Abstract 253: Sustained Activation of Toll-like Receptor 9 Increases Phenylephrine-Induced Contractions in Rat Mesenteric Resistance Arteries
Activation of Toll-like receptor 9 (TLR9) via bacterial or mitochondrial DNA induces systemic inflammation and is associated with heart failure and preeclampsia. TLR9 is expressed in the vasculature; however, whether activation of TLR9 affects vascular function is unknown. We hypothesized that sustained activation of TLR9 would increase rat mesenteric artery contractility. To test this hypothesis, female rats (16 weeks old) were injected intraperitoneally with a TLR9 agonist (ODN 2395, 0.1 μg/rat/day) or vehicle (saline) on 3 consecutive days and contractile responses to a thromboxane A2 analog (U46619, 10-9-10-5 M), potassium chloride (KCl, 10-80 mM), and phenylephrine (PE, 10-9-3x10-5 M), in the presence and absence of a nitric oxide synthase inhibitor (LNNA, 10-4 M) were measured in aortic and mesenteric rings from ODN- and vehicle-treated rats using a myograph. PE-induced contractions were increased in mesenteric but not in aortas from ODN-treated animals compared to vehicle group [Emax (% max KCl), ODN-treated: 167±10 vs. Vehicle-treated: 113±13, (Fig. 1A)] and the magnitude of this difference remained unaltered following NOS inhibition (Fig. 1B). ODN 2395 treatment had no effect on vascular responses to U46619 or KCl in either mesenteric or aortic rings. In summary, in vivo TLR9 activation increases vascular contractility and this effect is vascular bed- and agonist-specific. We propose that chronic immune system activation due to multiple bacterial infections or accumulation of mitochondrial DNA increases vascular contractility via TLR9 signaling pathways leading to vascular dysfunction and contributing to the development of vascular disease.
- © 2012 by American Heart Association, Inc.