doi: 10.1161/hy0102.099025
(Hypertension. 2002;39:16.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Vessel-Specific Stimulation of Protein Synthesis by Nitric Oxide Synthase Inhibition
Role of Extracellular Signal–Regulated Kinases 1/2
From the Faculty of Pharmacy (F.M.A.C.M., B.D., D.G., C.D., H.H.D., P.M.) and the Department of Pharmacology, Faculty of Medicine (D.d.B.), Université de Montréal, Montréal, Canada. Dr Martens is now at University Hospital of Utrecht, Utrecht, the Netherlands.
Correspondence to Pierre Moreau, PhD, Assistant Professor, Faculty of Pharmacy, Université de Montréal, 2900 Edouard-Montpetit, Room R-313, PO Box 6128, Stn "Centre-ville," Montréal, Québec, H3C 3J7 Canada. E-mail Pierre.Moreau{at}Umontreal.CA
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Abstract |
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Although conduit arteries develop hypertrophy after chronic NO synthesis blockade, resistance arteries remodel without hypertrophy under the same conditions. Similar findings have been described in essential hypertension. We postulated that this regional difference may be related to a heterogeneous effect of endogenous NO on proliferation along the vascular tree. Newly synthesized proteins were radiolabeled in vivo with [3H]L-leucine in basal conditions and during NO synthase inhibition, with or without PD98059 (inhibitor of the extracellular signal–regulated kinases [ERK] 1/2). Blocking the generation of NO by 3 different L-arginine analogues increased protein synthesis by an average of 75% in the aorta, in association with enhanced ERK 1/2 phosphorylation. PD98059 significantly reduced L-arginine analogue–induced protein synthesis and ERK 1/2 phosphorylation, confirming the involvement of ERK 1/2 as an important signaling element. In small arteries, L-arginine analogues did not influence the extent of protein synthesis, although phosphorylation of ERK 1/2 was also enhanced. To determine the role of NO in a condition of enhanced protein synthesis, angiotensin II was infused for 24 hours. Angiotensin II augmented protein synthesis in mesenteric arteries and the aorta, and was additive to NO synthase blockade in the aorta. In conclusion, endogenous NO exerts a tonic inhibitory influence on aortic growth, with limited impact on small arteries in basal and hypertrophic conditions. This heterogeneous role of NO on vascular growth may explain the heterogeneity of vascular remodeling observed in essential hypertension, a condition associated with endothelial dysfunction.
Key Words: hypertrophy • nitric oxide • nitric oxide synthase • kinase • arteries • aorta
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Introduction |
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The endothelium is an important modulator of vascular reactivity and structure, and NO is one of the main products synthesized and released by endothelial cells.1 Most of the biological effects of NO are mediated by cGMP and include regulation of vascular tone and endothelial permeability, inhibition of platelet adhesion and aggregation, and inhibition of leukocyte–endothelial cell interactions.2 In addition, early studies in vascular smooth muscle cells (VSMCs) in culture have shown that NO donors inhibit cellular proliferation3,4 (for review, see Sarkar and Webb5 and Jeremy et al6), which is an important event in the pathogenesis of atherosclerosis, restenosis, and possibly hypertension.7 Among the signaling pathways related to NO inhibition of cell proliferation, inhibition of extracellular signal–regulated kinase (ERK) 1/2 phosphorylation has been proposed to be important, considering the pivotal role of this signaling event in VSMC growth.6,8
In hypertension, arteries adapt to the pressure-induced elevation in wall stress by changing their geometry.9,10 Indeed, the elevated vascular resistance observed in hypertension is associated with an increased media thickness–lumen diameter ratio (remodeling) of resistance arteries.11,12 In essential hypertension, the amount of material in the vessel wall is not augmented but appears to be rearranged around a smaller lumen, and the process has been called eutrophic remodeling.13 In contrast, large arteries undergo mainly hypertrophic remodeling, because their lumen size is generally not reduced, and wall thickness increases in an effort to compensate for the increased wall stress.10,14
Chronic inhibition of NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME) leads to hypertension. Interestingly, in this model, small arteries undergo eutrophic remodeling in proportion to the elevation of arterial pressure.15,16 In addition, under conditions of stimulated growth with exogenous angiotensin II (Ang II) administration, chronic NO synthase inhibition does not worsen growth development but blunts it in cerebral arteries.17 These observations argue against a prominent inhibitory role of NO on VSMC growth in small arteries in vivo. In the aorta, however, chronic NO inhibition with L-NAME promotes medial hypertrophy and fibronectin deposition, suggesting a growth-inhibitory role for NO in large arteries.18 Our postulate is that endogenous NO exerts growth regulation in large arteries but that there is no such regulation in small arteries, possibly because of the different influence of signaling along the vascular tree. To address this issue, the vascular growth response to endogenous NO inhibition was determined in small and large arteries simultaneously under basal and Ang II–stimulated conditions in vivo. Furthermore, we tested the potential of ERK 1/2 to represent an important determinant of the heterogeneity.
