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. Author manuscript; available in PMC: 2009 Oct 1.
Published in final edited form as: Arterioscler Thromb Vasc Biol. 2008 May 15;28(8):1432–1438. doi: 10.1161/ATVBAHA.108.167205

Role of Advanced Glycation End Products with Oxidative Stress in Resistance Artery Dysfunction in Type 2 Diabetic mice

Jun Su 1, Pamela A Lucchesi 1, Romer A Gonzalez-Villalobos 2, Desiree I Palen 2, Bashir M Rezk 1, Yasuhiro Suzuki 1, Hamid A Boulares 1, Khalid Matrougui 2
PMCID: PMC2755261  NIHMSID: NIHMS124820  PMID: 18483403

Abstract

Objective

Type 2 diabetes is associated with increased advanced glycation end products (AGEs) formation and vasculopathy. We hypothesized that AGEs contribute to resistance artery dysfunction.

Methods and Results

Type 2 diabetic db−/db− (diabetic) and non-diabetic db−/db+ (control) mice were treated with the AGEs inhibitor (aminoguanidine: 50 mg/Kg/day) for 3 months. Isolated mesenteric resistance arteries (MRAs) were mounted in an arteriograph. Pressure-induced myogenic tone (MT) was increased in diabetic mice but was unaffected by aminoguanidine treatment. Phenylephrine-induced contraction and nitric oxide donor-induced endothelium-independent relaxation were similar in all groups. In diabetic mice, endothelium-dependent relaxation in response to shear-stress or acetylcholine was altered and was associated with reduced eNOS protein and mRNA expression. Aminoguanidine treatment improved endothelial function and restored eNOS expression. AGEs formation and hypoxia markers (PAI-1 and Bnip3) were increased in MRA from diabetic mice and normalized with Aminoguanidine. Primary cultured endothelial cells (EC) isolated from resistance arteries subjected to high glucose for 48 hrs showed decreased eNOS expression and phosphorylation in response to calcium ionophore. High glucose decreased anti-oxidant protein (MnSOD) and increased pro-oxidant proteins (gp91phox) expression leading to increased oxidative stress generation, as assessed by DHE staining and endothelial NADH/NADPH oxidase activity. The pre-incubation of endothelial cells with aminoguanidine restored eNOS-phosphorylation and expression as well as the balance between pro- and anti-oxidant factors induced by high glucose.

Conclusions

We provide evidence of a link between AGEs, oxidative stress and resistance artery endothelial cell dysfunction in type 2 diabetic mice. Thus, AGEs and oxidative stress may be a potential target for overcoming diabetic microvessels complications.

Keywords: Resistance artery, oxidative stress, AGEs, type 2 diabetic mice

INTRODUCTION

Resistance arteries are exposed to hemodynamic forces, including pressure and shear stress. Endothelial cells have been proposed to be the primary sensors of wall shear stress for the transduction of mechanical stimuli into biological responses.1 Resistance arteries play a crucial role in blood pressure control, tissue perfusion, and metabolism since they are prime determinant of local blood flow to subsequently tissues perfusion. Resistance artery tone is mainly regulated by mechanical factors (pressure and flow; mechanotransduction) and vasoactive agents.2 The control of resistance artery tone is dependent upon a complex interplay between endothelial cells (EC) and vascular smooth muscle cells (VSMC). In general, flow induces endothelium-dependent vasodilation via release of nitric oxide (NO), prostacylin I2 and endothelium-derived hyperpolarizing factor from EC.3 On the other hand, pressure-induced contraction (myogenic tone, MT) is endothelium-independent and is mediated by direct effect of intraluminal pressure on VSMC.2

Although the multi-factorial effects of diabetes on the regulatory mechanisms that govern blood vessel diameter are not well understood, it is likely that altered vascular reactivity is involved. Limited studies of the relationship between hyperglycemia and altered vascular responsiveness have been conducted in the microvasculature from diabetic models and conflicting results have been obtained. For example, skeletal muscle arterioles of streptozotocin treated rats exhibit enhanced pressure-induced myogenic responsiveness that is endothelium-independent but requires increased activation of L-type Ca2+ channels and protein kinase C. Lagaud et al4 demonstrated increased myogenic tone in mesenteric resistance arteries from 12 and 16 week diabetic mice compared to the controls that was insensitive to L-NAME treatment or removal of the endothelium. On the other hand, Bagi et al. saw no significant increase in myogenic tone in coronary arterioles from 12-week diabetic mice.5

The extracellular matrix (ECM) plays a major role in the control of endothelial and smooth muscle cells function. The content and the nature of ECM are highly controlled by the balance between matrix degradation via matrix metalloproteinases (MMPs) and the expression of matrix proteins such as collagen and laminin. More recently, MMPs have been shown to regulate growth factor receptor transactivation via the release of endogenous ligands from the plasma membrane or the ECM.6–8 For instance, we reported that MMP-2/9-mediated EGF receptor transactivation in the control of resistance artery MT.9

ECM in normal vessels serves several important functions, which include providing a supportive structural lattice and connecting individual cells to integrate individual smooth muscle contraction or relaxation. The ECM may also be involved in mechanotrandsuction that regulates resistance artery tone. We previously demonstrated altered shear stress-dependent relaxation of resistance artery from vimentin (intermediate filament connected to ECM) knockout mouse.10 It has been shown that the formation of connections between integrins and their specific ECM ligands is crucial in relaying the signal induced by shear stress to intracellular pathways11 indicating the importance of ECM on the function of vascular cells.

