 10 mM cacodylic acid, and 0.01% Triton X-100. After centrifugation at 4°C for 10 min at a speed of 800 g, the supernatant was concentrated by using a Centriplus concentrator. Samples were centrifuged at 3,000 g for 4.5 h at 4°C, and the protein content was measured by using protein assay (Bio-Rad; Richmond, CA). Samples were stored at –80°C in small aliquots. On the day of the experiment, samples were loaded on 10% gelatin zymography gels (Bio-Rad) and separated under nonreducing conditions. The gels were then rinsed twice in 2.5% Triton X-100 and incubated overnight (16 h) in substrate buffer containing 50 mM Tris·HCl, 5 mM CaCl₂, and 1 µM ZnCl₂ to remove SDS. Gels were then stained by Coomassie blue R-250 followed by destaining in 55% methanol and 7% acetic acid.

Western blot analysis. Vascular ET_A receptor density and MMP-2 and MMP-9 levels were determined by immunoblotting. Vascular extracts (20 µg) were separated on 10% SDS gels under nonreducing conditions by using a Tris-glycine running buffer (0.2 M Tris-base, 0.2 M glycine, pH 6.8, and 0.1% SDS). The separated samples were transferred to a nitrocellulose membrane in Tris-glycine transfer buffer supplemented with 20% methanol. The immunoblots were blocked for 1 h in blocking grade powdered goat milk (5%) diluted in 0.2 M Tris-base, 1.4 M NaCl, 0.1% Tween 20, and 0.02% NaN₃. The membranes were then incubated overnight with the primary antibody as recommended by the manufacturer (Research Diagnostics; Flanders, NJ). Bands were visualized by using an enhanced chemiluminescense detection kit from Amersham Life Sciences (Arlington Height, IL).

Immunohistochemistry. Aortic segments were fixed in 10% formalin, and sections were mounted on slides. Immediately before immunostaining, sections were permeabilized with 1% Triton X-100 for 10 min at room temperature and then washed with PBS. Slides were blocked by incubating with 10% goat serum for 1.5 h at 4°C and rinsed with PBS. Sections were then incubated with primary antibody (MMP-2, MMP-9, collagen type I, and ET-1) overnight at 4°C at dilutions recommended by the manufacturers. The next day, slides were rinsed with PBS and incubated with goat anti-rabbit or anti-mouse alkaline phosphatase-conjugated secondary antibody for 30 min at room temperature. Sections were rinsed with PBS and mounted with ProLong Antifade Kit (Molecular Probes; Eugene, OR). The slides were viewed with a Zeiss Axiovert microscope interfaced with a digital Spot camera. Multiple images from each slide starting with light staining to heavy staining were evaluated by Metamorph software, and average staining intensity was given.

Measurement of plasma ET-1. The amount of ET-1 in the plasma and tissue culture medium was determined by using an ELISA kit specifically designed for direct measurement of plasma ET-1 (American Research Products; Belmont, MA) as we reported previously (9). The sensitivity of the assay is 0.1–15 fmol/ml and the cross-reactivity of the antibodies used are reported to be <1% with Big ET-1 and <5% with Big ET-2.

	RESULTS

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION DISCLOSURES REFERENCES

 
Arterial pressure and ET-1 levels in response to stress. Mean arterial pressure was not significantly altered after 10 days of stress (125 ± 4 mmHg in control vs. 124 ± 4 mmHg in the stressed BHR). Additionally, the ET_A receptor antagonist ABT-627 did not significantly alter mean arterial blood pressure in control (124 ± 2 mmHg) or stressed (122 ± 6 mmHg) BHR. To ensure that both groups received the same amount of ABT-627, water intake was monitored, and in both groups, rats received 5–6 mg/kg antagonist per day.

To investigate whether behavioral stress alters ET-1 levels in the BHR model, both circulating and local vascular ET-1 levels were evaluated. Plasma ET-1 levels were increased by twofold in the stress group compared with control BHR (Fig. 1A). In animals treated with an ET_A receptor antagonist, a similar pattern was observed (Fig. 1A). Tissue ET-1 was assessed by immunohistochemistry, and as shown in Fig. 1B, an enhanced endothelial staining was detected in stressed rats. Adventitial staining that was unchanged in the absence of the primary ET-1 antibody was also observed, suggesting nonspecific staining due to lipids. In control and stress groups treated with ET_A antagonist ABT-627, a similar pattern of staining was observed (data not shown).

