Publications (51) View all
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Article: Reduced endothelium-dependent relaxation to anandamide in mesenteric arteries from young obese zucker rats.
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ABSTRACT: Impaired vascular function, manifested by an altered ability of the endothelium to release endothelium-derived relaxing factors and endothelium-derived contracting factors, is consistently reported in obesity. Considering that the endothelium plays a major role in the relaxant response to the cannabinoid agonist anandamide, the present study tested the hypothesis that vascular relaxation to anandamide is decreased in obese rats. Mechanisms contributing to decreased anandamide-induced vasodilation were determined. Resistance mesenteric arteries from young obese Zucker rats (OZRs) and their lean counterparts (LZRs) were used. Vascular reactivity was evaluated in a myograph for isometric tension recording. Protein expression and localization were analyzed by Western blotting and immunofluorescence, respectively. Vasorelaxation to anandamide, acetylcholine, and sodium nitroprusside, as well as to CB1, CB2, and TRPV1 agonists was decreased in endothelium-intact mesenteric arteries from OZRs. Incubation with an AMP-dependent protein kinase (AMPK) activator or a fatty acid amide hydrolase inhibitor restored anandamide-induced vascular relaxation in OZRs. CB1 and CB2 receptors protein expression was decreased in arteries from OZRs. Incubation of mesenteric arteries with anandamide evoked endothelial nitric oxide synthase (eNOS), AMPK and acetyl CoA carboxylase phosphorylation in LZRs, whereas it decreased phosphorylation of these proteins in OZRs. In conclusion, obesity decreases anandamide-induced relaxation in resistance arteries. Decreased cannabinoid receptors expression, increased anandamide degradation, decreased AMPK/eNOS activity as well as impairment of the response mediated by TRPV1 activation seem to contribute to reduce responses to cannabinoid agonists in obesity.PLoS ONE 01/2013; 8(5):e63449. · 4.09 Impact Factor -
Article: Involvement of endothelium in the maintenance of vasoconstrictor response in aortas of diabetic female rats: role of nitric oxide and endothelin.
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ABSTRACT: OBJECTIVES: Diabetes affects the vascular system in males and females differently. Studies of vascular contraction in diabetes show controversial results, but very few of these studies have been focused on females. We evaluated the contractile response to noradrenaline in the aortas of diabetic female rats and analyzed the modulation of this response by the endothelium. METHODS: In aortas of alloxan-induced diabetic female rats, we analyzed the concentration-response curve to noradrenaline in the absence or presence of L-NAME, indomethacin, losartan, tezosentan or Calphostin-C and the pre-pro-endothelin mRNA expression. In endothelial cells incubated with low or high glucose, we analyzed the noradrenaline-stimulated pAkt Ser(473) , peNOS Ser(1177) , and peNOS Ser(633) expression. RESULTS: The maximal response (R(max) ) to noradrenaline was similar between control and diabetic endothelium-intact aortas, but was reduced in diabetic endothelium-denuded aortas. The incubation of endothelium-intact aortas with L-NAME increased the R(max) only in the control group. The inhibition of cyclooxygenase and angiotensin II receptor antagonism reduced the R(max) in the endothelium-intact aortas of both the control and diabetic groups. Endothelin receptor antagonism and PKC inhibition reduced the R(max) only in diabetic endothelium-intact aortas. Pre-pro-ET-1 mRNA expression was increased in diabetic female rat aortas. The levels of pAkt Ser(473) , peNOS Ser(1177) , and peNOS Ser(633) were enhanced after stimulation with noradrenaline only in low glucose-treated endothelial cells. CONCLUSIONS: In the aortas of diabetic female rats, the reduction in smooth muscle contraction in response to noradrenaline is counterbalanced by modulation from the endothelium through reduced eNOS activation, and increased endothelin release and PKC activation. SIGNIFICANT FINDINGS OF THE STUDY: In female diabetic rats the endothelium compensates for the reduction in smooth muscle vascular contractile response to noradrenaline. Reduced nitric oxide, increased endothelin release, and PKC activation are all involved in the endothelial compensatory process. WHAT THIS STUDY ADDS: There are controversial data in the literature about the alterations in vascular contraction in diabetes. Unaltered, increased, and attenuated contractile vascular responses have been demonstrated. We demonstrated that presence/absence of endothelium and the vasoconstrictor agents analyzed may account for these conflicting data. © 2012 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and WileyPublishing Asia Pty Ltd.Journal of Diabetes 10/2012; -
Article: Toll-like receptor 4 contributes to blood pressure regulation and vascular contraction in spontaneously hypertensive rats.
