(555.9) Global Toll-like Receptor 4 Knockout Prevents Cerebrovascular Dysfunction Associated with Chronic Stress

Poster Board Number: E69

Emily Burrage (West Virginia University), Saina Prabhu (West Virginia University), James Frazier (West Virginia University), Phillip Englund (West Virginia University), James Mills (West Virginia University), Makenzie Casto (West Virginia University), Randy Bryner (West Virginia University), Eric Kelley (West Virginia University), Paul Chantler (West Virginia University)

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; plt;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; plt;0.05). 

These data suggest that TLR4 may play a role in the cerebrovascular dysfunction associated with chronic stress.

NIH CoBRE Grant 5P20GM109098; NIH Grant P20GM103434; BINP R01 NS117754-01 (PDC).