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Am J Physiol Heart Circ Physiol 292: H1789-H1795, 2007. First published December 1, 2006; doi:10.1152/ajpheart.01118.2006
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Resistance artery remodeling in deoxycorticosterone acetate-salt hypertension is dependent on vascular inflammation: evidence from m-CSF-deficient mice

Eun A. Ko,1 Farhad Amiri,1 Nihar R. Pandey,1 Danesh Javeshghani,1 Eyal Leibovitz,1 Rhian M. Touyz,2 and Ernesto L. Schiffrin1

1Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec and 2Kidney Research Centre, Ottawa Health Research Institute/University of Ottawa, Ottawa, Ontario, Canada

Submitted 12 October 2006 ; accepted in final form 30 November 2006


   ABSTRACT
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 ABSTRACT
METHODS
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 DISCUSSION
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Deoxycorticosterone acetate (DOCA)-salt hypertension has an important endothelin-1 (ET-1)-dependent component. ET-1-induced vascular damage may be mediated in part by oxidative stress and vascular inflammation. Homozygous osteopetrotic (Op/Op) mice, deficient in macrophage colony-stimulating factor (m-CSF), exhibit reduced inflammation. We investigated in osteopetrotic (Op/Op) mice the effects of DOCA-salt hypertension on vascular structure, function, and oxidative stress, the latter as manifested by reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase activity. Mice were implanted with DOCA (200 mg/mouse, under 5% isofluorane anesthesia) and given saline for 14 days. Systolic blood pressure (mmHg) was significantly increased (146 ± 2 and 138 ± 1; P < 0.001 vs. basal 115 ± 3 and 115 ± 3, respectively) by DOCA-salt in wild-type (+/+) and heterozygous (Op/+) mice, but not in Op/Op mice (130 ± 1 vs. basal 125 ± 3). Norepinephrine contractile response was significantly enhanced, while acetylcholine endothelium-dependent vasodilation was significantly impaired in DOCA-salt-treated +/+ and Op/+ mice compared with control mice. No changes in norepinephrine-induced contraction and acetylcholine-induced relaxation were observed in DOCA-salt Op/Op mice. DOCA-salt +/+ and Op/+ mice had significantly increased mesenteric resistance artery media-to-lumen ratio and media cross-sectional area, neither of which were altered in Op/Op mice. Basal vascular superoxide production and NAD(P)H oxidase activity, vascular cell adhesion molecule-1 expression, and macrophage infiltration were significantly increased only in DOCA-salt +/+ mice. Thus m-CSF-deficient mice developed less endothelial dysfunction, vascular remodeling, and oxidative stress induced by DOCA-salt than +/+ and Op/+ mice, suggesting that inflammation may play a role in DOCA-salt hypertension, a model that results in part from effects of ET-1, which has proinflammatory actions.

endothelial dysfunction; reactive oxygen species; macrophage/monocyte

THE ROLE OF INFLAMMATION through recruitment, activation, survival, and proliferation of mononuclear phagocytes in the vascular wall has been increasingly recognized in atherosclerosis and hypertension (18). This proinflammatory state is mediated through increased expression of several mediators, including leukocyte adhesion molecules, chemokines, and specific growth factors, and may be triggered by vasoactive agents such as endothelin-1 (ET-1) and angiotensin II (ANG II) (4, 22).

Macrophage colony-stimulating factor (m-CSF) regulates the differentiation, proliferation, and survival of macrophages (20). Osteopetrotic mice are homozygous for a naturally occurring recessive frame shift mutation (Op) in the m-CSF gene leading to absence of m-CSF expression (30, 31). As a consequence, these mice have a defect in osteoclast development, and deficiency in monocyte and macrophage number (21). m-CSF deficiency plays a protective role on the vasculature of atherosclerotic and hypertensive animals (7, 24), through effects on inflammatory pathways [nuclear factor-{kappa}B (NF-{kappa}B) and adhesion molecules such as vascular cell adhesion molecule (VCAM)-1] or via reduced generation of reactive oxygen species (ROS). However, whether inflammation plays an important role and m-CSF deficiency confers vascular protective effects to a form of hypertension with an important ET-1-dependent component is unknown. We used the deoxycorticosterone acetate (DOCA)-salt hypertensive model, which has an ET-1-dependent component (14, 16), to test the hypothesis that m-CSF deficiency could exert vasculoprotective effects in this hypertensive model.


