Wan Zhu1, Wanqiu Chen1, Dingquan Zou1,2, Liang Wang1, Chen Bao1, Lei Zhan1, Daniel Saw1, Sen Wang1, Ethan Winkler3, Zhengxi Li1, Meng Zhang1, Fanxia Shen1, Sonali Shaligram1, Michael Lawton3, Hua Su4. 1. From the Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care (W.Z., W.C., D.Z., L.W., C.B., L.Z., D.S., S.W., Z.L., M.Z., F.S., S.S., H.S.). 2. University of California, San Francisco; and Department of Anesthesiology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China (D.Z.). 3. Department of Neurological Surgery (E.W., M.L.). 4. From the Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care (W.Z., W.C., D.Z., L.W., C.B., L.Z., D.S., S.W., Z.L., M.Z., F.S., S.S., H.S.) hua.su@ucsf.edu.
Abstract
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.
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.
Authors: Yi Guo; Tara Saunders; Hua Su; Helen Kim; Deniz Akkoc; David A Saloner; Steven W Hetts; Christopher Hess; Michael T Lawton; Andrew W Bollen; Tony Pourmohamad; Charles E McCulloch; Tarik Tihan; William L Young Journal: Stroke Date: 2012-02-02 Impact factor: 7.914
Authors: J P Mohr; Michael K Parides; Christian Stapf; Ellen Moquete; Claudia S Moy; Jessica R Overbey; Rustam Al-Shahi Salman; Eric Vicaut; William L Young; Emmanuel Houdart; Charlotte Cordonnier; Marco A Stefani; Andreas Hartmann; Rüdiger von Kummer; Alessandra Biondi; Joachim Berkefeld; Catharina J M Klijn; Kirsty Harkness; Richard Libman; Xavier Barreau; Alan J Moskowitz Journal: Lancet Date: 2013-11-20 Impact factor: 79.321
Authors: Andrée-Anne Berthiaume; David A Hartmann; Mark W Majesky; Narayan R Bhat; Andy Y Shih Journal: Front Aging Neurosci Date: 2018-07-17 Impact factor: 5.750
Authors: Rachel Muster; Nerissa Ko; Wade Smith; Hua Su; Melissa A Dickey; Jeffrey Nelson; Charles E McCulloch; Patricia K Sneed; Jennifer L Clarke; David A Saloner; Laura Eisenmenger; Helen Kim; Daniel L Cooke Journal: BMJ Neurol Open Date: 2021-03-17