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Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFβ expression |
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| Authors: | Mahmod Panahi Naeimeh Yousefi Mesri Eva‐Britt Samuelsson Kirsten G Coupland Charlotte Forsell Caroline Graff Saara Tikka Bengt Winblad Matti Viitanen Helena Karlström Erik Sundström Homira Behbahani |
| Affiliation: | 1. Karolinska Institute, Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Huddinge, Sweden;2. Division of Neurodegeneration, Huddinge, Sweden;3. Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital, Stockholm, Sweden;4. Medicum, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland;5. Folkh?lsan Institute of Genetics, Helsinki, Finland;6. Department of Geriatrics, Turun Kaupunginsairaala, University Hospital of Turku, University of Turku, Turku, Finland;7. Karolinska Institute, Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska University Hospital, Huddinge, Sweden;8. Stockholms Sjukhem, R&D unit, Stockholm, Sweden |
| Abstract: | Cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial fatal progressive degenerative disorder. One of the pathological hallmarks of CADASIL is a dramatic reduction of vascular smooth muscle cells (VSMCs) in cerebral arteries. Using VSMCs from the vasculature of the human umbilical cord, placenta and cerebrum of CADASIL patients, we found that CADASIL VSMCs had a lower proliferation rate compared to control VSMCs. Exposure of control VSMCs and endothelial cells (ECs) to media derived from CADASIL VSMCs lowered the proliferation rate of all cells examined. By quantitative RT‐PCR analysis, we observed increased Transforming growth factor‐β (TGFβ) gene expression in CADASIL VSMCs. Adding TGFβ‐neutralizing antibody restored the proliferation rate of CADASIL VSMCs. We assessed proliferation differences in the presence or absence of TGFβ‐neutralizing antibody in ECs co‐cultured with VSMCs. ECs co‐cultured with CADASIL VSMCs exhibited a lower proliferation rate than those co‐cultured with control VSMCs, and neutralization of TGFβ normalized the proliferation rate of ECs co‐cultured with CADASIL VSMCs. We suggest that increased TGFβ expression in CADASIL VSMCs is involved in the reduced VSMC proliferation in CADASIL and may play a role in situ in altered proliferation of neighbouring cells in the vasculature. |
| Keywords: | CADASIL endothelial cells NOTCH3 Transforming growth factor‐β vascular smooth muscle cells |
