Cardiometabolic Disease Results in Sex‐ and Age‐Dependent Cerebrovascular Degeneration and Arteriolar Morphological Changes

Abstract

In the past 20 years, no drug therapies have been successfully translated into human use for intracerebral hemorrhage (ICH), the most devastating stroke subset. One likely factor is lack of effective animal models of human disease including common comorbidities, such as hypertension and diabetes. We evaluated the cardiometabolic rodent model, (mRen2)27, where overexpression of Ren2 results in extreme hypertension, glucose intolerance and obesity, as an appropriate ICH model. Methods: Sprague Dawley (SD) and (mRen2)27 rats were sacrificed at 14‐, 32‐, and 52‐weeks. Brains were sectioned sagittally at 5 μm. Whole‐brain sections were stained using Hematoxylin & Eosin (H&E) and Van Geison (VG) collagen staining to visualize the pial blood vessels. Wall‐to‐lumen ratios for vessels were calculated and compared using a student t‐test to determine significance. Results: There was no significant difference in arteriolar morphology at 14‐weeks between male SD and mRen animals (SD, n=16 and mRen, n=16). At 32‐weeks, there was a significant difference in mRen male rats (SD, n=13 and mRen, n=17; p<0.0001), with significantly increased wall thickness and decreased Lumen size in the mRen animals (increased W:L ratio). However, at this timeframe, there was no significant difference between the female SD and mRen cohorts (SD, n=6 and mRen, n=8). At 52‐weeks, there was a significant increase in W:L ratios in both male (SD, n=4 and mRen, n=7; p<0.01) and female (SD, n=9 and mRen, n=8; p<0.05) mRen animals compared to control. Conclusion: The (mRen2)27 cardiometabolic animal model demonstrates age‐related sex changes in the wall:lumen ratio of cerebral vasculature consistent with cerebrovascular disease seen in ischemic and hemorrhagic stroke patients. Males develop these vascular changes earlier than females, but both sexes in this model develop cerebral vascular changes by 1 year of age. The (mRen2)27 model appears to recapitulate human disease and sex differences, and may serve as an appropriate translational model of ICH.