Abstract
Diabetes exacerbates brain damage in cerebral ischemic stroke. Our previous study has demonstrated that after cerebral ischemia, type 2 diabetes rats displayed worse neurological outcomes, larger cerebral infarction and severer blood-brain barrier disruption. However, our knowledge of the mechanisms of how diabetes impacts the cerebrovascular repair process is limited. This study was aimed to characterize structural alterations and potential mechanisms in brain microvessels before and after ischemic stroke in type 2 diabetic rats treated with high-fat diet and streptozotocin (HFD/STZ). Furtherly, we tested our hypothesis that dysregulated intercellular Jagged1-Notch1 signaling was involved in the dysfunctional cerebral neovascularization both before and after ischemic stroke in HFD/STZ rats. In our study, we found increased yet dysfunctional neovascularization with activated Jagged1-Notch1 signaling in the cerebrovasculature before cerebral ischemia in HFD/STZ rats compared with non-diabetic rats. Furthermore, we observed delayed angiogenesis as well as suppressed Jagged1-Notch1 signaling after ischemic stroke. Our results elucidate the potential mechanisms underlying diabetes-related cerebral microvasculature dysfunction after ischemic stroke.
Highlights
As of 2019, the global estimate of diabetes prevalence is 9.3% (463 million people), with type 2 diabetes mellitus (T2DM) accounting for approximately 90% of the total (Saeedi et al, 2019)
We provided novel evidence of increased yet dysfunctional baseline neovascularization in the cerebrovasculature of high fat diet (HFD)/STZ rats accompanying with the activated Jagged1-Notch1 signaling
We observed delayed angiogenesis after cerebral ischemia as well as suppressed Jagged1-Notch1 signaling in T2DM rats compared with non-diabetic rats
Summary
As of 2019, the global estimate of diabetes prevalence is 9.3% (463 million people), with type 2 diabetes mellitus (T2DM) accounting for approximately 90% of the total (Saeedi et al, 2019). Due to atherosclerotic lesions of intracranial and extracranial arteries in T2DM, ischemic stroke is generally regarded as a macrovascular complication of diabetes. According to previous studies focusing on T2DM patients, diffuse brain atrophy, white matter lesions, microbleeds, and asymptomatic lacunar infarcts have been shown on brain magnetic resonance imaging (MRI) or in postmortem studies (Sima, 2010). These lesions may be clinically asymptomatic if they are single, but more and more single lesion and combinations of lesion types are associated with cognitive and mood disorder, and more impressively, higher risk and poorer prognosis of stroke (Wardlaw et al, 2019). Emerging evidence indicates that cerebral microvascular dysfunction in T2DM is one of the key underlying mechanisms of stroke, dementia, and depression (van Sloten et al, 2020)
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