   METHODS
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Animals. The present study was performed under protocols approved by the Animal Care Committee of the Clinical Research Institute of Montreal and performed according to recommendations of the Canadian Council of Animal Care. Heterozygous m-CSF mice (Op/+, B6C3Fe-a/a-CSF-1 op/CSF-11), purchased from Jackson Labs (Bar Harbor, ME), were cross-bred to obtain mice homozygous for the CSF-1 Op allele (Op/Op, B6C3Fe-a/a-CSF-11/CSF-11). Op/+ and +/+ littermates had no distinguishing phenotypic features, whereas Op/Op mice were identified by the absence of tooth eruption, because of which they had to be fed a soft nutritionally balanced Transgenic Dough diet (BioServ, Frenchtown, NJ). Mice were unilaterally nephrectomized (UniNx). In 3- to 4-mo-old mice, silicone rubber impregnated with DOCA (200 mg/mouse) was implanted subcutaneously and mice were offered 1% saline to drink. Control mice received a silicone rubber implant without DOCA and were offered tap water. To dissect the role of blood pressure (BP) elevation, we infused a pressor dose of norepinephrine (3.8 µg·kg–1·min–1) with Alzet osmotic minipumps (Durect, Cupertino, CA) in a parallel set of animals of all genotypes, as described elsewhere (10). After surgery systolic BP (SBP) was measured weekly by the tail-cuff method, and after 2 wk of treatment mice were killed by decapitation.

Genotyping. All animals were genotyped at 6 wk of age by tail biopsy and PCR (1, 7) to distinguish Op/Op, Op/+, and +/+ mice.

Preparation and study of arterial function. Second-order branches of mesenteric artery (~2 mm in length with internal diameter ~150–250 µm) were dissected and mounted on a pressurized myograph (7). Briefly, vessels were equilibrated (60 min, 45 mmHg of intraluminal pressure) in warmed, oxygenated (95% air-5% CO2) physiological salt solution (PSS, pH 7.4) containing (mmol/l) 120 NaCl, 25 NaHCO3, 4.7 KCl, 1.18 KH2PO4, 1.18 MgSO4, 2.5 CaCl2, 0.026 EDTA, and 5.5 glucose. Endothelium-dependent relaxations were assessed by measuring dilatory responses in norepinephrine-precontracted vessels (5 x 10–5 mol/l) to cumulative increasing concentrations of acetylcholine (10–9-10–4 mol/l). To evaluate NO bioavailability, acetylcholine concentration-response curves were repeated after 20-min incubation with the nitric oxide synthase inhibitor N{omega}-nitro-L-arginine methyl ester (L-NAME, 10–4 mol/l). Concentration-response curves to norepinephrine (10–7-10–4 mol/l) and ET-1 (10–10-10–7 mol/l) were performed to evaluate vascular contractility and calculated as a percentage of basal values. Thereafter, vessels were perfused with Ca2+-free PSS containing 10 mmol/l EGTA for 30 min to eliminate any tone, and lumen and media dimensions were measured. Concentrations causing half-maximal response (EC50 values) were expressed as geometric means with 95% confidence intervals (CI).

Measurement of vascular reduced nicotinamide adenine dinucleotide phosphate oxidase and basal superoxide activity. Vascular superoxide (O2bullet–) and reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase activity was measured by chemiluminescence with lucigenin and NAD(P)H on mesenteric artery segments as previously described (2).

Laser confocal microscopy. Laser confocal microscopy (Zeiss LSM 510 system, Carl Zeiss MicroImaging, Thornwood, NY) was performed on mesenteric resistance arteries as previously described (23). Briefly, fixed pressurized vessels were incubated with macrophage-specific antigen MOMA-2 antibody (Serotec, Raleigh, NC) for 16 h at 4°C. After being washed, vessels were incubated with 200 µg/ml Alexa Fluor 647 anti-rat IgG (Molecular Probes, Eugene, OR) for 30 min at 37°C. {alpha}-Actin staining was achieved by incubation with 10 µmol/l phalloidin (Molecular Probes) for 30 min at room temperature. MOMA-2 staining was quantified with Northern Eclipse and expressed as a percentage of MOMA-2/total surface area.

