Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFβ expression

• Published in: Journal of cellular and molecular medicine 2018-06, Vol.22 (6), p.3016-3024
• Main Authors: Panahi, Mahmod, Yousefi Mesri, Naeimeh, Samuelsson, Eva‐Britt, Coupland, Kirsten G., Forsell, Charlotte, Graff, Caroline, Tikka, Saara, Winblad, Bengt, Viitanen, Matti, Karlström, Helena, Sundström, Erik, Behbahani, Homira
• Format: Article
• Language: English
• Subjects: Antibodies; Antibodies, Neutralizing - pharmacology; Arteries; Blood platelets; CADASIL; CADASIL - genetics; CADASIL - metabolism; CADASIL - pathology; Cell culture; Cell cycle; Cell division; Cell growth; Cell proliferation; Cell Proliferation - genetics; Cerebrum; Coculture Techniques; Endothelial cells; Endothelial Cells - metabolism; Fibroblasts; Flow cytometry; Gene expression; Gene Expression Regulation - genetics; Genes; Growth factors; Humans; Kinases; Leukoencephalopathy; Medicin och hälsovetenskap; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Muscles; Mutation; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Neutralization; Neutralizing; NOTCH3; Original; Patients; Placenta; Proteins; Smooth muscle; Transforming growth factor; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - genetics; Transforming growth factor-b; Transforming growth factor‐β; Umbilical cord; vascular smooth muscle cells
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.13534

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.