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Reduced endothelial dependent vasodilation in vessels from TLR4(-/-) mice is associated with increased superoxide generation.

Harrington LS, Lundberg MH, Waight M, Rozario A, Mitchell JA - Biochem. Biophys. Res. Commun. (2011)

Bottom Line: Using the isometric wire myograph, mesenteric artery vasodilator responses to acetylcholine and MnCl(2) (a superoxide dismutase mimetic) were measured.Our observations suggest that loss of TLR4 increases superoxide generation which reduces the biological activity of endothelial derived nitric oxide and thereby explains the endothelial dysfunction and associated cardiovascular phenotype in TLR4(-/-) mice.These data implicate a novel cardio-protective role for TLR4 in vascular homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Cardiothoracic Pharmacology, NHLI, Imperial College, Dovehouse Street, London, UK. l.harrington@imperial.ac.uk

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Dilatory responses in arteries from wild type and TLR4−/− mice, pre-contracted with EC80 U46619. Dilation induced by (A) acetylcholine (Ach); n = 11 for wild type and n = 10 for TLR4−/− vessels. (B) SNP; n = 11 for wild type and n = 10 for TLR4−/− vessels. (C) MnCl2; n = 10 for wild type and n = 5 for TLR4−/− vessels. (D) Superoxide dismutase (SOD); n = 8 for wild type and n = 5 for TLR4−/− vessels. Data are represented as mean ± SEM. ∗p < 0.05; ns, not significant by two-way ANOVA.
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f0005: Dilatory responses in arteries from wild type and TLR4−/− mice, pre-contracted with EC80 U46619. Dilation induced by (A) acetylcholine (Ach); n = 11 for wild type and n = 10 for TLR4−/− vessels. (B) SNP; n = 11 for wild type and n = 10 for TLR4−/− vessels. (C) MnCl2; n = 10 for wild type and n = 5 for TLR4−/− vessels. (D) Superoxide dismutase (SOD); n = 8 for wild type and n = 5 for TLR4−/− vessels. Data are represented as mean ± SEM. ∗p < 0.05; ns, not significant by two-way ANOVA.

Mentions: Each mouse genotype was confirmed to being a homozygous wild type or TLR4−/− by PCR. As we have shown previously [4], vessels from TLR4−/− mice had reduced endothelial dependent vasodilator response when stimulated with acetylcholine (Fig. 1A). Endothelium independent vasodilation induced by sodium nitroprusside (SNP) was unaffected by the deletion of the TLR4 gene (Fig. 1B). Vasodilation induced by the cell permeable superoxide dismutase mimetic, MnCl2[9], was similar in tissues from wild type and TLR4−/− mice (Fig. 1C). Addition of authentic superoxide dismutase (SOD), which does not enter cells readily, did not induce vasodilation in arteries from either wild type or TLR4−/− mice (Fig. 1D). Contractile responses to U46619 (Fig. 2A) and high [K+] (Fig. 2B) were modestly reduced in arteries from TLR4−/− mice compared with those from wild type controls.


Reduced endothelial dependent vasodilation in vessels from TLR4(-/-) mice is associated with increased superoxide generation.

Harrington LS, Lundberg MH, Waight M, Rozario A, Mitchell JA - Biochem. Biophys. Res. Commun. (2011)

Dilatory responses in arteries from wild type and TLR4−/− mice, pre-contracted with EC80 U46619. Dilation induced by (A) acetylcholine (Ach); n = 11 for wild type and n = 10 for TLR4−/− vessels. (B) SNP; n = 11 for wild type and n = 10 for TLR4−/− vessels. (C) MnCl2; n = 10 for wild type and n = 5 for TLR4−/− vessels. (D) Superoxide dismutase (SOD); n = 8 for wild type and n = 5 for TLR4−/− vessels. Data are represented as mean ± SEM. ∗p < 0.05; ns, not significant by two-way ANOVA.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105224&req=5

f0005: Dilatory responses in arteries from wild type and TLR4−/− mice, pre-contracted with EC80 U46619. Dilation induced by (A) acetylcholine (Ach); n = 11 for wild type and n = 10 for TLR4−/− vessels. (B) SNP; n = 11 for wild type and n = 10 for TLR4−/− vessels. (C) MnCl2; n = 10 for wild type and n = 5 for TLR4−/− vessels. (D) Superoxide dismutase (SOD); n = 8 for wild type and n = 5 for TLR4−/− vessels. Data are represented as mean ± SEM. ∗p < 0.05; ns, not significant by two-way ANOVA.
Mentions: Each mouse genotype was confirmed to being a homozygous wild type or TLR4−/− by PCR. As we have shown previously [4], vessels from TLR4−/− mice had reduced endothelial dependent vasodilator response when stimulated with acetylcholine (Fig. 1A). Endothelium independent vasodilation induced by sodium nitroprusside (SNP) was unaffected by the deletion of the TLR4 gene (Fig. 1B). Vasodilation induced by the cell permeable superoxide dismutase mimetic, MnCl2[9], was similar in tissues from wild type and TLR4−/− mice (Fig. 1C). Addition of authentic superoxide dismutase (SOD), which does not enter cells readily, did not induce vasodilation in arteries from either wild type or TLR4−/− mice (Fig. 1D). Contractile responses to U46619 (Fig. 2A) and high [K+] (Fig. 2B) were modestly reduced in arteries from TLR4−/− mice compared with those from wild type controls.

Bottom Line: Using the isometric wire myograph, mesenteric artery vasodilator responses to acetylcholine and MnCl(2) (a superoxide dismutase mimetic) were measured.Our observations suggest that loss of TLR4 increases superoxide generation which reduces the biological activity of endothelial derived nitric oxide and thereby explains the endothelial dysfunction and associated cardiovascular phenotype in TLR4(-/-) mice.These data implicate a novel cardio-protective role for TLR4 in vascular homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Cardiothoracic Pharmacology, NHLI, Imperial College, Dovehouse Street, London, UK. l.harrington@imperial.ac.uk

Show MeSH
Related in: MedlinePlus