Type 2 diabetes is characterized by a chronic hyperglycemia due to deficiency in insulin action (insulin resistance) and is often associated with obesity, hypercholesterolemia and hyperlipidemia.12–14 The morbidity and mortality of diabetes are due to the development of both macrovascular and microvascular complications.15–17 Despite major advances in the diagnosis and treatment of diabetes and the related vasculopathy in the past century; it remains a serious clinical and public health problem. There is increasing evidence of a causal role for AGEs formation in the development of diabetic complications, including nephropathy and vascular disease.18–20 Increased levels of glucose in diabetes react non-enzymatically at their carbonyl ends with the amino groups of proteins to form reversible Schiff bases and then Amadori compounds. These early Amadori compounds undergo further chemical modifications to become irreversibly cross-linked derivatives called AGEs. Accumulated AGEs in circulating blood and various tissues are implicated in the development of diabetic vasculopathy.21–23 AGEs exert effects both directly through the formation of protein cross-links that alter the structure and function of ECM and by interacting with specific cell surface receptors.24–26

Type 2 diabetes is well known as oxidative stress disease.27 Hyperglycemia increases the production of reactive oxygen species (ROS), although the precise mechanisms remain to be elucidated. Little is known about the role of AGEs formation with oxidative stress on resistance artery reactivity in type 2 diabetes.

Thus, in the present study, we explored the mechanisms by which AGEs formation leads to resistance artery dysfunction seen in diabetes. Mesenteric resistance artery function was studied in type 2 diabetic db−/db− mice without or with aminoguanidine treatment to prevent AGEs formation.

METHODS

Animal Model

Obese type 2 diabetic db−/db− (diabetic) and non-diabetic db+/db− (control) adult male mice were obtained from Jackson Laboratory. Mice were divided into 4 groups: 1) diabetic mice with no treatment (n=7); 2) diabetic mice that received 50 mg/Kg/day of aminoguanidine in the drinking water for 3 months (n=7); 3) control mice with no treatment (n=7); and 4) control mice who received 50 mg/Kg/day of aminoguanidine in the drinking water for 3 months (n=7).

These studies conformed to the principles of the National Institutes of Health “Guide for the Care and Use of Laboratory Animals”, and were approved by the LSU Institutional Animal Care and Use Committee.

Mean arterial pressure measurement

Isolated mesenteric resistance artery

Western blot analysis:

Endothelial Cell Culture:

NADH and NADPH oxidase activity

Dihydroethidium staining

Quantitative real-time PCR

RESULTS

Blood glucose was significantly high in diabetic compared to control mice (370±40 mg/dl vs. 109±13 mg/dl respectively, p<0.05). The treatment with aminoguanidine had no effect on blood glucose.

Blood pressure was similar in all groups of mice (93.3±3.4 vs. 95±5.1 mmHg, diabetic vs. control respectively, p>0.05) indicating that type 2 diabetes is not associated with blood pressure increase (Figure 1A). The treatment with aminoguanidine had no effect on blood pressure (Figure 1A). The treatment with AG reduced body weight of diabetic mice, but no effect was observed in control mice (Figure 1B).

Figure 1. Blood pressure and body weight.

Figure 1

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1A: Similar mean arterial pressure measured at left carotid artery in both groups with and without treatment with aminoguanidine (AG) n=7 in each group; 1B: A comparison of body weight between diabetic and control with and without treatment aminoguanidine (AG), n=7 in each group.

In freshly isolated and mounted mesenteric resistance arteries in arteriograph, stepwise increases intraluminal pressure induced myogenic tone (MT) development, which was significantly enhanced in diabetic compared to control mice (Figure 2A). The aminoguanidine treatment for 3 months did not affect MT in all groups (Figure 2B–C) indicating that AGEs formation is not involved in the development and enhanced MT. Phenylephrine dose-response induced contraction of resistance arteries was similar in all groups (Figure 2D–E). Endothelium-independent relaxation of MRA to SNP was similar in all groups indicating that the sensitivity of SMC to nitric oxide was not altered in type 2 diabetes (Figure 2E).

Figure 2.

Figure 2

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2A: Pressure-induced myogenic tone (MT) in MRA from diabetic and control (n=7) mice, *P<0.05 diabetic vs. control mice; 2B: Pressure-induced MT in MRA from control with or without aminoguanidine (AG) (n=7) and from diabetic with or without AG (2C) (n=7); 2D: Phenylephrine-induced contraction of MRA (n=6); 2E: Sodium nitroprusside (SNP)-induced relaxation in MRA (n=6), P>0.05.

