Thalidomide Reduces Hemorrhage of Brain Arteriovenous Malformations in a Mouse Model
| Autor: | Michael T. Lawton, Sonali Shaligram, Sen Wang, Liang Wang, Meng Zhang, Hua Su, Lei Zhan, Daniel Saw, Wan Zhu, Dingquan Zou, Chen Bao, Ethan A. Winkler, Fanxia Shen, Wanqiu Chen, Zhengxi Li |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pathology Angiogenesis Activin Receptors Activin Receptors Type II Messenger Type I arteriovenous malformation Angiogenesis Inhibitors Cardiorespiratory Medicine and Haematology Cardiovascular Muscle Smooth Vascular Mice 0302 clinical medicine Smooth Muscle 2.1 Biological and endogenous factors Aetiology Lenalidomide Pediatric Platelet-Derived Growth Factor Lymphokines PDGFB CD68 Arteriovenous malformation Hematology Proto-Oncogene Proteins c-sis Platelet-Derived Growth Factor beta Thalidomide Stroke Muscle Smooth hemorrhage medicine.symptom Cardiology and Cardiovascular Medicine Intracranial Hemorrhages Receptor medicine.drug Intracranial Arteriovenous Malformations medicine.medical_specialty brain Clinical Sciences Myocytes Smooth Muscle Down-Regulation Type II Article Mural cell Receptor Platelet-Derived Growth Factor beta Lesion 03 medical and health sciences Rare Diseases Vascular thalidomide Genetics medicine Animals Humans RNA Messenger Inflammation Advanced and Specialized Nursing Myocytes Neurology & Neurosurgery Animal business.industry Neurosciences Endothelial Cells medicine.disease Disease Models Animal 030104 developmental biology Disease Models Microvessels RNA Congenital Structural Anomalies Blood Vessels Neurology (clinical) Pericytes business Activin Receptors Type I 030217 neurology & neurosurgery |
| Zdroj: | Stroke, vol 49, iss 5 |
| ISSN: | 1524-4628 0039-2499 |
| DOI: | 10.1161/strokeaha.117.020356 |
| Popis: | Background and Purpose— Brain arteriovenous malformation (bAVM) is an important risk factor for intracranial hemorrhage. Current treatments for bAVM are all associated with considerable risks. There is no safe method to prevent bAVM hemorrhage. Thalidomide reduces nose bleeding in patients with hereditary hemorrhagic telangiectasia, an inherited disorder characterized by vascular malformations. In this study, we tested whether thalidomide and its less toxic analog, lenalidomide, reduce bAVM hemorrhage using a mouse model. Methods— bAVMs were induced through induction of brain focal activin-like kinase 1 ( Alk1 , an AVM causative gene) gene deletion and angiogenesis in adult Alk1 -floxed mice. Thalidomide was injected intraperitoneally twice per week for 6 weeks, starting either 2 or 8 weeks after AVM induction. Lenalidomide was injected intraperitoneally daily starting 8 weeks after AVM induction for 6 weeks. Brain samples were collected at the end of the treatments for morphology, mRNA, and protein analyses. The influence of Alk1 downregulation on PDGFB (platelet-derived growth factor B) expression was also studied on cultured human brain microvascular endothelial cells. The effect of PDGFB in mural cell recruitment in bAVM was explored by injection of a PDGFB overexpressing lentiviral vector to the mouse brain. Results— Thalidomide or lenalidomide treatment reduced the number of dysplastic vessels and hemorrhage and increased mural cell (vascular smooth muscle cells and pericytes) coverage in the bAVM lesion. Thalidomide reduced the burden of CD68 + cells and the expression of inflammatory cytokines in the bAVM lesions. PDGFB expression was reduced in ALK1-knockdown human brain microvascular endothelial cells and in mouse bAVM lesion. Thalidomide increased Pdgfb expression in bAVM lesion. Overexpression of PDGFB mimicked the effect of thalidomide. Conclusions— Thalidomide and lenalidomide improve mural cell coverage of bAVM vessels and reduce bAVM hemorrhage, which is likely through upregulation of Pdgfb expression. |
| Databáze: | OpenAIRE |
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