Small vessel disease lesion type and brain atrophy: The role of co‐occurring amyloid

Key pathological features of cerebral small vessel disease (cSVD) include impairment of the blood brain barrier (BBB) and the progression of white matter lesions (WMLs) amongst other structural lesions, leading to the clinical manifestations of cSVD. The function of endothelial cells (ECs) is of major importance to maintain a proper BBB. ECs interact with several cell types to provide structural and functional support to the brain. Oligodendrocytes (OLs) myelinate axons in the central nervous system and are crucial in sustaining the integrity of white matter. The interplay between ECs and OLs and their precursor cells (OPCs) has received limited attention yet seems of relevance for the study of BBB dysfunction and white matter injury in cSVD. Emerging evidence shows a crosstalk between ECs and OPCs/OLs, mediated by signaling through the Wingless and Int-1 (WNT)/β-catenin pathway. As the latter is involved in EC function (e.g., angiogenesis) and oligodendrogenesis, we reviewed the role of WNT/β-catenin signaling for both cell types and performed a systematic search to identify studies describing a WNT-mediated interplay between ECs and OPCs/OLs. Dysregulation of this interaction may limit remyelination of WMLs and render the BBB leaky, thereby initiating a vicious neuroinflammatory cycle. A better understanding of the role of this signaling pathway in EC–OL crosstalk is essential in understanding cSVD development.

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The role of small diffusion-weighted imaging lesions in cerebral small vessel disease

Neurology ◽

10.1212/wnl.0000000000008364 ◽

2019 ◽

pp. 10.1212/WNL.0000000000008364 ◽

Cited By ~ 1

Author(s):

Kim Wiegertjes ◽

Annemieke ter Telgte ◽

Pedro B. Oliveira ◽

Esther M.C. van Leijsen ◽

Mayra I. Bergkamp ◽

...

Keyword(s):

Diffusion Weighted Imaging ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Small Diffusion ◽

Vessel Disease ◽

Diffusion Weighted

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Biomarkers to predict clinical progression in small vessel disease strokes: Prognostic role of albuminuria and oxidized LDL cholesterol

Atherosclerosis ◽

10.1016/j.atherosclerosis.2011.07.114 ◽

2011 ◽

Vol 219 (1) ◽

pp. 368-372 ◽

Cited By ~ 11

Author(s):

Elisa Cuadrado-Godia ◽

Angel Ois ◽

Eva Garcia-Ramallo ◽

Eva Giralt ◽

Sara Jimena ◽

...

Keyword(s):

Ldl Cholesterol ◽

Small Vessel Disease ◽

Oxidized Ldl ◽

Small Vessel ◽

Clinical Progression ◽

Prognostic Role ◽

Vessel Disease

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Critical role of Kv channels in cerebrovascular dysfunction associated with ischemic small vessel disease in a mouse genetic model

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.925.7 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Fabrice Dabertrand ◽

Adrian D Bonev ◽

Cristel Krøigaard ◽

Joseph E Brayden ◽

Anne Joutel ◽

...

Keyword(s):

Genetic Model ◽

Small Vessel Disease ◽

Critical Role ◽

Small Vessel ◽

Vessel Disease ◽

Kv Channels ◽

Cerebrovascular Dysfunction ◽

Mouse Genetic Model ◽

Mouse Genetic

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Loss of the serine protease HTRA1 impairs smooth muscle cells maturation

Scientific Reports ◽

10.1038/s41598-019-54807-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Ralph Klose ◽

Alexander Prinz ◽

Fabian Tetzlaff ◽

Eva-Maria Weis ◽

Iris Moll ◽

...

Keyword(s):

Smooth Muscle ◽

Small Vessel Disease ◽

Small Vessel ◽

Marker Genes ◽

Transcriptional Repressors ◽

Tgfβ Signaling ◽

Protein Levels ◽

Vessel Disease ◽

Signaling Activity

AbstractVascular smooth muscle cell (VSMC) dysfunction is a hallmark of small vessel disease, a common cause of stroke and dementia. Two of the most frequently mutated genes in familial small vessel disease are HTRA1 and NOTCH3. The protease HTRA1 cleaves the NOTCH3 ligand JAG1 implying a mechanistic link between HTRA1 and Notch signaling. Here we report that HTRA1 is essential for VSMC differentiation into the contractile phenotype. Mechanistically, loss of HTRA1 increased JAG1 protein levels and NOTCH3 signaling activity in VSMC. In addition, the loss of HTRA1 enhanced TGFβ-SMAD2/3 signaling activity. Activation of either NOTCH3 or TGFβ signaling resulted in increased transcription of the HES and HEY transcriptional repressors and promoted the contractile VSMC phenotype. However, their combined over-activation led to an additive accumulation of HES and HEY proteins, which repressed the expression of contractile VSMC marker genes. As a result, VSMC adopted an immature phenotype with impaired arterial vasoconstriction in Htra1-deficient mice. These data demonstrate an essential role of HTRA1 in vascular maturation and homeostasis by controlling Notch and TGFβ signaling.

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