On the other hand, endothelium-dependent relaxation was significantly altered in diabetic compared to control mice assessed by alteration of flow-induced dilation (Figure 3). The inhibition of eNOS with L-NAME decreased flow-induced dilation, which was more pronounced in control compared to diabetic mice (data not shown). The treatment with aminoguanidine for 3 months significantly improved the endothelium-dependent relaxation in response to shear stress in diabetic mice and no effect was observed in control mice (Figure 3A). Similarly, acetylcholine (dose-response)-induced endothelium-dependent relaxation was significantly reduced in diabetic compared to control mice (figure 3B), which was improved after treatment with aminoguanidine for 3 months.

Figure 3.

Figure 3

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3A: Diameter changes in response to flow in MRA from control and diabetic±AG (n=6), *P<0.001 diabetic vs. control±AG, diabetic+AG; 3B: Diameter changes in response to acetylcholine in MRA from control and diabetic±AG (n=7), *P<0.001 diabetic vs. control±AG, diabetic+AG; 3C: eNOS expression in MRA from control and diabetic±AG (n=6), *P<0.001 diabetic vs control±AG, diabetic+AG; 3D: eNOS mRNA of MRA from control±AG and diabetic±AG, (n=5), P>0.05.

Resistance artery endothelium dysfunction in diabetic mice was associated with a decrease in endothelial nitric oxide synthesis (eNOS) expression, which was normalized with aminoguanidine treatment (figure 3C). It has been shown that endothelial cells dysfunction is associated with hypoxia. PAI-1 and bnip3 are considered as markers of hypoxia.32 Thus, we showed an increase of PAI-1 and bnip3 expression in diabetic mice compared to control mice MRA (Figure 4A, C). Real time PCR revealed a similar eNOS (Figure 3D), PAI-1 and bnip3 mRNA levels (figure 4B, D) indicating that type 2 diabetes affect mRNA transcription rather than gene expression.

Figure 4.

Figure 4

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4A–B: Expression and mRNA level of PAI-1 in MRA from control±AG and diabetic±AG, (n=5), PAI-1 expression (*P<0.001 control vs. diabetic±AG), PAI-1 mRNA was different in all groups; 4C–D: Expression and mRNA level of Bnip3 in MRA from control±AG and diabetic±AG, (n=5), Bnip3 expression (*P<0.001 control vs. diabetic±AG), PAI-1 mRNA was different in all groups.

MRA subjected to immunostaining using AGEs antibodies revealed an increase of AGEs formation, which was more pronounced on endothelium in diabetic compared to control (Figure 5). In order to rule out non-specific binding, these experiments were repeated in the presence of secondary antibodies alone and no staining was observed (data not shown). AG treatment for 3 months significantly reduced AGE formation in MRA from diabetic mice (Figure 5).

Figure 5.

Figure 5

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Immunhistochemical staining showing the formation of advanced glycation end product (AGEs) in MRA from control, diabetic and diabetic + aminoguanidine (AG), n=4 for each experiment. The yellow and green arrows indicate AGEs staining on endothelial cells and smooth muscle cells, respectively.

To gain insight into the mechanisms by which hyperglycemia alters endothelial function, we treated primary cultured endothelial cells from resistance arteries with high glucose treatment (20 mM) for 48 hrs. The treatment with high glucose was associated with a decrease of eNOS expression and phosphorylation in response to calcium ionophore (Figure 6A, B).

Figure 6.

Figure 6

Figure 6

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High glucose also decreased the endogenous anti-oxidant MnSOD (Figure 6C). On the other hand, the treatment with high glucose induced an increase in NADPH subunit gp91 expression (Figure 6D). Endothelial cells treated with high glucose showed an increased oxidative stress assessed with DHE staining (Figure 6E) and NADH/NADPH oxidase activity (Figure 6F). Endothelial cells pretreated with apocynin (specific NADPH oxidase inhibitor) significantly prevent the activation of NADPH induced by high glucose (data not shown). The pretreatment of cultured endothelial cells with aminoguanidine blocked the effect of high glucose on eNOS, MnSOD, gp91 subunit and NADH/NADPH oxidase activity leading to reduction of oxidative stress generation and subsequently improvement of endothelial cells function (Figure 6A, B, C, D, F). Endothelial cells treated with mannitol did not change eNOs expression ruling out the non-specific osmotic effect (Figure 6G). Additionally, endothelial cells treated with HG and tempol did not affect eNOs expression (Figure 6G).

DISCUSSION

In this study we have shown a dysfunction of resistance artery endothelial and smooth muscle cells in type 2 diabetes. AGEs formation was selectively involved in endothelial cell dysfunction but not in enhanced smooth muscle cell-dependent myogenic tone. Altered endothelial cell function was associated with decreased eNOS phosphorylation/expression, decreased MnSOD levels and increased NADPH subunit gp91 expression, NADH/NADPH oxidase activity. These changes resulted in an increase in oxidative stress that is likely responsible for the observed changes in endothelial function. Treatment with aminoguanidine to prevent AGEs formation attenuated these changes an improved endothelial function in vivo.