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Methods |
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Under anesthesia, the left femoral vein and artery of Sprague-Dawley rats (300 to 400 g) were catheterized with a polyethylene tubing that was tunneled subcutaneously, exteriorized at the back of the neck, and protected by a tethering system. In rats treated with Ang II, an osmotic pump delivering 400 ng/kg per minute was inserted subcutaneously at the same time.
Twenty hours after surgery, arterial pressure and heart rate were recorded. In the first series of experiments, a bolus of L-arginine analogues was administered through the venous catheter to control and Ang II–treated rats. Three different L-arginine analogues were used: L-NAME, NG-methyl-L-arginine (L-NMMA), and NG-nitro-L-arginine (L-NA), all at a dose of 3 mg/kg (n=8 per group). One hour after this bolus, a 4-hour intravenous infusion of L-(4,5-3H)leucine was started (adapted from McNulty et al19). A second dose of L-arginine analogues was administered intra-arterially 90 minutes after the start of the infusion. In the second series of experiments, rats received vehicle, L-NA (as above), PD98059 (10 mg/kg IP, at the time of the first L-NA administration, n=8), or the combination of L-NA and PD 098,059 (n=8). L-(4,5-3H)Leucine infusion was started 1 hour after injection of the drugs in half of the animals. The protocols were approved by the Animal Care Committee of Université de Montréal.
Protein Synthesis Measurement and Autoradiography:
Frozen aortas and mesenteric arteries were powdered in liquid nitrogen, and proteins were precipitated overnight in trichloroacetic acid (TCA), washed once with TCA and twice with water, and solubilized in KOH to which the scintillation liquid was added. The other half of the tissue was also left overnight in TCA, and the precipitate was solubilized in NaOH to measure protein concentration by the method of Lowry et al.20 The final results are expressed as counts per minute per milligram protein.
Slides of paraffin-embedded aortic sections were soaked in an autoradiography emulsion, dried, and kept at 4°C for 8 weeks in complete darkness. Slides were then developed, fixed, and counterstained with hematoxylin to reveal the nuclei. Images were digitalized at a final magnification of x400.
Phosphospecific Immunoblot of ERK 1/2, cGMP, and Plasma Renin Activity Measurements
ERK /2 activity was estimated by Western blot, with the use of a phospho-specific antibody, as previously described by Touyz et al.21 Equal amounts of proteins (20 µg) were loaded on a 10% SDS–polyacrylamide gel. Proteins were then transferred to a polyvinylidene difluoride membrane and incubated with a phospho-specific ERK 1/2 antibody. The membrane was then washed and incubated with a second antibody. The membrane was incubated with enhanced chemiluminescence (ECL) Western blotting reagents and exposed on Hyperfilm ECL. Results were normalized to control values on each gel to account for methodological variation.
cGMP measurements were performed by using the acetylation procedure, as suggested by the Biotrak cGMP enzyme immunoassay system. Plasma renin activity (PRA) was assessed by a commercial radioimmunoassay kit on plasma samples taken from 6 control rats and 6 rats treated with L-NA (2 injections of 3 mg/kg). Samples were taken before and 5 hours after the first drug injection.
An expanded Methods section can be found in an online data supplement available at http://www.hypertensionaha.org.
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Results |
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Hemodynamic Measurements
In the first series of experiments, administration of L-arginine analogues in 2 boluses over a 5-hour period increased mean arterial pressure (MAP) only slightly compared with preadministration values, with only L-NA having a significant effect (Table). The dose of Ang II selected did not produce a significant elevation of MAP in 24 hours. Administered in combination with Ang II, L-NA and L-NAME produced a significant pressor effect (Table). In the second series of experiments, PD98059 administered either alone or with L-NA did not modify arterial pressure significantly (Table).
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Protein Synthesis and Autoradiography
Basal protein synthesis was 406±42 and 276±26 cpm/mg protein in mesenteric arteries and in the aorta, respectively (Figure 1). In mesenteric arteries, the administration of L-arginine analogues 1 hour before labeled L-leucine infusion did not influence the extent of protein synthesis (Figure 1A). However, in the aorta, the analogues enhanced protein synthesis by 70% to 86% (Figure 1B). Ang II significantly increased protein synthesis by 70% in small (mesenteric) and by 66% in large (aortic) arteries (Figure 1). When endogenous NO production was blocked by L-arginine analogues in addition to Ang II, we observed no modification of protein synthesis in mesenteric arteries (Figure 1C), but we did observe enhanced protein synthesis ranging from 58% to 72% in the aorta (Figure 1D). The effects of Ang II and L-arginine analogues were clearly additive in the aorta. The augmented protein synthesis found in the aorta did not correlate with mean, systolic, or diastolic arterial pressure (data not shown).