NF-{kappa}B activation assay. Mesenteric artery proteins were extracted from frozen tissue as described above and in Ref. 2. Thereafter, NF-{kappa}B activation was quantified by using a TransAM kit to measure activated p50 subunit of NF-{kappa}B as previously described (7) according to the manufacturer's protocol (Active Motif, Carlsbad, CA).

Western blot analysis. Mesenteric artery proteins were extracted from frozen tissue as previously described (23). Thereafter, samples were separated by SDS-PAGE, transferred to nitrocellulose membranes, and incubated with specific antibody to VCAM-1 (Santa Cruz Biotechnology, Santa Cruz, CA). Bands were visualized by chemiluminescence (Pierce Biotechnology, Rockford, IL) and were quantified by densitometry (Northern Eclipse 5.0, EMPIX Imaging, Mississauga, ON, Canada).

Data analysis. Results are presented as means ± SE, except for EC50 values, which are presented as means with 95% CI. Comparisons between groups were made by two-way ANOVA or repeated-measures one-way ANOVA followed by a Student-Newman-Keuls test, as appropriate. P < 0.05 was considered statistically significant.


   RESULTS
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Physiological parameters. Body weight was significantly lower in Op/Op mice than in +/+ and Op/+ mice and was unaffected by DOCA-salt treatment. DOCA-salt treatment significantly increased SBP only in +/+ and Op/+ mice (Table 1).


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  		Table 1. Physiological and morphological characteristics of mesenteric resistance arteries of all experimental groups

 
Vascular function of mesenteric resistance arteries. Vasodilation to acetylcholine was significantly impaired in DOCA-salt +/+ and Op/+ mice compared with UniNx mice. No impairment of endothelium-dependent vasorelaxation was observed in DOCA-salt Op/Op mice (Fig. 1, A–D) and in norepinephrine-infused mice of all genotypes (Fig. 1E). Relaxation to acetylcholine was significantly impaired by the nitric oxide synthase inhibitor L-NAME in DOCA-salt and UniNx +/+ and Op/+ mice but to a lesser extent in DOCA-salt and UniNx Op/Op mice (Fig. 2). Endothelium-independent relaxation to sodium nitroprusside was similar in all groups (Supplemental Fig. I; the online version of this article contains these supplemental data). Norepinephrine contractile responses were significantly enhanced in DOCA-salt +/+ and Op/+ mice, whereas no effect was observed in DOCA-salt Op/Op mice compared with UniNx mice (Fig. 3). ET-1 contractile responses were similar in all groups (Fig. 4).


Figure 1
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  		Fig. 1. Mesenteric resistance artery endothelium-dependent relaxation to acetylcholine (ACh). Relaxation is expressed as % increase of intraluminal diameter of norepinephrine (5 x 10–5 mol/l)-precontracted vessels in response to concentration-response curves to ACh in uninephrectomized (UniNx) and deoxycorticosterone acetate (DOCA)-salt +/+ mice (A), in Op/+ mice (B), in Op/Op mice (C), and in all mice (D) and in norepinephrine-infused mice (E). Open and closed symbols represent UniNx and DOCA-salt mice, respectively. Results for dose-response curves are means ± SE, and EC50 values are presented as geometric means [95% confidence intervals (CI)]. Results were analyzed by 1-way repeated measures ANOVA followed by Newman-Keuls test; n = 6 or 7 animals/group. *P < 0.01 vs. UniNx littermates; {dagger}P < 0.05 vs. UniNx littermates.

 

Figure 2
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  		Fig. 2. Endothelium-dependent relaxation of mesenteric resistance arteries from DOCA-salt or UniNx +/+ (A), Op/+ (B) and Op/Op (C) mice to ACh in the absence (saline, open symbols) and presence (closed symbols) of N{omega}-nitro-L-arginine methyl ester (L-NAME). Results are means ± SE and were analyzed by 1-way repeated-measures ANOVA followed by Newman-Keuls test; n = 6 or 7 animals/group. *P < 0.01 vs. UniNx littermates; {dagger}P < 0.001 vs. UniNx littermates.