Resistance arteries play a crucial role in blood pressure and control of tissue perfusion. These resistance arteries develop tone, which is mainly regulated by mechanical factors (pressure and shear stress) and hormonal factors.33,34 Generally shear stress induces endothelium-dependent vasodilation.35,36 On the other hand, intraluminal pressure induces myogenic tone (MT),2 which is generally modulated by shear stress through endothelial cells activation.35,37

Blood glucose was significantly higher in diabetic mice compared to control. The treatment with aminoguanidine did not affect blood glucose concentration indicating that AGEs formation has no effect on glucose metabolism. In a recent study, using telemetry, we have shown that db/db mice are normotensive.38 Blood pressure was normal and similar in all groups indicating that type 2 diabetic mice are not hypertensive. Our data are not in agreement with Bagi et al study showing an increase of systolic blood pressure in diabetic mice.5 Bagi et al measured systolic and diastolic blood pressures by the tail-cuff method in conscious mice, which is known to induce a stress generation, which may be responsible for the small increase in systolic blood pressure. On the other hand, our data are in agreement with previous study showing a normal blood pressure in diabetic vs. control mice.39 Surprisingly aminoguanidine decreased body weight of diabetic mice and no adverse effects on mice were observed in control mice. This could be partially related to the beneficial effect of aminoguanidine on AGE formation and therefore reduction of metabolism, AGE-RAGE interaction leading to overgeneration of intracellular ROS reduction, thus indicating that it is involved in the development of obesity-related insulin resistance,40 and on beta cells function.41 Our data are not in agreement with previous study using aging rats treated with aminoguanidine.42 These difference could be related to species, age and state of disease.

It is well known that type 2 diabetes is associated with microvessels complications.43 The multi-factorial effects of obese type 2 diabetes on the regulatory mechanisms that govern resistance artery function are not well understood. Limited studies of the relationship between diabetes and altered vascular responsiveness have been conducted in the microvasculature from diabetic models and conflicting results have been obtained. Lagaud et al demonstrated increased myogenic tone in mesenteric resistance arteries from 12- and 16-week diabetic mice compared to the control controls that was independent of endothelium removal. In contrast4 Bagi et al. showed no significant increase in myogenic tone in coronary arterioles from 12-week db/db mice.44 Small arteries (65–230 µm) from patients with Type 2 diabetes demonstrated decreased myogenic responsiveness.45 The explanations of these discrepancies are unclear but could be related to a difference in vascular beds and species. Our data showed increased MT in resistance arteries from diabetic compared to their control, which are in accordance with a study by Lagaud et al4 Treatment with aminoguanidine did not affect the development and enhanced myogenic tone in control and diabetic mice respectively, indicating that AGEs formation in type 2 diabetes is not involved in the mechanism leading to MT potentiation. Similarly, contraction of resistance arteries SMC in response to phenylephrine was similar, with and without aminoguanidine treatment, in all groups. These data indicate that AGEs formation had no specific effect on resistance artery smooth muscle cell contraction. In agreement with our study, Malik et al have shown that vasoconstriction to phenylephrine and angiotensin II was similar in small arteries from patients with and without type 2 diabetes mellitus.46 This study strengthens our data indicating that resistance arteries SMC do not develop hypersensitivity to vasconstrictor in type 2 diabetes.

Endothelial dysfunction has been demonstrated to occur in small arteries from patients with type 2 diabetes. Resistance artery endothelial cells are sensitive to increased shear stress, leading to relaxation of smooth muscle cells.35 In diabetic mice, flow-induced, endothelium-dependent dilation was significantly decreased compared to control mice. Our data are concordant with others studies showing a dysfunction of endothelial cells in diabetes.44,47 To strengthen our data, we used acetylcholine, which induces nitric oxide release from endothelial cells leading to resistance artery relaxation. Dose-response of acetylcholine-induced relaxation was significantly decreased in MRA from diabetic mice compared to control mice. The treatment of diabetic mice with aminoguanidine significantly improved relaxation to shear stress and acetylcholine of MRA and no effect was observed in control mice. The dysfunction of the endothelium was associated with a decrease of eNOS phosphorylation-expression in MRA from diabetic mice compared to control mice but no effect on mRNA level was observed. Interestingly, Ohashi et al have shown a decrease of eNOS at mRNA level in KKAy mice, which develop a maturity-onset obesity, type 2 diabetes and hypertension.48 Together, these data provide evidence of a link between type 2 diabetes and eNOS regulation. Interestingly, the treatment of diabetic mice with aminoguanidine for 3 months significantly improved flow-induced dilation and eNOS expression. These data demonstrate the presence of a relationship between AGEs formation in type 2 diabetes, endothelial cell dysfunction and eNOS expression. Further studies are needed to explore the molecular mechanisms involved in decreased eNOS expression in type 2 diabetes.