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P<0.05 vs true CTLs (ANOVA+Bonferroni correction for multiple comparisons).In our second series of experiments, the effect of L-NA on protein synthesis was reproduced. Indeed, it amplified protein synthesis in the aorta but not in small arteries (Figure 2A and 2B). PD98059, which had no significant effect on its own, blocked L-NA–induced augmentation of protein synthesis in the aorta by 56%.
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Autoradiography of aortic cross sections was performed to localize the enhanced protein synthesis in the aortic wall. It revealed that most of protein synthesis occurred in the media and intima in an evenly distributed fashion, both in control conditions and after L-NA treatment (Figure 3). Indeed, the number of silver grains in the adventitia appears reduced compared with those remaining in the aortic wall.
ERK 1/2 Activity
In the aorta, ERK 1/2 phosphorylation increased after L-NA administration (Figure 2C and 2D). As expected, this effect was abrogated by PD98059, which even decreased ERK 1/2 phosphorylation below control levels. ERK 1/2 activity was also significantly enhanced in small mesenteric arteries during L-NA administration (165±7% from control).
cGMP and PRA Measurements
To confirm that the L-arginine analogues reduced NO production and that Ang II exerted its effect independently from NO, we measured aortic cGMP levels in control and in L-NMMA– and Ang II–treated rats. Two and a half hours after the second bolus injections of L-NMMA, cGMP levels were halved (2.2±0.3 fmol/mg compared with 4.3±0.4 fmol/mg in the control group). In contrast, Ang II had no significant effect on vascular cGMP levels (4.0±0.5 fmol/mg).
To rule out any global effect of Ang II on protein synthesis during NOS inhibition, PRA was measured. In control rats, repeated measurements of PRA were similar at the beginning and 5 hours later (6.2±1.2 and 7.1±1.1 ng angiotensin I/mL per hour, respectively). In L-NA–treated animals, however, PRA decreased from 4.3±0.4 to 1.7±0.5 ng angiotensin I/mL per hour after the 2 bolus injections of the drug.
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Discussion |
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Using a model enabling us to measure pharmacological modulation of protein synthesis, we report that endogenous NO exerts tonic inhibition of vascular wall growth in a vessel-specific manner. In large arteries, NOS blockade stimulated protein synthesis by enhancing ERK 1/2 phosphorylation, whereas in small arteries, NOS blockade did not induce protein synthesis despite elevation of ERK 1/2 phosphorylation. These results suggest heterogeneity in vascular growth responses to NOS blockade and to ERK 1/2 activation.
Although vascular heterogeneity to the relaxing properties of NO has been reported,22 to the best of our knowledge the concept of vascular heterogeneity to the antiproliferative action of NO has never been put forward and has never been examined directly in the same animals. NOS inhibition did not augment protein synthesis in small arteries, consistent with previous reports, including ours, showing that chronic NO deficiency leads to eutrophic remodeling but not to hypertrophy (no change in cross-sectional area despite an enhanced media/lumen ratio) of small mesenteric and cerebral arteries.15,16,23,24 During chronic NO deficiency, these arteries normally undergo eutrophic remodeling in proportion to the elevation of arterial pressure.16 One exception may be the coronary circulation, which seems to have pressure-independent remodeling, possibly related to local Ang II formation.24,25 Indeed, Ang II leads to a pressure-independent hypertrophic remodeling of small arteries when it is administered for long periods,26–28 and we could measure a significant increase of protein synthesis after 24 hours of administration in the present model.
In large arteries, NOS blockade, confirmed by cGMP measurements, enhanced protein synthesis and ERK 1/2 phosphorylation, demonstrating that endogenous NO exerts a tonic inhibition of vascular growth. The involvement of ERK 1/2 in the growth response was confirmed by the efficacy of PD98059 to reduce it. The partial effect of PD98059 suggests that other signaling events could also contribute to the response. Alternatively, higher doses of PD98059 may be required, but 10 mg/kg proved to block 100% of Ang II–induced vascular protein synthesis (C. Daigle, P. Moreau, unpublished data, 2001). The goal of using Ang II was to determine the modulation, by NOS inhibition, of enhanced vascular protein synthesis (compared with physiological protein synthesis) and not to specifically look for interactions. In fact, measurement of PRA shows that acute NOS inhibition decreases the circulating renin-angiotensin system. It appears quite clear that the 2 treatments had additive effects in large arteries, suggesting that NO also exerts a modulation of protein synthesis in conditions of enhanced growth. One may argue that pressure elevation secondary to NOS blockade could promote arterial remodeling, thus explaining part of the enhanced protein synthesis. However, we could not find a correlation between mean, systolic, and diastolic pressure values and protein synthesis, arguing against a secondary effect of NOS blockade. In addition, it is quite clear that increased protein synthesis can occur without elevation of arterial pressure, as we have shown with the administration of a subpressor dose of Ang II.