 

Figure 3
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  		Fig. 3. Mesenteric resistance artery concentration-response curves to norepinephrine in UniNx and DOCA-salt +/+ mice (A), in Op/+ mice (B), in Op/Op mice (C), and in all mice (D) and in norepinephrine-infused mice (E). Open and closed symbols represent UniNx and DOCA-salt mice, respectively. Results for dose response curves are means ± SE, and EC50 values are presented as geometric means (95% CI). Results were analyzed by 1-way repeated measures ANOVA followed by Newman-Keuls test; n = 6 or 7 animals/group. *P < 0.01 vs. UniNx littermates; {dagger}P < 0.05 vs. UniNx littermates.

 

Figure 4
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  		Fig. 4. Mesenteric resistance artery concentration-response curves to endothelin-1 in +/+ mice (A), in Op/+ mice (B), in Op/Op mice (C), and in all mice (D). Open and closed symbols represent UniNx and DOCA-salt mice, respectively. Results for dose-response curves are means ± SE, and EC50 values are presented as geometric means (95% CI). Results were analyzed by 1-way repeated-measures ANOVA followed by Newman-Keuls test; n = 6 or 7 animals/group.

 
Mesenteric resistance artery morphology. DOCA-salt treatment resulted in increased mesenteric resistance artery media-to-lumen ratio (M/L) and media cross-sectional area (MCSA), indicating hypertrophic remodeling of these vessels, only in +/+ and Op/+ mice compared with untreated UniNx +/+ and Op/+ mice (Table 1). Media thickness, M/L, and MCSA were similar in DOCA-salt treated and UniNx Op/Op mice and in all genotypes of norepinephrine-infused mice (Table 1).

Vascular superoxide and NAD(P)H oxidase activity. DOCA-salt treatment increased both O2bullet– generation and NAD(P)H oxidase activity in mesenteric arteries in +/+ mice, whereas it only increased NAD(P)H oxidase activity in Op/+ mice (Fig. 5). Neither O2bullet– generation nor NAD(P)H oxidase activity of mesenteric arteries was affected by DOCA-salt treatment in Op/Op mice (Fig. 5).


Figure 5
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  		Fig. 5. Vascular O2bullet– (A) and reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase (B) activity in mesenteric arteries. Open and filled bars represent UniNx and DOCA-salt mice, respectively. Results are means ± SE and were analyzed by 2-way ANOVA followed by Newman-Keuls test; n = 5–7 animals/group. *P < 0.05 vs. UniNx littermates.

 
Vascular inflammatory markers. Macrophage infiltration in mesenteric resistance arteries was significantly increased only in DOCA-salt-treated +/+ and Op/+ mice compared with UniNx littermates (Fig. 6A), whereas in DOCA-salt Op/Op mice there was no significant change. On the other hand, DOCA-salt treatment activated NF-{kappa}B in mesenteric arteries only in +/+ mice (Fig. 6B). Probably resulting from NF-{kappa}B activation, VCAM-1 expression was increased only by DOCA-salt in mesenteric arteries in +/+ mice (Fig. 6C).


Figure 6
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  		Fig. 6. Vascular inflammation in mesenteric arteries of DOCA-salt and UniNx mice. A: quantification of macrophage infiltration into the media of mesenteric arteries of all groups. Data are expressed as % of MOMA-2/total surface area. B: nuclear factor-{kappa}B (NF-{kappa}B) p50 subunit activation in mesenteric resistance arteries as determined by ELISA. C: vascular expression of vascular cell adhesion molecule (VCAM)-1 (top) and beta-actin (bottom) in mesenteric arteries of DOCA-salt and UniNx mice. Results are presented as means ± SE and were analyzed by 2-way ANOVA followed by Newman-Keuls test; n = 4 or 5 animals/group. *P < 0.01 vs. UniNx littermates; {dagger}P < 0.05 vs. UniNx littermates.

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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m-CSF deficiency in the present study was associated with attenuated BP rise and vascular remodeling, endothelial dysfunction, NAD(P)H oxidase activation, and vascular inflammation in mesenteric resistance arteries from DOCA-salt hypertensive mice, a model of hypertension that has a significant ET-1-dependent component (13, 16). These results, taken together with our previously published findings on the role of inflammation in ANG II-mediated effects (7), suggest that inflammation may be an important mediator of vascular remodeling effects of potent vasoactive agents such as ET-1 and ANG II.

