Reduced endothelial dependent vasodilation in vessels from TLR4(-/-) mice is associated with increased superoxide generation.
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.
Affiliation: Cardiothoracic Pharmacology, NHLI, Imperial College, Dovehouse Street, London, UK. email@example.comShow MeSH
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Mentions: Each mouse genotype was confirmed to being a homozygous wild type or TLR4âˆ’/âˆ’ by PCR. As we have shown previously , vessels from TLR4âˆ’/âˆ’ 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, was similar in tissues from wild type and TLR4âˆ’/âˆ’ 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 TLR4âˆ’/âˆ’ mice (Fig. 1D). Contractile responses to U46619 (Fig. 2A) and high [K+] (Fig. 2B) were modestly reduced in arteries from TLR4âˆ’/âˆ’ mice compared with those from wild type controls.
Affiliation: Cardiothoracic Pharmacology, NHLI, Imperial College, Dovehouse Street, London, UK. firstname.lastname@example.org