The enhanced protein synthesis during NOS inhibition could result directly from the reduction of NO production, inasmuch as NO has been shown to modulate growth in vitro (for review, see Sarkar and Webb5 and Jeremy et al6). However, the in vivo situation is more complex, and numerous molecules could be recruited and contribute to the enhancement of protein synthesis and the remodeling process. In that respect, it has been demonstrated that chronic NOS inhibition leads to ACE activation and to the formation of a proinflammatory milieu in the vasculature that could influence VSMC protein synthesis and the development of hypertrophy.25,29,30 Thus, the in vivo measurement of protein synthesis provides an assessment of the final integration of the tissue to the different circulating and local influences and clearly demonstrates that under NOS inhibition, large arteries react with a trophic response partly involving ERK 1/2.
The heterogeneous growth response to NOS inhibition between large and small arteries is not unlikely, because many other vascular functions, including growth responses, differ between distant segments of the arterial tree.31 In an effort to characterize the heterogeneity at the molecular level, ERK 1/2 phosphorylation was measured, because it represents a central element of growth signaling. Furthermore, NO donors have been shown to interact with this element by reducing its phosphorylation.6 Our in vivo study extends these in vitro findings by showing that NOS inhibition amplifies ERK 1/2 phosphorylation. However, activation of ERK 1/2 was observed in both small and large arteries, suggesting that it is not its activation but its vascular effect that is heterogeneous. We are currently testing the role of ERK 1/2 in small-artery vasoconstriction in vivo under NOS inhibition, because this pathway has been shown to be involved in resistance artery VSMC contraction,32,33 a condition associated with the attenuation of growth responses.34
The method used in the present study does not allow for the determination of the nature of the proteins newly synthesized by NOS inhibition or Ang II, although most of the activity appears to be located in the media and the intima with NOS inhibition. Kato et al18 have reported that both hypertensive stimuli, administered alone or in combination, lead to medial thickening of the aorta by cellular hypertrophy and enhanced matrix deposition in the form of fibronectin. It is also noteworthy that intimal and adventitial cell division occurred only during the second day of Ang II administration and not with NOS inhibition. Thus, although not confirmed in the present study, previous results suggest that both intracellular and extracellular proteins account for the elevation of protein synthesis during NOS inhibition and Ang II administration, at least in large arteries.
It has been suggested that L-NAME exerts NO-independent negative metabolic effects on protein synthesis that could account for the lack of hypertrophy, at least in the heart.35 In vessels, we found no evidence that L-NAME is less specific than other L-arginine analogues in terms of growth regulation at doses comparable to that used to induce hypertension (6 mg/kg over 5 hours versus 50 mg/kg per day in chronic studies). Although we solely measured protein synthesis, it represents a prerequisite to the development of vascular hypertrophy, and it appears unlikely that L-NAME has a nonspecific effect. This does not exclude the possibility that L-NAME, being a muscarinic antagonist in vitro,36 could affect the proliferation of specific tissues, such as astrocytes and prostate cancer cells, which have been shown to be modulated by muscarinic interventions.37,38
In conclusion, we report that NO is an endogenous inhibitor of vascular protein synthesis in conduit arteries under physiological and Ang II–stimulated conditions, in part by modulating ERK 1/2 phosphorylation. In contrast, in small arteries from the mesenteric circulation, endogenous NO does not exert any growth inhibition, although it also modulates ERK 1/2 activity. Our findings may help to explain the heterogeneous remodeling of large and small arteries in conditions of endothelial dysfunction, such as essential hypertension.
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Acknowledgments |
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This work was supported by operating grants from the Canadian Institutes for Health Research (CIHR, MT-14380), the Fonds Canadiens pour l’Avancement de la Recherche, and the Heart and Stroke Foundation of Canada. Drs deBlois and Moreau are research scholars from the Fonds de la Recherche en Santé du Québec (FRSQ) and the CIHR, respectively. The following studentships are also acknowledged: Dutch Kidney Foundation (Dr Martens); Société Québécoise d’Hypertension Artérielle (C. Daigle and D. Girardot); and Canadian Society of Hypertension (fellowship, Dr Demeilliers). The authors acknowledge the skillful technical assistance of Louise Ida Grondin.
Received August 1, 2001; first decision August 20, 2001; accepted August 27, 2001.
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