Insufficient blood flow through end-resistance arteries leads to symptoms associated with microvessels complications. This may be caused in part by poor macrocirculatory inflow or impaired microcirculatory function. We speculated that impaired flow-induced dilation in MRA could result in hypoxia in resistance arteries and intestines. We therefore analyzed changes in the expression levels of hypoxia inducible genes such PAI-1 and bnip3 (markers of hypoxia) by RT-PCR and western blot analysis.32 In MRA from diabetic mice, protein expression of PAI-1 and bnip3 were markedly up-regulated compared to control mice. The increased PAI-1 and bnip3 expression was similar to that previously observed in other hypoxia models such as in myocyte-specific vascular endothelial growth factor mutant mice.49 The mRNA level of PAI-1 and bnip3 was similar in all groups indicating that type 2 diabetes affects mRNA transcription rather that gene activation. The up-regulation of PAI-1 and bnip3 expression was normalized by the treatment with aminoguanidine. Together, these data strengthen our data that impaired endothelial function in diabetes is linked to increased AGEs formation.

Immunostaining of cryosections of MRA showed increased AGEs formation in diabetic mice compared to control mice, which was normalized with aminoguanidine treatment. These data strengthen a link between the increased AGEs formation in type 2 diabetes and microvessels complications. Our data are supported by different studies indicating an increase of AGEs formation in animal models and human type 2 diabetes.22,50

Western blot analysis performed on artery lysates cannot identify the relative contributions of specific cell types within the vessel wall. For this reason, we used primary cultured resistance artery endothelial cells. The treatment of endothelial cells with high glucose for 48 hrs significantly decreased eNOS expression and phosphorylation in response to acute stimulation (5 min) with calcium ionophore indicating that hyperglycemia takes a part in altered microvessels endothelial dysfunction observed in diabetic. In addition, high glucose decreased MnSOD and increased gp91phox (NADPH subunit) expression leading to increased oxidative stress as assessed with DHE staining and NADH/NADPH oxidase activity. These data indicate that, in type 2 diabetes, hyperglycemia-induced AGEs formation plays a crucial role in resistance artery endothelial cells dysfunction.

Thus, this study provides evidence of a selective effect of AGEs formation in type 2 diabetes on endothelial cells dysfunction, which was improved by the treatment with aminoguanidine. The effect of aminoguanidine could be related to decreased AGEs formation in the absence of changes in collagen and elastin content.51

Thus we propose the following model (Figure 6G) of endothelial resistance artery dysfunction, in which AGEs formation is involved in oxidative stress production increase leading to nitric oxide synthesis pathway alteration. Our study provides a novel insight into the basic mechanisms in the function of endothelial cells in obese type 2 diabetic mice. These data emphasize that diabetic vascular complications is mediated by AGEs with oxidative stress (risk factor for disease progression) and that targeting the AGEs/oxidative stress pathway represents an effective therapeutic strategy for prevention and treatment of microvessels complications in type 2 diabetes.

Acknowledgments

We greatly thank Dr. Souad Belmadani for advises and immuno-staining assistance

Sources of Funding

We acknowledge grant support from National American Heart Association (0430278N), Enhancement Research Phase II Award Tulane University, National Institutes of Health (P20RR017659, HL26371 NCRR), (HL072889), (HL56046), and COSEHC Warren Trust Fellowship Award.

Footnotes

Disclosures

None.

