CADASIL Mutations and shRNA Silencing of NOTCH3 Affect Actin Organization in Cultured Vascular Smooth Muscle Cells
| Autor: | Minna Pöyhönen, Matti Viitanen, Kati Mykkänen, Ismo Virtanen, Saara Tikka, Yan Peng Ng, Giuseppe Di Maio, Tatiana Lepikhova, Maija Siitonen, Marc Baumann, Hannu Kalimo |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Male
Aging Vascular smooth muscle CADASIL Muscle Smooth Vascular Small hairpin RNA Leukoencephalopathy 0302 clinical medicine Transduction Genetic NOTCH3 ta318 RNA Small Interfering Receptor Notch3 0303 health sciences Receptors Notch shRNA silencing musculoskeletal system Cell biology Actin Cytoskeleton Neurology Organ Specificity cardiovascular system Original Article Female Cardiology and Cardiovascular Medicine medicine.medical_specialty actin filament Myocytes Smooth Muscle Mutation Missense macromolecular substances Biology adhesion site Cell Line 03 medical and health sciences Internal medicine medicine Animals Humans Gene silencing Gene Silencing Actin 030304 developmental biology ta1184 Infant Newborn ta1182 medicine.disease Actin cytoskeleton Actins Endocrinology Amino Acid Substitution Cell culture Neurology (clinical) vascular smooth muscle cell 030217 neurology & neurosurgery |
| Zdroj: | Journal of Cerebral Blood Flow & Metabolism |
| ISSN: | 1559-7016 0271-678X |
| Popis: | Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary vascular dementia caused by mutations in NOTCH3 gene. Pathology is manifested in small- and middle-sized arteries throughout the body, though primarily in cerebral white matter. Hemodynamics is altered in CADASIL and NOTCH3 is suggested to regulate actin filament polymerization and thereby vascular tone. We analyzed NOTCH3 expression and morphology of actin cytoskeleton in genetically genuine cultured human CADASIL vascular smooth muscle cells (VSMCs) (including a cell line homozygous for p. Arg133Cys mutation) derived from different organs, and in control VSMCs with short hairpin RNA (shRNA)-silenced NOTCH3. NOTCH3 protein level was higher in VSMCs derived from adult than newborn arteries in both CADASIL and control VSMCs. CADASIL VSMCs showed altered actin cytoskeleton including increased branching and node formation, and more numerous and smaller adhesion sites than control VSMCs. Alterations in actin cytoskeleton in shRNA-silenced VSMCs were similar as in CADASIL VSMCs. Severity of the alterations in actin filaments corresponded to NOTCH3 expression level being most severe in VSMCs derived from adult cerebral arteries. These observations suggest that hypomorphic NOTCH3 activity causes alterations in actin organization in CADASIL. Furthermore, arteries from different organs have specific characteristics, which modify the effects of the NOTCH3 mutation and which is one explanation for the exceptional susceptibility of cerebral white matter arteries. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|