In hypertension, the vascular changes that result in decreased lumen size and increased M/L may be structural, functional, or mechanical and may be caused by different local agents or by hormonal factors (12). In DOCA-salt +/+ and Op/+ mice, remodeled resistance vessels had increased MCSA, indicating the presence of hypertrophic remodeling, which has been considered a hallmark of ET-1-dependent hypertension (6, 8, 9).

There is abundant evidence that increased ROS production by NAD(P)H oxidase in hypertension may contribute to vascular injury by promoting vascular smooth muscle cell growth, extracellular matrix deposition, activation of matrix metalloproteinases, inflammation, endothelial dysfunction, and increased vascular tone (5, 29). We (2, 28) and others (3) have shown that NAD(P)H oxidase activity, one of the main sources of O2bullet– in the blood vessel wall, is enhanced in ET-1-dependent hypertension. However, our results indicate that BP elevation may not depend on NAD(P)H oxidase activity and increased ROS generation in the model examined in this study, since we found increased SBP in DOCA-salt Op/+ mice in the absence of increased NAD(P)H oxidase activity. This agrees with previous findings from our laboratory in some other models of hypertension (2, 7).

In addition to altered vascular structure, DOCA-salt-treated +/+ and Op/+ mice exhibited impaired endothelial function compared with all UniNx mice and DOCA-salt treated Op/Op mice. Endothelial dysfunction could be a consequence of decreased NO bioavailability due to increased ROS production. To assess this, mesenteric resistance vessels from DOCA-salt +/+ and Op/+ mice were incubated with L-NAME and were found to have significant further impairment of acetylcholine-induced relaxation, which was abrogated by L-NAME. This suggests that reduced NO production or bioavailability, which may participate in DOCA-salt-induced endothelial dysfunction (17, 19, 27), was not prominent in the present experiment paradigm in +/+ and Op/+ mice, since the significant L-NAME-induced effect found on acetylcholine-induced relaxation demonstrates the presence of abundant NO production by nitric oxide synthase in resistance vessels from these mice. However, impaired endothelial function was not observed in DOCA-salt-treated Op/Op mice. Furthermore, L-NAME did not abrogate acetylcholine-induced relaxation, but reduced it only partially. Thus L-NAME was less effective on Op/Op mice, whether UniNx- or DOCA-salt treated, than on UniNx or DOCA-salt +/+ and Op/+ mice This suggests that in Op/Op mice there may be a switch from NO-mediated acetylcholine-stimulated endothelium-dependent relaxation to endothelium-derived hyperpolarizing factor-mediated relaxation. This result is paradoxical, since it would be expected that m-CSF-dependent cells (macrophages) would contribute to macrophage-derived NAD(P)H oxidase and ROS formation in the vascular wall (26) and to decreased bioavailability of NO leading to endothelial dysfunction, which should be less evident in Op/Op mice, which is not the case.

Oxidative stress has been shown to be linked to a proinflammatory state that includes upregulation of adhesion molecules (VCAM-1 and ICAM-1) and chemotactic molecules such as monocyte chemoattractant peptide-1 (11). Indeed, DOCA-salt treatment induced a proinflammatory state as demonstrated by increased macrophage infiltration and increased activity of transcription factor NF-{kappa}B, and its downstream target VCAM-1 in +/+ mice and to a lesser extent in Op/+ mice. The absence of DOCA-salt induced activation of NAD(P)H oxidase and vascular NF-{kappa}B and VCAM-1 expression in Op/Op mice supports the important role of inflammation in this model of hypertension, probably a consequence in part of the action of ET-1, which we previously showed (15, 25) contributes to remodeling of resistance vessels in this hypertensive model.

Mesenteric resistance arteries from DOCA-salt-treated +/+ and Op/+ mice showed enhanced contractility to norepinephrine that was not observed in DOCA-salt Op/Op mice. Increased responsiveness to norepinephrine and impaired endothelium-dependent relaxation contribute to increased peripheral resistance and, together with the structural and functional vascular changes, can ultimately affect BP, all of which were significantly increased only in DOCA-salt +/+ and Op/+ mice and not in DOCA-salt Op/Op mice. This may explain in part the differences in BP elevation observed and the blunting of BP elevation in Op/Op mice. Additionally, data obtained from the norepinephrine-infused mice suggest that the observed vascular changes of mesenteric resistance arteries were merely due to SBP elevation since norepinephrine-induced hypertensive mice did not exhibit altered vascular morphology and function in any genotype.

