Ultrastructural changes in cerebral capillary pericytes in aged Notch3 mutant transgenic mice.

Pericytes, the specialized vascular smooth muscle cells (VSMCs), play an important role in supporting and maintaining the structure of capillaries. Pericytes show biochemical and physiologic features similar to VSMC, usually containing smooth muscle actin fibers and rich endoplasm reticulum. Studies have indicated that degeneration of VSMCs due to Notch3 mutations is the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, it remains unclear whether the Notch3 mutation also affects cerebral cortex capillary pericytes. In this ultrastructural morphologic study, the authors have observed pathological changes in the cerebral cortex capillary pericytes in aged mice that carry human mutant Notch3 genes. The number of abnormal pericytes in the cerebral cortex in Notch3 gene mutant mice was slightly increased when compared to an age-matched control group. Morphologically, the pericytes in the brains of Notch3 gene mutant mice showed more severe cellular injury, such as the presence of damaged mitochondria, secondary lysosomes, and large cytoplasmic vesicles. In addition, morphologic structures related to autophagy were also present in the pericytes of Notch3 gene mutant group. These ultrastructural morphologic alterations suggest that Notch3 mutation precipitates age-related pericytic degeneration that might result in cellular injury and trigger autophagic apoptosis. Microvascular dysfunction due to pericyte degeneration could initiate secondary neurodegenerative changes in brain parenchyma. These findings provide new insight into understanding the role of pericyte degeneration in the phathogenesis of CADASIL disease.