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Angiogenesis. 2016 Oct;19(4):451-61. doi: 10.1007/s10456-016-9519-4. Epub 2016 Jun 20.

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

Author information

  • 1Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, 1001 Potrero Avenue, Box 1363, San Francisco, CA, 94143, USA.
  • 2INSERM, U676, Hôpital Robert Debré, Paris, France.
  • 3Department of Radiology, University of California, San Francisco, San Francisco, CA, USA.
  • 4Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle, UK.
  • 5Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA.
  • 6Department of Medicine, University of Toronto, Toronto, ON, Canada.
  • 7Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, 1001 Potrero Avenue, Box 1363, San Francisco, CA, 94143, USA. hua.su@ucsf.edu.

Abstract

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

PMID:
27325285
PMCID:
PMC5029790
[Available on 2017-10-01]
DOI:
10.1007/s10456-016-9519-4
[PubMed - in process]
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