In conclusion, this is the first report that m-CSF deficiency resulting in reduced vascular inflammation plays an important protective effect in the deleterious vascular effects of DOCA-salt and potentially of ET-1, which has been shown to be a major mediator in this model, on remodeling, ROS generation, and inflammation in mesenteric resistance arteries. These findings support the hypothesis that vascular inflammation may be one of the factors that participate in mechanisms leading to remodeling of resistance vessels in experimental hypertension.


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This research was supported by Grants 13570 and 37917 (to E. L. Schiffrin) and a Group Grant to the Multidisciplinary Research Group on Hypertension, all from the Canadian Institutes of Health Research.


   ACKNOWLEDGMENTS
 
The authors thank Marie-Josée Lacombe and Marie-Eve Deschênes for technical help.


   FOOTNOTES
 

Address for reprint requests and other correspondence: E. L. Schiffrin, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Côte Ste-Catherine Road, B-127, Montreal, QC, Canada H3T 1E2 (e-mail: ernesto.schiffrin{at}mcgill.ca)

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
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  1. Abboud SL, Woodruff K, Liu C, Shen V, Ghosh-Choudhury N. Rescue of the osteopetrotic defect in op/op mice by osteoblast-specific targeting of soluble colony-stimulating factor-1. Endocrinology 143: 1942–1949, 2002.[Abstract/Free Full Text]
  2. Amiri F, Virdis A, Neves MF, Iglarz M, Seidah NG, Touyz RM, Reudelhuber TL, Schiffrin EL. Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction. Circulation 110: 2233–2240, 2004.[Abstract/Free Full Text]
  3. Beswick RA, Dorrance AM, Leite R, Webb RC. NADH/NADPH oxidase and enhanced superoxide production in the mineralocorticoid hypertensive rat. Hypertension 38: 1107–1111, 2001.[Abstract/Free Full Text]
  4. Bush E, Maeda N, Kuziel WA, Dawson TC, Wilcox JN, DeLeon H, Taylor WR. CC chemokine receptor 2 is required for macrophage infiltration and vascular hypertrophy in angiotensin II-induced hypertension. Hypertension 36: 360–363, 2000.[Abstract/Free Full Text]
  5. Chen X, Touyz RM, Park JB, Schiffrin EL. Antioxidant effects of vitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. Hypertension 38: 606–611, 2001.[Abstract/Free Full Text]
  6. d'Uscio LV, Barton M, Shaw S, Moreau P, Luscher TF. Structure and function of small arteries in salt-induced hypertension: effects of chronic endothelin-subtype-A-receptor blockade. Hypertension 30: 905–911, 1997.[Abstract/Free Full Text]
  7. De Ciuceis C, Amiri F, Brassard P, Endemann DH, Touyz RM, Schiffrin EL. Reduced vascular remodeling, endothelial dysfunction, and oxidative stress in resistance arteries of angiotensin II-infused macrophage colony-stimulating factor-deficient mice: evidence for a role in inflammation in angiotensin-induced vascular injury. Arterioscler Thromb Vasc Biol 25: 2106–2113, 2005.[Abstract/Free Full Text]
  8. Deng LY, Schiffrin EL. Morphological and functional alterations of mesenteric small resistance arteries in early renal hypertension in rats. Am J Physiol Heart Circ Physiol 261: H1171–H1177, 1991.[Abstract/Free Full Text]
  9. Deng LY, Schiffrin EL. Effects of endothelin on resistance arteries of DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol 262: H1782–H1787, 1992.[Abstract/Free Full Text]
  10. Fukai T, Siegfried MR, Ushio-Fukai M, Griendling KK, Harrison DG. Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. Circ Res 85: 23–28, 1999.[Abstract/Free Full Text]
  11. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 86: 494–501, 2000.[Abstract/Free Full Text]
  12. Intengan HD, Schiffrin EL. Structure and mechanical properties of resistance arteries in hypertension: role of adhesion molecules and extracellular matrix determinants. Hypertension 36: 312–318, 2000.[Abstract/Free Full Text]