View larger version (44K): [in this window] [in a new window]   Fig. 1. Effects of 10-day exposure to behavioral stress on endothelin (ET)-1 levels. Blood samples were obtained from untreated control and stressed animals (n = 8/group) and ABT-627-treated control and stressed animals (n = 4/group) on day 11. A: plasma ET-1 levels were measured by ELISA, and results are given as means ± SE. *P < 0.05 vs. control. B: local ET-1 levels were assessed by immunocytochemistry, and a representative slide is shown.

ET_A receptor density was determined by immunoblotting and two bands at 54 and 39 kDa corresponding to native and glycosylated forms of receptors, respectively, were detected. Densitometric analysis of both bands indicated a twofold increase in stressed animals compared with controls (Fig. 2). In ABT-627-treated animals, there was no difference between the control and stress groups.

View larger version (44K): [in this window] [in a new window]   Fig. 2. A representative immunoblot demonstrating the vascular ETA receptor profile in control and stress animals. A: immunoreactive bands corresponding to the molecular mass of ETA receptors at 54 and 39 kDa were detected. B: densitometric analysis of immunoreactive bands in each group (means ± SE, n = 8) indicates that ETA receptor density is increased in the untreated stress group but that in ABT-627-treated animals, there is no significant difference in the receptor profile between control and stress groups. *P < 0.05 vs. control.

Vascular MMP activity. Total MMP activity in thoracic aorta of control and stressed BHR as well as ABT-627-treated control and stressed rats was assessed by using gelatin zymography. A representative gelatin zymogram is shown in Fig. 3A. The main proteolytic activity in the untreated group corresponds to 72 kDa proMMP-2 and two active forms of MMP-2 at 67 and 55 kDa, whereas in the ET_A receptor antagonist-treated group, a 55-kDa band was not detected. In addition, there was very faint activity corresponding to proMMP-9, which did not differ among groups (data not shown). Densitometric analysis of all the lytic bands combined in each sample demonstrated that total MMP activity was increased in the stress BHR group (P < 0.05 vs. control) and the ET_A receptor antagonism prevented the increase in MMP activation especially at the 55-kDa level (P < 0.05 vs. untreated BHR) (Fig. 3B).

View larger version (48K): [in this window] [in a new window]   Fig. 3. A: representative SDS-PAGE gelatin zymogram of aortic specimens from control and stress animals. Matrix metalloproteinase (MMP)-2 activity determined by white lytic bands was detected between the 72- to 50-kDa region. B: densitometric analysis of lytic bands detected in gelatin zymograms was plotted as total MMP activity (means ± SE, n = 8). *P < 0.05 vs. control.

To determine whether and to what extent MMP activity correlates with protein levels and to evaluate the localization in the vessel wall, MMP-2 and MMP-9 were investigated by immunohistochemistry. Breast cancer tissue (for MMP-2 and MMP-9) was used as a positive control. As shown by representative images in Figs. 4 and 5, there was augmented staining for MMP-2 and to a lesser extent for MMP-9 in the stress group, and treatment with ABT-627 decreased staining in the stress group. Staining was observed both in the medial and adventitial layers. Medial staining was diminished in the absence of a primary antibody, indicating specific staining for MMP proteins, whereas adventitial staining was unchanged, suggesting non-specific staining due to lipids. The increase in MMP-2 and MMP-9 levels was also confirmed by immunoblotting of vascular homogenates. As shown in Figs. 4 and 5, both MMP-2 and MMP-9 were significantly elevated in the stress group, which was prevented by ABT-627.

View larger version (56K): [in this window] [in a new window]   Fig. 4. Increased MMP-2 expression in the medial layer of aortic rings from control and stress animals (n = 3 in each group). A: breast cancer tissue was used as positive control. B: nonspecific staining in the absence of primary antibody is shown. C–F: MMP-2 levels in vascular homogenates were determined by immunoblotting, and a representative blot is given under each group. G: staining intensity in immunohistochemistry slides was analyzed by Metamorph analysis software and plotted as average staining intensity (means ± SE). *P < 0.05 vs. control or treatment groups.