REFERENCES

  • 1.Bevan JA, Garcia-Roldan JL, Joyce EH. Resistance artery tone is influenced independently by pressure and by flow. Blood Vessels. 1990;27:202–207. doi: 10.1159/000158811. [DOI] [PubMed] [Google Scholar]
  • 2.Davis MJ, Hill MA. Signaling mechanisms underlying the vascular myogenic response. Physiol Rev. 1999;79:387–423. doi: 10.1152/physrev.1999.79.2.387. [DOI] [PubMed] [Google Scholar]
  • 3.Shimokawa H, Takeshita A. Endothelium-dependent regulation of the cardiovascular system. Intern Med. 1995;34:939–946. doi: 10.2169/internalmedicine.34.939. [DOI] [PubMed] [Google Scholar]
  • 4.Lagaud GJ, Masih-Khan E, Kai S, van Breemen C, Dube GP. Influence of type II diabetes on arterial tone and endothelial function in murine mesenteric resistance arteries. J Vasc Res. 2001;38:578–589. doi: 10.1159/000051094. [DOI] [PubMed] [Google Scholar]
  • 5.Bagi Z, Erdei N, Toth A, Li W, Hintze TH, Koller A, Kaley G. Type 2 diabetic mice have increased arteriolar tone and blood pressure: enhanced release of COX-2-derived constrictor prostaglandins. Arterioscler Thromb Vasc Biol. 2005;25:1610–1616. doi: 10.1161/01.ATV.0000172688.26838.9f. [DOI] [PubMed] [Google Scholar]
  • 6.Fujiyama S, Matsubara H, Nozawa Y, Maruyama K, Mori Y, Tsutsumi Y, Masaki H, Uchiyama Y, Koyama Y, Nose A, Iba O, Tateishi E, Ogata N, Jyo N, Higashiyama S, Iwasaka T. Angiotensin AT(1) and AT(2) receptors differentially regulate angiopoietin-2 and vascular endothelial growth factor expression and angiogenesis by modulating heparin binding-epidermal growth factor (EGF)-mediated EGF receptor transactivation. Circ Res. 2001;88:22–29. doi: 10.1161/01.res.88.1.22. [DOI] [PubMed] [Google Scholar]
  • 7.Shah BH, Catt KJ. A central role of EGF receptor transactivation in angiotensin II -induced cardiac hypertrophy. Trends Pharmacol Sci. 2003;24:239–244. doi: 10.1016/S0165-6147(03)00079-8. [DOI] [PubMed] [Google Scholar]
  • 8.Ohtsu H, Dempsey PJ, Frank GD, Brailoiu E, Higuchi S, Suzuki H, Nakashima H, Eguchi K, Eguchi S. ADAM17 mediates epidermal growth factor receptor transactivation and vascular smooth muscle cell hypertrophy induced by angiotensin II. Arterioscler Thromb Vasc Biol. 2006;26:e133–e137. doi: 10.1161/01.ATV.0000236203.90331.d0. [DOI] [PubMed] [Google Scholar]
  • 9.Lucchesi PA, Sabri A, Belmadani S, Matrougui K. Involvement of metalloproteinases 2/9 in epidermal growth factor receptor transactivation in pressure-induced myogenic tone in mouse mesenteric resistance arteries. Circulation. 2004;110:3587–3593. doi: 10.1161/01.CIR.0000148780.36121.47. [DOI] [PubMed] [Google Scholar]
  • 10.Henrion D, Terzi F, Matrougui K, Duriez M, Boulanger CM, Colucci-Guyon E, Babinet C, Briand P, Friedlander G, Poitevin P, Levy BI. Impaired flow-induced dilation in mesenteric resistance arteries from mice lacking vimentin. J Clin Invest. 1997;100:2909–2914. doi: 10.1172/JCI119840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Jalali S, del Pozo MA, Chen K, Miao H, Li Y, Schwartz MA, Shyy JY, Chien S. Integrin-mediated mechanotransduction requires its dynamic interaction with specific extracellular matrix (ECM) ligands. Proc Natl Acad Sci U S A. 2001;98:1042–1046. doi: 10.1073/pnas.031562998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Del PratoS, Marchetti P, Bonadonna RC. Phasic insulin release and metabolic regulation in type 2 diabetes. Diabetes. 2002;51:S109–S116. doi: 10.2337/diabetes.51.2007.s109. [DOI] [PubMed] [Google Scholar]
  • 13.Pfeiffer A, Spranger J, Meyer-Schwickerath R, Schatz H. Growth factor alterations in advanced diabetic retinopathy: a possible role of blood retina barrier breakdown. Diabetes. 1997;46:S26–S30. doi: 10.2337/diab.46.2.s26. [DOI] [PubMed] [Google Scholar]
  • 14.Sharma K, Ziyadeh FN. Hyperglycemia and diabetic kidney disease. The case for transforming growth factor-beta as a key mediator. Diabetes. 1995;44:1139–1146. doi: 10.2337/diab.44.10.1139. [DOI] [PubMed] [Google Scholar]
  • 15.Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–820. doi: 10.1038/414813a. [DOI] [PubMed] [Google Scholar]
  • 16.Stern DM, Yan SD, Yan SF, Schmidt AM. Receptor for advanced glycation endproducts (RAGE) and the complications of diabetes. Ageing Res Rev. 2002;1:1–15. doi: 10.1016/s0047-6374(01)00366-9. [DOI] [PubMed] [Google Scholar]
  • 17.Sakurai S, Yonekura H, Yamamoto Y, Watanabe T, Tanaka N, Li H, Rahman AK, Myint KM, Kim CH, Yamamoto H. The AGE-RAGE system and diabetic nephropathy. J Am Soc Nephrol. 2003;14:S259–S263. doi: 10.1097/01.asn.0000077414.59717.74. [DOI] [PubMed] [Google Scholar]
