Immunolocalization of platelet‐derived growth factor receptor‐β (PDGFR‐β) and pericytes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
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چکیده
AIMS Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is identified by aggregates of NOTCH3 extracellular domain (N3ECD) along capillaries and the deposition of granular osmiophilic material (GOM). We assessed the pattern of distribution of pericytes in relation to N3ECD deposits in cerebral microvessels of CADASIL subjects. METHODS We assessed post mortem brains from (n = 50) subjects with CADASIL, cerebral small vessel disease, and similar-age cognitively normal and older controls. Immunohistochemical and immunofluorescent staining methods were used to study the distribution and quantify immunoreactivities of the platelet-derived growth factor receptor-β (PDGFR-β) (for pericytes) and microvascular markers in the frontal cortex and white matter. RESULTS PDGFR-β antibody stained cells typical of pericytes in capillaries and small arterioles in both the grey and white matter. PDGFR-β reactive pericytes adopted 'crescent' morphology wrapped closely around capillary walls readily evident in cross-sections. We noted considerable overlap between PDGFR-β and N3ECD imunoreactivities in capillaries. Quantitative analysis of PDGFR-β immunoreactivity revealed significant differences in PDGFR-β %A in CADASIL compared with young controls (P < 0.05). PDGFR-β %A was further positively correlated with the basement membrane marker collagen IV (r = 0.529, P = 0.009), but was not associated with GLUT-1, the marker for endothelial cells. CONCLUSIONS Our results suggest increased expression of PDGFR-β immunoreactive pericytes in cerebral microvessels in CADASIL compared with similar age controls. While we cannot confirm whether PDGFR-β-expressing pericytes produce N3ECD and hence GOM, our findings demonstrate that up-regulation of pericyte-like cells is associated with microvascular changes, including loss of vascular smooth muscle cells in CADASIL.
منابع مشابه
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification.
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a single-gene disorder directly affecting the cerebral small blood vessels, that is caused by mutations in the HTRA1 gene encoding HtrA serine peptidase/protease 1 (HTRA1). CARASIL is the second known genetic form of ischemic, nonhypertensive, cerebral small-vessel disease with an identified...
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BACKGROUND AND PURPOSE Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is caused by mutations in the NOTCH3 gene and is clinically characterized by recurrent stroke and cognitive decline. Previous studies have shown an association between white matter hyperintensities on brain MRI and cognitive dysfunction in cerebral autosomal dominant arteriopathy wi...
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Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease caused by mutations in the NOTCH3 gene.1 NOTCH3 gene encodes a cell surface receptor on smooth muscle cell (SMC) and pericyte.1 The mutant Notch3 accumulated in pericyte and SMC causes non-amyloid, non-artherosclerotic angiopathy.2 The main clinical ...
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small vessel diseases caused by a mutation in the NOTCH3 gene. The clinical manifestations of CADASIL range from single or multiple lacunar infarcts, transient ischemic attacks, dementia, migraine with aura to psychiatric disorders. The features of brain ...
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