Persistent infiltration and pro-inflammatory differentiation of monocytes cause unresolved inflammation in brain arteriovenous malformation.
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.
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
Rui
R
Zhang
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
Zhenying
Z
Han
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.|INSERM, U676, Hôpital Robert Debré, Paris, France.
Vincent
V
Degos
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
Fanxia
F
Shen
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
Eun-Jung
EJ
Choi
Department of Radiology, University of California, San Francisco, San Francisco, CA, USA.
Zhengda
Z
Sun
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
Shuai
S
Kang
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
Michael
M
Wong
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
Wan
W
Zhu
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
Lei
L
Zhan
Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle, United Kingdom.
Helen M
HM
Arthur
Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA.
S Paul
SP
Oh
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Marie E
ME
Faughnan
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
Hua
H
Su
D030201:Activin Receptors, Type I / Q000172:deficiency / Q000235:genetics; D030301:Activin Receptors, Type II; D000818:Animals; D002454:Cell Differentiation; D018920:Coculture Techniques; D004195:Disease Models, Animal; D000071063:Endoglin / Q000172:deficiency / Q000235:genetics; D042783:Endothelial Cells / Q000473:pathology; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics
D000071063:Endoglin; C502004:Eng protein, mouse; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse
Angiogenesis; Animal models; Arteriovenous malformations; Cerebrovascular disease; Macrophages; Microglia