Persistent infiltration and pro-inflammatory differentiation of monocytes cause unresolved inflammation in brain arteriovenous malformation

Authors

Rui Zhang, University of California, San Francisco
Zhenying Han, University of California, San Francisco
Vincent Degos, University of California, San Francisco
Fanxia Shen, University of California, San Francisco
Eun Jung Choi, University of California, San Francisco
Zhengda Sun, University of California, San Francisco
Shuai Kang, University of California, San Francisco
Michael Wong, University of California, San Francisco
Wan Zhu, University of California, San Francisco
Lei Zhan, University of California, San Francisco
Helen M. Arthur, University of Newcastle upon Tyne, Faculty of Medical Sciences
S. Paul Oh, University of FloridaFollow
Marie E. Faughnan, University of Toronto
Hua Su, University of California, San Francisco

Document Type

Article

Abstract

© 2016, Springer Science+Business Media Dordrecht. An abnormally high number of macrophages are present in human brain arteriovenous malformations (bAVM) with or without evidence of prior hemorrhage, causing unresolved inflammation that may enhance abnormal vascular remodeling and exacerbate the bAVM phenotype. The reasons for macrophage accumulation at the bAVM sites are not known. We tested the hypothesis that persistent infiltration and pro-inflammatory differentiation of monocytes in angiogenic tissues increase the macrophage burden in bAVM using two mouse models and human monocytes. Mouse bAVM was induced through deletion of AVM causative genes, Endoglin (Eng) globally or Alk1 focally, plus brain focal angiogenic stimulation. An endothelial cell and vascular smooth muscle cell co-culture system was used to analyze monocyte differentiation in the angiogenic niche. After angiogenic stimulation, the Eng-deleted mice had fewer CD68+ cells at 2 weeks (P = 0.02), similar numbers at 4 weeks (P = 0.97), and more at 8 weeks (P = 0.01) in the brain angiogenic region compared with wild-type (WT) mice. Alk1-deficient mice also had a trend toward more macrophages/microglia 8 weeks (P = 0.064) after angiogenic stimulation and more RFP+ bone marrow-derived macrophages than WT mice (P = 0.01). More CD34+ cells isolated from peripheral blood of patients with ENG or ALK1 gene mutation differentiated into macrophages than those from healthy controls (P < 0.001). These data indicate that persistent infiltration and pro-inflammatory differentiation of monocytes might contribute to macrophage accumulation in bAVM. Blocking macrophage homing to bAVM lesions should be tested as a strategy to reduce the severity of bAVM.

Keywords

Angiogenesis, Animal models, Arteriovenous malformations, Cerebrovascular disease, Macrophages, Microglia

Publication Date

10-1-2016

Publication Title

Angiogenesis

ISSN

09696970

E-ISSN

15737209

Volume

19

Issue

4

First Page

451

Last Page

461

PubMed ID

27325285

Digital Object Identifier (DOI)

10.1007/s10456-016-9519-4

Recommended Citation

Zhang, Rui; Han, Zhenying; Degos, Vincent; Shen, Fanxia; Choi, Eun Jung; Sun, Zhengda; Kang, Shuai; Wong, Michael; Zhu, Wan; Zhan, Lei; Arthur, Helen M.; Oh, S. Paul; Faughnan, Marie E.; and Su, Hua, "Persistent infiltration and pro-inflammatory differentiation of monocytes cause unresolved inflammation in brain arteriovenous malformation" (2016). Translational Neuroscience. 657.
https://scholar.barrowneuro.org/neurobiology/657