  • 18.Yan SF, Ramasamy R, Bucciarelli LG, Wendt T, Lee LK, Hudson BI, Stern DM, DUY S, Rong LL, Naka Y, Schmidt AM. RAGE and its ligands: a lasting memory in diabetic complications. Diab Vasc Dis Res. 2004;1:10–20. doi: 10.3132/dvdr.2004.001. [DOI] [PubMed] [Google Scholar]
  • 19.Yonekura H, Yamamoto Y, Sakurai S, Petrova RG, Abedin MJ, Li H, Yasui K, Takeuchi M, Makita Z, Takasawa S, Okamoto H, Watanabe T, Yamamoto H. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J. 2003;370:1097–1109. doi: 10.1042/BJ20021371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Yamamoto Y, Sakurai S, Watanabe T, Yonekura H, Yamamoto H. [Possible participation of advanced glycation endproducts and their receptor system in the development of diabetic vascular complications] Nippon Yakurigaku Zasshi. 2003;121:49–55. doi: 10.1254/fpj.121.49. [DOI] [PubMed] [Google Scholar]
  • 21.Thomas MC, Baynes JW, Thorpe SR, Cooper ME. The role of AGEs and AGE inhibitors in diabetic cardiovascular disease. Curr Drug Targets. 2005;6:453–474. doi: 10.2174/1389450054021873. [DOI] [PubMed] [Google Scholar]
  • 22.Yonekura H, Yamamoto Y, Sakurai S, Watanabe T, Yamamoto H. Roles of the receptor for advanced glycation endproducts in diabetes-induced vascular injury. J Pharmacol Sci. 2005;97:305–311. doi: 10.1254/jphs.cpj04005x. [DOI] [PubMed] [Google Scholar]
  • 23.Jakus V, Rietbrock N. Advanced glycation end-products and the progress of diabetic vascular complications. Physiol Res. 2004;53:131–142. [PubMed] [Google Scholar]
  • 24.Ha H, Lee HB. Oxidative stress in diabetic nephropathy: basic and clinical information. Curr Diab Rep. 2001;1:282–287. doi: 10.1007/s11892-001-0047-1. [DOI] [PubMed] [Google Scholar]
  • 25.Heidland A, Sebekova K, Schinzel R. Advanced glycation end products and the progressive course of renal disease. Am J Kidney Dis. 2001;38:S100–S106. doi: 10.1053/ajkd.2001.27414. [DOI] [PubMed] [Google Scholar]
  • 26.Baynes JW. The role of AGEs in aging: causation or correlation. Exp Gerontol. 2001;36:1527–1537. doi: 10.1016/s0531-5565(01)00138-3. [DOI] [PubMed] [Google Scholar]
  • 27.Chen H, Karne RJ, Hall G, Campia U, Panza JA, Cannon RO, 3rd, Wang Y, Katz A, Levine M, Quon MJ. High-dose oral vitamin C partially replenishes vitamin C levels in patients with Type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance. Am J Physiol Heart Circ Physiol. 2006;290:H137–H145. doi: 10.1152/ajpheart.00768.2005. [DOI] [PubMed] [Google Scholar]
  • 28.Lucchesi PA, Belmadani S, Matrougui K. Hydrogen peroxide acts as both vasodilator and vasoconstrictor in the control of perfused mouse mesenteric resistance arteries. J Hypertens. 2005;23:571–579. doi: 10.1097/01.hjh.0000160214.40855.79. [DOI] [PubMed] [Google Scholar]
  • 29.Matrougui K, Loufrani L, Heymes C, Levy BI, Henrion D. Activation of AT(2) receptors by endogenous angiotensin II is involved in flow-induced dilation in rat resistance arteries. Hypertension. 1999;34:659–665. doi: 10.1161/01.hyp.34.4.659. [DOI] [PubMed] [Google Scholar]
  • 30.Palen DI, Belmadani S, Lucchesi PA, Matrougui K. Role of SHP-1, Kv.1.2, and cGMP in nitric oxide-induced ERK1/2 MAP kinase dephosphorylation in rat vascular smooth muscle cells. Cardiovasc Res. 2005;68:268–277. doi: 10.1016/j.cardiores.2005.05.031. [DOI] [PubMed] [Google Scholar]
  • 31.Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–408. doi: 10.1006/meth.2001.1262. [DOI] [PubMed] [Google Scholar]
  • 32.Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, da Costa J, Zhang L, Pei Y, Scholey J, Ferrario CM, Manoukian AS, Chappell MC, Backx PH, Yagil Y, Penninger JM. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417:822–828. doi: 10.1038/nature00786. [DOI] [PubMed] [Google Scholar]
  • 33.Matrougui K, Levy BI, Henrion D. Tissue angiotensin II and endothelin-1 modulate differently the response to flow in mesenteric resistance arteries of normotensive and spontaneously hypertensive rats. Br J Pharmacol. 2000;130:521–526. doi: 10.1038/sj.bjp.0703371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Matrougui K, Eskildsen-Helmond YE, Fiebeler A, Henrion D, Levy BI, Tedgui A, Mulvany MJ. Angiotensin II stimulates extracellular signal-regulated kinase activity in intact pressurized rat mesenteric resistance arteries. Hypertension. 2000;36:617–621. doi: 10.1161/01.hyp.36.4.617. [DOI] [PubMed] [Google Scholar]
