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Differential Effects of Toll‐like Receptors 2 and 4 in Endotoxin‐Induced Vascular Dysfunction
Author(s) -
Battson Micah L,
Lee Dustin M,
Hou Shoufei,
Jarrell Dillon K,
Santangelo Kelly S,
CoxYork Kimberly A,
Gentile Christopher L
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.956.9
Subject(s) - tlr4 , tlr2 , vasodilation , lipopolysaccharide , medicine , endocrinology , sodium nitroprusside , vasoconstriction , agonist , endothelium , receptor , constriction , chemistry , nitric oxide
Bacterial endotoxin (lipopolysaccharide, LPS) may contribute to diabetes‐related inflammation and has been shown to cause generalized vascular dysfunction, including arterial hypocontractility and impaired endothelium‐dependent and –independent vasodilation. These vascular impairments are thought to be mediated in large part via Toll‐like receptor 4 (TLR4). However, contribution of other TLRs, in particular TLR2, has not been well characterized. We therefore examined the relative contribution of TLR2 and TLR4 in mediating the acute effects of LPS on vascular dysfunction. Vascular reactivity was assessed via ex vivo pressure myography in isolated carotid arteries from male wild‐type (WT), TLR2‐KO and TLR4‐KO mice following 1 hour incubation with or without endotoxin ( E. coli LPS 50ug/ml). LPS decreased maximal constriction to the thromboxane A2 agonist U46619 in WT (CON: 30 ± 3% vs LPS: 17 ± 3%) but not TLR2‐KO (CON: 29 ± 4% vs LPS: 25 ± 3%) or TLR4‐KO (CON: 33 ± 2% vs LPS: 32 ± 6%). LPS reduced endothelium‐dependent dilation (EDD) to acetylcholine in WT (CON: 95 ± 1% vs LPS: 73 ± 4%) and TLR2‐KO (CON: 84 ± 3% vs LPS: 64 ± 5%) but not TLR4‐KO (CON: 94 ± 2% vs LPS: 89 ± 3%). Finally, LPS reduced maximal endothelium‐independent dilation (EID) to sodium nitroprusside in WT (CON: 94 ± 1% vs LPS: 76 ± 6%) but not TLR2 (CON: 78 ± 5% vs LPS: 74 ± 6%) or TLR4‐KO (CON: 89 ± 3% vs LPS: 80 ± 2%). These findings suggest that lack of TLR2 protects carotid arteries against the LPS‐induced reductions in constriction and EID and that arteries of TLR4‐KO mice display additional protection against impaired EDD. Future studies will investigate the mechanism underlying these differential effects and may provide insight into potential treatments for endotoxin‐related vascular dysfunction. Support or Funding Information Funding: Boettcher Foundation's Webb‐Waring Biomedical Research Program (CLG); National Institutes of Health DK087777 (CLG)