View larger version (67K): [in this window] [in a new window]   Fig. 5. Increased MMP-9 expression in the medial layer of aortic rings from control and stress animals (n = 3 in each group). A: breast cancer tissue was used as positive control. B: nonspecific staining in the absence of a primary antibody is shown. C–F: MMP-9 levels in vascular homogenates were determined by immunoblotting, and a representative blot is given under each group. G: staining intensity in immunohistochemistry slides was analyzed by Metamorph analysis software and plotted as average staining intensity (means ± SE). *P < 0.05 vs. control or treatment groups.

	DISCUSSION

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION DISCLOSURES REFERENCES

 
Because the BHR model is sensitive to a number of environmental stimuli, it has been used extensively for studies focusing on behavioral stress (29). Prolonged exposure to stress ultimately results in elevated blood pressure that persists even after removal of the stress (29). Although 10 days of air-jet stress as used in this study does not alter the resting arterial blood pressure, changes in vascular reactivity can be detected in this period of time before the development of hypertension (10, 11). Therefore, 10-day exposure of BHRs to stress offers a good model to study changes in vascular function and structure before the development of hypertension allowing for determination of vascular changes independent of changes in blood pressure. With the use of this model, the present study sought to answer three important questions: 1) Is the ET system activated in early stages preceding the development of hypertension in a stress-induced model of hypertension? 2) Is the MMP system, critical for the regulation of vascular structure, altered in response to stress? and 3) Are changes in the MMP system mediated by ET-1? Our findings demonstrate for the first time that stress stimulates the production of ET-1 and increases MMP activity in the vasculature before changes in blood pressure. Furthermore, MMP activation can be prevented by the administration of an ET_A receptor antagonist during the stress period, providing evidence that ET-1 is, in part, responsible for the stimulation of vascular MMP activity.

There is accumulating evidence that ET-1 is important in the pathogenesis of hypertension in several experimental models, including DOCA-salt hypertensive rats (19–21), Dahl salt-sensitive rats (5), as well as angiotensin II-infused rats (22). In addition to lowering blood pressure, ET receptor antagonists provide protective effects on target organs in these models (30). Recent studies reported that ET_A receptor antagonism decreases collagen accumulation and improves MMP-2 activity in kidneys from stroke-prone SHRs (32) as well as decreasing fibronectin levels and MMP activity in the left ventricle of DOCA-salt hypertensive rats that display cardiac fibrosis (2). In clinical hypertension, there is a consensus that ET-1 levels are increased in patients with low-renin and salt-sensitive forms of hypertension, which is predominantly seen in the African-American population (6–8, 30). In this patient population, frequent exposure to behavioral and environmental stress plays an important role in the development of hypertension (9). Interestingly, Treiber and colleagues (33) reported that in young healthy African-American adolescents with a family history of hypertension, stress induces elevations in plasma ET-1 levels. The same group (4) also reported that in this cohort, left ventricular mass is significantly greater even before the development of hypertension. On the basis of these past observations, we wished to investigate the ET system as well as vascular structure at different stages in a stress-induced model of hypertension. The present study provides evidence that both plasma and local vascular ET-1 levels are increased as early as 10 days after exposure to behavioral stress. In addition, with the use of an immunoblotting approach, we studied the expression of ET_A receptors, and two specific bands corresponding to the native and glycosylated form of receptors were detected as previously reported (14). ET_A receptors that mediate the contractile and proliferative response to ET-1 are upregulated in response to stress, and this increase in ET_A expression is diminished in animals treated with ABT-627. The explanation for this intriguing result is threefold. First, ET-1 may stimulate ET_A receptor expression directly, and in the presence of receptor antagonist, this stimulation is blocked. Elevated ET-1 levels have been reported to decrease ET-1 binding due to receptor desensitization (28, 31), but whether decreased binding is associated with alterations in protein levels is unclear. Second, ET-1 may regulate ET_A expression indirectly via the activation of intermediate factors, and this possibility warrants future studies. Third, although it has not been reported in the literature, ABT-627 may have a nonspecific effect on ET_A receptor expression. Although the reason(s) for restored ET_A expression in the ABT-627-treated stress group remains to be determined, the novel finding of this study is that the ET system is activated before the development of hypertension in the stress-induced hypertension model.

