Ultrastructural Changes in Cerebral Capillary Pericytes in Aged Notch3 Mutant Transgenic Mice

Abstract

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.

Notch3 deficiency impairs coronary microvascular maturation and reduces cardiac recovery after myocardial ischemia

“…Since Notch3 has a critical role in the recruitment of pericytes as well as VSMC proliferation [24,25], we first examined the role of Notch3 deficiency on pericyte coverage and VSMC in vivo using the mouse model of retinal angiogenesis. As shown in Fig.…”

Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

“…These findings reconfirm previous observations by other groups that used electron microscopy to detect ultrastructural changes in pericytes in postmortem tissue samples from CADASIL patients. 17,18 To rule out the possibility that overexpressing mutant Notch3 merely caused a downregulation of PDGFRb in well-preserved pericyte processes, we used a second pericyte-specific marker, desmin, confirming that pericyte coverage of the microvasculature decreases with age. In contrast to previous reports using PDGFRb-knockout mice, 9,13 the age-dependent loss of microvascular pericyte coverage in our CADASIL mouse model was not accompanied by a decrease in capillary density or vascular diameter.…”

“…The Notch3 receptor is also expressed in capillary pericytes, and recent electron microscopy studies found altered pericyte morphology in CADASIL mice. 17,18 However, the functional relevance of these findings is unclear, and the role of pericytes in the initiation and progression of CADASIL is currently unknown. Therefore, the aim of this study was to examine whether pericytes play a role in the pathogenesis of CADASIL.…”

Emerging Roles of Pericytes in the Regulation of the Neurovascular Unit in Health and Disease

“…These data indicate an abnormal BBB in Notch3 mutated animals. Notch3 mutant pericytes in mice show an increase in the number of abnormal pericytes in vivo , and morphologically, these cells display severe cellular injury(Gu et al, 2012). Recent evidence demonstrate that newborn Notch3-deficient mice have greatly reduced expression of PDGF-Rβ on pericytes, and PDGF-Rβ expression was amplified with Notch ligand activation(Jin et al, 2008).…”