  • 35.Matrougui K, Maclouf J, Levy BI, Henrion D. Impaired nitric oxide- and prostaglandin-mediated responses to flow in resistance arteries of hypertensive rats. Hypertension. 1997;30:942–947. doi: 10.1161/01.hyp.30.4.942. [DOI] [PubMed] [Google Scholar]
  • 36.Arnal JF, Dinh-Xuan AT, Pueyo M, Darblade B, Rami J. Endothelium-derived nitric oxide and vascular physiology and pathology. Cell Mol Life Sci. 1999;55:1078–1087. doi: 10.1007/s000180050358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Muller JM, Davis MJ, Chilian WM. Integrated regulation of pressure and flow in the coronary microcirculation. Cardiovasc Res. 1996;32:668–678. [PubMed] [Google Scholar]
  • 38.Belmadani S, Palen DI, Gonzalez-Villalobos RA, Boulares HA, Matrougui K. Elevated Epidermal Growth Factor Receptor Phosphorylation Induces Resistance Artery Dysfunction in Diabetic db/db mice. Diabetes. 2008 doi: 10.2337/db07-0739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Guo C, Martinez-Vasquez D, Mendez GP, Toniolo MF, Yao TM, Oestreicher EM, Kikuchi T, Lapointe N, Pojoga L, Williams GH, Ricchiuti V, Adler GK. Mineralocorticoid Receptor Antagonist Reduces Renal Injury in Rodent Models of Type 1 and 2 Diabetes Mellitus. Endocrinology. 2006 doi: 10.1210/en.2006-0944. [DOI] [PubMed] [Google Scholar]
  • 40.Unoki H, Bujo H, Yamagishi S, Takeuchi M, Imaizumi T, Saito Y. Advanced glycation end products attenuate cellular insulin sensitivity by increasing the generation of intracellular reactive oxygen species in adipocytes. Diabetes Res Clin Pract. 2007;76:236–244. doi: 10.1016/j.diabres.2006.09.016. [DOI] [PubMed] [Google Scholar]
  • 41.Qiu L, List EO, Kopchick JJ. Differentially expressed proteins in the pancreas of diet-induced diabetic mice. Mol Cell Proteomics. 2005;4:1311–1318. doi: 10.1074/mcp.M500016-MCP200. [DOI] [PubMed] [Google Scholar]
  • 42.Corman B, Duriez M, Poitevin P, Heudes D, Bruneval P, Tedgui A, Levy BI. Aminoguanidine prevents age-related arterial stiffening and cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America. 1998;95:1301–1306. doi: 10.1073/pnas.95.3.1301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Abularrage CJ, Sidawy AN, Aidinian G, Singh N, Weiswasser JM, Arora S. Evaluation of the microcirculation in vascular disease. J Vasc Surg. 2005;42:574–581. doi: 10.1016/j.jvs.2005.05.019. [DOI] [PubMed] [Google Scholar]
  • 44.Bagi Z, Koller A, Kaley G. PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. Am J Physiol Heart Circ Physiol. 2004;286:H742–H748. doi: 10.1152/ajpheart.00718.2003. [DOI] [PubMed] [Google Scholar]
  • 45.Schofield I, Malik R, Izzard A, Austin C, Heagerty A. Vascular structural and functional changes in type 2 diabetes mellitus: evidence for the roles of abnormal myogenic responsiveness and dyslipidemia. Circulation. 2002;106:3037–3043. doi: 10.1161/01.cir.0000041432.80615.a5. [DOI] [PubMed] [Google Scholar]
  • 46.Malik RA, Schofield IJ, Izzard A, Austin C, Bermann G, Heagerty AM. Effects of angiotensin type-1 receptor antagonism on small artery function in patients with type 2 diabetes mellitus. Hypertension. 2005;45:264–269. doi: 10.1161/01.HYP.0000153305.50128.a1. [DOI] [PubMed] [Google Scholar]
  • 47.Avogaro A, Fadini GP, Gallo A, Pagnin E, de Kreutzenberg S. Endothelial dysfunction in type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis. 2006;16:S39–S45. doi: 10.1016/j.numecd.2005.10.015. [DOI] [PubMed] [Google Scholar]
  • 48.Ohashi K, Kihara S, Ouchi N, Kumada M, Fujita K, Hiuge A, Hibuse T, Ryo M, Nishizawa H, Maeda N, Maeda K, Shibata R, Walsh K, Funahashi T, Shimomura I. Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension. 2006;47:1108–1116. doi: 10.1161/01.HYP.0000222368.43759.a1. [DOI] [PubMed] [Google Scholar]
  • 49.Giordano FJ, Gerber HP, Williams SP, VanBruggen N, Bunting S, Ruiz-Lozano P, Gu Y, Nath AK, Huang Y, Hickey R, Dalton N, Peterson KL, Ross J, Jr, Chien KR, Ferrara N. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. Proc Natl Acad Sci U S A. 2001;98:5780–5785. doi: 10.1073/pnas.091415198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Schmidt AM, Hori O, Brett J, Yan SD, Wautier JL, Stern D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb. 1994;14:1521–1528. doi: 10.1161/01.atv.14.10.1521. [DOI] [PubMed] [Google Scholar]
  • 51.Thornalley PJ. Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. Arch Biochem Biophys. 2003;419:31–40. doi: 10.1016/j.abb.2003.08.013. [DOI] [PubMed] [Google Scholar]

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