Cerebrovasculature Remodeling Accompanies Functional Impairment in Chronically Stressed Mice

Abstract

The cerebrovasculature system is inherently complex in both structure and function allowing it to dynamically regulate oxygen and nutrient flow within the brain. Chronic stress has been linked to various cerebrovasculature diseases, resulting from impaired function and altered architecture. Here we examined the effects of chronic stress on cerebrovasculature function, cerebral bloodflow, and angioarchitecture. Beginning at week 18, mice were exposed to the unpredictable chronic mild stress paradigm for 8 weeks (UCMS; 5 days/week for 7 hrs/day) or control conditions. Prior to euthanization, cerebral blood perfusion was examined using speckle‐pinpoint laser doppler flowmetry. Subsequently, mice were either subjected to vascular corrosion casting to provide a detailed 3D reconstruction of the complete cerebro‐microvasculature, or the middle cerebral arteries (MCA) were removed and positioned in a pressurize myobath and exposed to increasing concentrations of acetylcholine (ACh; 10 ‐9 M to 10 ‐4 M), phenylephrine (PE; 10 ‐9 M to 10 ‐4 M), and sodium nitroprusside (SNP; 10 ‐9 M to 10 ‐4 M). UCMS mice displayed a 25% (p<0.05) reduction in cerebral blood flow, and 18%(p<0.05) impairment in MCA dilation to ACh vs. control mice. MCA smooth muscle function was similar in UCMS and control mice, while UCMS mice displayed hypersensitivity to PE (20% increase vs. control, p<0.05). Cerebrovascular corrosion casting revealed increased tortuosity of microvasculature (49%), decreased cerebrovascular density, along with a 28% and 56% reduction capillaries and arteriole/veniole length in the overall brain (p<0.05). These data suggest that chronic stress results in significant changes to cerebrovascular function and angioarchitecture resulting in altered cerebral blood flow.Support or Funding InformationSupport: NIH Cobra Grant 5P20GM109098; NIH INBRE P20GM103434