Thalidomide reduces hemorrhage of brain arteriovenous malformations in a mouse model

Authors

Wan Zhu, University of California, San Francisco
Wanqiu Chen, University of California, San Francisco
Dingquan Zou, University of California, San Francisco
Liang Wang, University of California, San Francisco
Chen Bao, University of California, San Francisco
Lei Zhan, University of California, San Francisco
Daniel Saw, University of California, San Francisco
Sen Wang, University of California, San Francisco
Ethan Winkler, University of California, San Francisco
Zhengxi Li, University of California, San Francisco
Meng Zhang, University of California, San Francisco
Fanxia Shen, University of California, San Francisco
Sonali Shaligram, University of California, San Francisco
Michael Lawton, University of California, San FranciscoFollow
Hua Su, University of California, San Francisco

Document Type

Article

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.

Publication Date

1-1-2018

Publication Title

Stroke

ISSN

00392499

E-ISSN

15244628

Volume

49

Issue

5

First Page

1232

Last Page

1240

PubMed ID

29593101

Digital Object Identifier (DOI)

10.1161/STROKEAHA.117.020356

Recommended Citation

Zhu, Wan; Chen, Wanqiu; Zou, Dingquan; Wang, Liang; Bao, Chen; Zhan, Lei; Saw, Daniel; Wang, Sen; Winkler, Ethan; Li, Zhengxi; Zhang, Meng; Shen, Fanxia; Shaligram, Sonali; Lawton, Michael; and Su, Hua, "Thalidomide reduces hemorrhage of brain arteriovenous malformations in a mouse model" (2018). Neurosurgery. 1277.
https://scholar.barrowneuro.org/neurosurgery/1277