  13. Lariviere R, Day R, Schiffrin EL. Increased expression of endothelin-1 gene in blood vessels of deoxycorticosterone acetate-salt hypertensive rats. Hypertension 21: 916–920, 1993.[Abstract/Free Full Text]
  14. Lariviere R, Thibault G, Schiffrin EL. Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate-salt hypertensive but not in spontaneously hypertensive rats. Hypertension 21: 294–300, 1993.[Abstract/Free Full Text]
  15. Li JS, Lariviere R, Schiffrin EL. Effect of a nonselective endothelin antagonist on vascular remodeling in deoxycorticosterone acetate-salt hypertensive rats. Evidence for a role of endothelin in vascular hypertrophy. Hypertension 24: 183–188, 1994.[Abstract/Free Full Text]
  16. Li JS, Schiffrin EL. Effect of chronic treatment of adult spontaneously hypertensive rats with an endothelin receptor antagonist. Hypertension 25: 495–500, 1995.[Abstract/Free Full Text]
  17. Li JS, Sventek P, Schiffrin EL. Effect of antihypertensive treatment and N{omega}-nitro-L-arginine methyl ester on cardiovascular structure in deoxycorticosterone acetate-salt hypertensive rats. J Hypertens 14: 1331–1339, 1996.[CrossRef][ISI][Medline]
  18. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 105: 1135–1143, 2002.[Abstract/Free Full Text]
  19. Luscher TF, Diederich D, Weber E, Vanhoutte PM, Buhler FR. Endothelium-dependent responses in carotid and renal arteries of normotensive and hypertensive rats. Hypertension 11: 573–578, 1988.[Abstract/Free Full Text]
  20. Naito M, Nomura H, Esaki T, Iguchi A. Characteristics of macrophage-derived foam cells isolated from atherosclerotic lesions of rabbits. Atherosclerosis 135: 241–247, 1997.[CrossRef][ISI][Medline]
  21. Naito M, Umeda S, Takahashi K, Shultz LD. Macrophage differentiation and granulomatous inflammation in osteopetrotic mice (op/op) defective in the production of CSF-1. Mol Reprod Dev 46: 85–91, 1997.[CrossRef][ISI][Medline]
  22. Neves MF, Amiri F, Virdis A, Diep QN, Schiffrin EL. Role of aldosterone in angiotensin II-induced cardiac and aortic inflammation, fibrosis, and hypertrophy. Can J Physiol Pharmacol 83: 999–1006, 2005.[CrossRef][ISI][Medline]
  23. Neves MF, Endemann D, Amiri F, Virdis A, Pu Q, Rozen R, Schiffrin EL. Small artery mechanics in hyperhomocysteinemic mice: effects of angiotensin II. J Hypertens 22: 959–966, 2004.[CrossRef][ISI][Medline]
  24. Rajavashisth T, Qiao JH, Tripathi S, Tripathi J, Mishra N, Hua M, Wang XP, Loussararian A, Clinton S, Libby P, Lusis A. Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest 101: 2702–2710, 1998.[ISI][Medline]
  25. Schiffrin EL, Lariviere R, Li JS, Sventek P, Touyz RM. Deoxycorticosterone acetate plus salt induces overexpression of vascular endothelin-1 and severe vascular hypertrophy in spontaneously hypertensive rats. Hypertension 25: 769–773, 1995.[Abstract/Free Full Text]
  26. Schiffrin EL, Touyz RM. Inflammation and vascular hypertrophy induced by angiotensin II: role of NADPH oxidase-derived reactive oxygen species independently of blood pressure elevation? Arterioscler Thromb Vasc Biol 23: 707–709, 2003.[Free Full Text]
  27. Somers MJ, Mavromatis K, Galis ZS, Harrison DG. Vascular superoxide production and vasomotor function in hypertension induced by deoxycorticosterone acetate-salt. Circulation 101: 1722–1728, 2000.[Abstract/Free Full Text]
  28. Touyz RM, Chen X, Tabet F, Yao G, He G, Quinn MT, Pagano PJ, Schiffrin EL. Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res 90: 1205–1213, 2002.[Abstract/Free Full Text]
  29. Touyz RM, Schiffrin EL. Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 122: 339–352, 2004.[CrossRef][ISI][Medline]
  30. Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW Jr, Ahmed-Ansari A, Sell KW, Pollard JW, Stanley ER. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci USA 87: 4828–4832, 1990.[Abstract/Free Full Text]
  31. Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa S. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345: 442–444, 1990.[CrossRef][Medline]



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