In essential hypertension, peripheral vascular resistance is increased due to decreased lumen diameter, and abnormal vascular reactivity may originate from structural and functional changes of blood vessels (15, 16). Functional changes involve impaired vascular relaxation and increased sensitivity to vasoconstrictors. Alterations in vascular structure arise from vascular remodeling and result in collagen deposition leading to decreased arterial compliance. Our group demonstrated previously that behavioral stress causes decreased vasorelaxation, which is linked to altered phosphorylation of small heat shock proteins that bind to actin cytoskeleton, and these changes in vascular function occur before the development of hypertension in the BHR model (10). However, whether vascular structure is influenced by stress early in the disease process remained unknown. Because MMPs regulate the turnover of extracellular matrix proteins that are critical for vascular structure, the present study investigated whether MMP activity is altered in response to stress. MMPs are a family of zinc-dependent enzymes, and several species are commonly expressed in the vasculature, including MMP-1, MMP-2, and MMP-9 (2, 12, 23, 27). All of these enzymes are secreted in zymogen forms (proMMPs), which are later activated by other proteinases to yield active MMPs (23). MMP-1, a 52- and 42-kDa protein in latent and active forms, respectively, can degrade fibrillar collagen, whereas MMP-2 and MMP-9 can process gelatin (denatured collagen) into smaller fragments. proMMP-2 is a 72-kDa protein with two active forms 66 and 54 kDa (17). Molecular mass of MMP-9 is 92 and 82 kDa for latent and active forms, respectively (12). To be able to evaluate both MMP and ET systems in each animal individually without pooling tissue from several animals, we chose to study aortas in the present study. Vascular MMP activity was assessed by gelatin zymography, which detects primarily MMP-2 and MMP-9 activity. Total vascular MMP activity was increased in the stress group compared with control, and this increase was predominantly in the 66- and 54-kDa forms. In ABT-627-treated animals, total MMP activity was restored to control levels. However, compared with untreated control and the stress group, the 56-kDa form was not detected in animals that received ABT-627, and 72-kDa proMMP was more prominent. These findings suggest that ET-1 antagonism prevented the processing of latent enzyme to smaller molecular mass active form. Because there was no significant difference in blood pressure measurements among the study groups, effects of ABT-627 on MMP activation appear to be independent of blood pressure lowering. These results suggest that ET-1 plays an important role in the regulation of MMP activation in aorta. Whether similar changes occur in small resistance arteries remains to be determined. In addition, this study evaluated early changes in extracellular matrix proteins involved in the vascular remodeling process. After 10 days of stress, MMP activity was stimulated, but collagen type I levels were not altered (data not shown). Although this study did not the assess lumen-to-wall ratio, we speculate that stress induces MMP activation with no significant change in wall thickness in 10 days.

In conclusion, the expression and activity of vascular MMP proteins that are important for the regulation of extracellular matrix proteins and remodeling processes are upregulated in response to behavioral stress. This increase is associated with parallel increases in plasma and local ET-1 levels, and ET_A receptor antagonism restores the MMP activity in the stressed animals. These intriguing findings provide direct evidence that stress induces early changes in the vascular structure via the stimulation of the ET system.

	DISCLOSURES

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION DISCLOSURES REFERENCES

 
This study was supported by grants from Pfizer, the American Heart Association, and the American Diabetes Association (to A. Ergul) and National Heart, Lung, and Blood Institute Grant HL-49924 (to L. Fuchs).

	ACKNOWLEDGMENTS

 
We thank Abbott Laboratories and Dr. Jerry Wessale for the ABT-627 compound.

	FOOTNOTES

 

Address for reprint requests and other correspondence: A. Ergul, Medical College of Georgia, Clinical Pharmacy CJ-1020, 1120 15th St., Augusta, GA 30912 (E-mail: aergul{at}mail.mcg.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

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION DISCLOSURES REFERENCES

 

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