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Published on: February 20, 2019
Multi-omic profiling reveals pericyte and smooth muscle cell contributions to CADASIL pathology in cell-specific
Yazi Huang1, Veronica Clementel1, Mingzi Zhang1
1Department of Physiology and Neuroscience, University of Southern California, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Insights
Researchers investigated how specific cell types contribute to CADASIL, a genetic cause of stroke and dementia. They found that mutations in Notch3 within smooth muscle cells or pericytes lead to distinct brain changes and memory deficits.
Area of Science:
- Neuroscience
- Genetics
- Vascular Biology
Background:
- Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a primary cause of vascular dementia and stroke.
- CADASIL arises from mutations in the Notch3 gene, but the specific roles of different cell types in its pathology are unclear.
Purpose of the Study:
- To elucidate the cell-type-specific contributions of Notch3 mutations in smooth muscle cells (SMCs) and pericytes to CADASIL pathogenesis.
- To investigate the distinct neurovascular and inflammatory consequences of Notch3 mutations in these mural cell populations.
Main Methods:
- Generation of conditional knockin mouse models with the CADASIL-associated Notch3R170C mutation specifically in SMCs or pericytes.
- Analysis of neurovascular changes, neuroinflammation, and memory deficits in mutant mice.
- Proteomic profiling of brain vessels and integration with single-cell RNA sequencing (RNA-seq) data.
Main Results:
- Both SMC-Notch3R170C and pericyte-Notch3R170C models exhibited perivascular NOTCH3 accumulation but displayed distinct neurovascular pathologies and memory impairments.
- Proteomic analysis revealed cell-specific responses, including metabolic dysregulation in pericyte-mutant mice and immune signaling alterations in SMC-mutant mice.
- Findings suggest potential involvement of brain endothelial cells and highlight distinct mural cell-driven mechanisms in CADASIL.
Conclusions:
- Mural cell-specific Notch3 mutations drive distinct pathological pathways in CADASIL.
- Understanding these cell-specific mechanisms is crucial for developing targeted therapies for CADASIL and related small vessel diseases.
Abstract:
Cerebral ischemic small vessel disease (SVD) is a leading cause of vascular dementia and stroke. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common monogenic SVD, is caused by dominant missense mutations in Notch3 expressed in smooth muscle cells (SMCs) and pericytes. However, cell-type-specific contributions driving CADASIL remain unknown. Here, we generate two conditional knockin mouse models carrying the CADASIL-causing Notch3R170C mutation in SMCs or pericytes. Both Notch3R170C models show perivascular accumulation of the NOTCH3 yet develop distinct neurovascular changes. These changes are associated with regionally distinct vascular and neuroinflammatory pathology and memory deficits. Proteomic profiling of brain vessels reveals distinct cell-specific responses, with metabolic pathway dysregulation in pericyte-Notch3R170C mice and immune signaling in SMC-Notch3R170C mice. Integration with single-cell RNA sequencing (RNA-seq) suggests that these changes may also involve brain endothelial cells. Together, these findings define mural cell-specific mechanisms that contribute to the CADASIL-associated vascular pathology.
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