Remodeling of the brain angioarchitecture in experimental chronic neurodegeneration

Abstract

Chronic neurodegenerative diseases are characterized by substantial inflammation with putative impairment of the brain vasculature also commonly observed. To address effects of chronic neurodegeneration on the regional vasculature under experimentally controlled circumstances, the glutamate receptor agonist ibotenic acid was injected into striatum of adult rats, which causes excitotoxicity in the substantia nigra pars reticulata (SNpr) due to imbalance between inhibitory inputs from the striatum and excitatory signals from the subthalamic nucleus. Brains were examined at 28 days (short-term neurodegeneration) and 91 days (long-term neurodegeneration) and analyzed for vascular remodeling taking both 2D and 3D approaches, the latter involving confocal microscopy of optically cleared samples combined with machine learning-based image analysis. Crysectioned and microdissected samples were analyzed for protein and gene expression respectively. The resulting neurodegeneration was accompanied by regional tissue loss and inflammation. The 3D analysis of the degenerating SNpr revealed substantial changes of the vasculature with higher density, increased diameter, and number of tortuous vessels already after 28 days, evidently continuing at 91 days. Interestingly, the vascular remodeling changes occurred without changes in the expression of endothelial tight junction proteins, vascular basement membrane proteins, or markers of angiogenesis. We propose that remodeling of the vasculature in neurodegeneration occurs due to regional tissue atrophy, which leaves the vasculature operating but prone to additional pathologies.