Proteomic landscape and molecular mechanisms of encephalomyosynangiosis in a rodent model of chronic cerebral hypoperfusion.

OBJECTIVE

The purpose of the present study was to establish a reproducible 2-vessel occlusion (2VO) rat model combined with encephalomyosynangiosis (EMS) to investigate angiogenic and proteomic mechanisms of indirect cerebral revascularization as a basis for further study in order to improve angiogenesis and cognition.

METHODS

Fifteen rats underwent 2VO of the bilateral common carotid arteries 1 week apart. At the time of the second occlusion, 10 animals underwent EMS while 5 animals received a sham surgery. Adequate hypoperfusion was considered established if the cerebral blood flow decreased to 40% of baseline. Six weeks after surgery, reperfusion outcomes were assessed with the Longa model, novel object recognition, immunohistochemical analysis, and proteomic analysis.

RESULTS

Animals that underwent EMS surgery demonstrated minimal neurological deficits on the Longa model, and EMS animals spent more time with both the old (mean 16.08 seconds vs 8.07 seconds) and novel (18.21 seconds vs 10.84 seconds) objects, suggesting that the EMS animals overall spent more time exploring in both scenarios compared to the 2VO animals that were more sedentary. Immunohistochemical analysis revealed evidence of increased angiogenesis in tissue specimens collected from the experimental cohort. Proteomic analysis showed that the EMS mechanism of action likely alters metabolism, notably by stimulating aerobic respiration, reducing neutrophil-mediated neuroinflammation, altering synapses, reorganizing cytoskeletal protein binding, and activating MAPK/ERK signaling through L1CAM activation.

CONCLUSIONS

Establishing a 2VO and EMS rat model lays the groundwork for future research across laboratories to explore novel strategies for enhancing neovascularization, ultimately contributing to improved therapeutic approaches for patients with moyamoya disease and other vaso-occlusive cerebrovascular disorders.