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ABSTRACT: Activation of TLRs (Toll-like receptors) induces gene expression of proteins involved in the immune system response. TLR4 has been implicated in the development and progression of CVDs (cardio-vascular diseases). Innate and adaptive immunity contribute to hypertension-associated end-organ damage, although the mechanism by which this occurs remains unclear. In the present study, we hypothesize that inhibition of TLR4 decreases BP (blood pressure) and improves vascular contractility in resistance arteries from SHR (spontaneously hypertensive rats). TLR4 protein expression in mesenteric resistance arteries was higher in 15-week-old SHR than in age-matched Wistar controls or in 5-week-old SHR. To decrease the activation of TLR4, 15-week-old SHR and Wistar rats were treated with anti-TLR4 (anti-TLR4 antibody) or non-specific IgG control antibody for 15 days (1 μg per day, intraperitoneal). Treatment with anti-TLR4 decreased MAP (mean arterial pressure) as well as TLR4 protein expression in mesenteric resistance arteries and IL-6 (interleukin 6) serum levels from SHR when compared with SHR treated with IgG. No changes in these parameters were found in treated Wistar control rats. Mesenteric resistance arteries from anti-TLR4-treated SHR exhibited decreased maximal contractile response to NA (noradrenaline) compared with IgG-treated SHR. Inhibition of COX (cyclo-oxygenase)-1 and COX-2, enzymes related to inflammatory pathways, decreased NA responses only in mesenteric resistance arteries of SHR treated with IgG. COX-2 expression and TXA2 (thromboxane A2) release were decreased in SHR treated with anti-TLR4 compared with IgG-treated SHR. Our results suggest that TLR4 activation contributes to increased BP, low-grade inflammation and plays a role in the augmented vascular contractility displayed by SHR.Clinical Science 06/2012; 122(11):535-43. · 4.61 Impact Factor -
Article: Pyk2 mediates increased adrenergic contractile responses in arteries from DOCA-salt mice - VASOACTIVE PEPTIDE SYMPOSIUM.
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ABSTRACT: The calcium-dependent proline-rich tyrosine kinase (Pyk2), a nonreceptor protein activated by tyrosine phosphorylation, links G protein-coupled receptors to vascular responses. We tested the hypothesis that enhanced vascular reactivity in DOCA-salt hypertensive mice are due to increased activation of Pyk2. Aorta and small mesenteric arteries from DOCA-salt and uninephrectomized (UNI) male C57Bl/6 mice were used. Systolic blood pressure (mmHg) was higher in DOCA (126+/-3) vs. UNI (100+/-4) mice. Vascular responses to phenylephrine (1nM to 100muM) were greater both in aorta and small mesenteric arteries from DOCA-salt than UNI, but treatment with Tyrphostin A-9 (0.1muM, Pyk2 inhibitor) abolished the difference among the groups. Pyk2 levels, as well as phospho-Pyk2(Tyr402), paxillin and phospho-paxillin(Tyr118) were increased in DOCA-salt aorta. Incubation of vessels with Tyrphostin A-9 restored phosphorylation of Pyk2 and paxillin. Increased activation of Pyk2 contributes to increased vascular contractile-responses in DOCA-salt mice.Journal of the American Society of Hypertension 11/2008; 2(6):431-8. · 2.12 Impact Factor -
Article: Increased vascular O-GlcNAcylation augments reactivity to constrictor stimuli - VASOACTIVE PEPTIDE SYMPOSIUM.
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ABSTRACT: O-Linked N-acetylglucosaminylation (O-GlcNAcylation) plays a role in many aspects of protein function. Whereas elevated O-GlcNAc levels contribute to diabetes related end-organ damage, O-GlcNAcylation is also physiologically important. Because proteins that play a role in vascular tone regulation can be O-GlcNAcylated, we hypothesized that O-GlcNAcylation increases vascular reactivity to constrictor stimuli. Aortas from male Sprague-Dawley rats and C57BL/6 mice were incubated for 24 h with vehicle or PugNAc (O-GlcNAcase inhibitor, 100muM). PugNAc incubation significantly increased O-GlcNAc-proteins, as determined by Western blot. PugNAc also increased vascular contractions to phenylephrine and serotonin, an effect not observed in the presence of L-NAME or in endothelium-denuded vessels. Acetylcholine-induced relaxation, but not that to sodium nitroprusside was decreased by PugNAc treatment, an effect accompanied by decreased levels of phosphorylated eNOS(Ser-1177) and Akt(Ser-473). Augmented O-GlcNAcylation increases vascular reactivity to constrictor stimuli, possibly due to its effects on eNOS expression and activity, reinforcing the concept that O-GlcNAcylation modulates vascular reactivity and may play a role in pathological conditions associated with abnormal vascular function.Journal of the American Society of Hypertension 11/2008; 2(6):410-7. · 2.12 Impact Factor
