Global Toll‐like Receptor 4 Knockout Prevents Cerebrovascular Dysfunction Associated with Chronic Stress

Abstract

Chronic stress is a risk factor for many cerebrovascular diseases including stroke and vascular dementia and our lab has previously shown that chronic stress impairs cerebrovascular function and induces a pro‐inflammatory environment. It is possible that this pro‐inflammatory environment is driven by the activation of toll‐like receptor 4 (TLR4), a potent mediator of inflammation. However, the potential role of TLR4 in chronic stress induced cerebrovascular dysfunction has yet to be examined.Here, we utilized a global TLR4 knock out (TLR4‐/‐) combined with our unpredicted chronic mild stress paradigm (UCMS) to assess middle cerebral artery (MCA) function. At 18 weeks‐of‐age, mice underwent the UCMS paradigm (5 days/weeks for 7hrs/day) to elicit a chronic stress phenotype. On week 26, mice were euthanized and the MCAs were removed and positioned in a pressurized myobath. To test for vessel health, the MCA was exposed to increasing concentrations of acetylcholine (ACh; 10‐9M to 10‐4M), phenylephrine (PE; 10‐9M to 10‐4M), and sodium nitroprusside (SNP; 10‐9M to 10‐4M).TLR4‐/‐ mice displayed a similar MCA response to ACh compared to controls (18.4±0.7mm to 19.4±0.5mm, respectively). Mice exposed to UCMS displayed impaired MCA response to ACh while TLR4‐/‐ mice exposed to UCMS did not display MCA impairment in response to ACh (8.1±0.4mm vs 18.1±0.4mm, respectively; p<0.05). No differences in response to SNP were noted between groups however both TLR4‐/‐and TLR4‐/‐ UCMS mice displayed an impaired response to PE compared to controls (‐16.6±2.3mm and ‐17.6±1.6mm and ‐24.2±2mm, respectively; p<0.05).These data suggest that TLR4 may play a role in the cerebrovascular dysfunction associated with chronic stress.