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TLR‐9 activation potentiates the role of ERK1/2 in thromboxane A 2 ‐induced contractions in uterine but not in resistance arteries
Author(s) -
Goulopoulou Styliani,
Matsumoto Takayuki,
Webb R. Clinton
Publication year - 2012
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.26.1_supplement.870.9
Subject(s) - agonist , chemistry , thromboxane a2 , thromboxane , endocrinology , thromboxane receptor , medicine , receptor , mapk/erk pathway , contraction (grammar) , pharmacology , kinase , biochemistry , platelet
The innate immune system detects viral, bacterial and apoptotic cell‐released DNA using the toll‐like receptor 9 (TLR‐9), which activates the release of pro‐inflammatory cytokines via a signaling cascade involving mitogen‐activated protein kinases (MAPKs). In this study, we investigated the role of TLR‐9 activation in vascular function. We hypothesized that activation of TLR‐9 will increase vascular contractility to thromboxane A 2 (TXA 2 ), a potent vasoconstrictor, via MAPK‐related pathways. Mesenteric (MA) and uterine artery (UA) segments from virgin, Sprague‐Dawley rats (12 weeks old) were incubated for 12 hours with a TLR‐9 agonist (ODN 2395, 10 −5 M) or vehicle. Concentration response curves to a TXA 2 analogue (U46619, 10 −9 – 3×10 −6 M) were performed in the absence and presence of a p38MAPK inhibitor (SB203058, 10 −5 M, 30 min) or an ERK1/2 inhibitor (PD98059, 10 − 5 M, 30 min). UA but not MA segments incubated with the TLR‐9 agonist had greater sensitivity to U46619 (UA, TLR‐9 agonist: 6.96 ± 0.09 vs. vehicle: 6.68 ± 0.10). Inhibition of ERK1/2 reduced maximum contraction to U46619 in vehicle‐treated UA and MA by 50% and 40%, respectively (p>0.05). TLR‐9 agonist‐treated MA showed a reduction in U46619‐induced contraction by 50% following ERK1/2 inhibition; however, TLR‐9 agonist treatment did not affect UA responses to U46619. These data suggest that TLR‐9 activation “protects” the role of ERK1/2 in U46619‐induced contractions selectively in UA and not in resistance vessels, imposing vessel‐specific risk for vascular inflammation upon initiation of the innate immune response. (Funded by NIH)