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high macrophage burden develop micro‑hemorrhage?). pathophysiology, Diagnosis, and Management. 5 ed., Ch. 12.
th
This will be difficult to test in human studies, and would Philadelphia: Churchill Livingstone Elsevier; 2011. p. 169‑86.
probably be best addressed in an animal model. An 7. Kim H, Marchuk DA, Pawlikowska L, Chen Y, Su H, Yang GY,
Young WL. Genetic considerations relevant to intracranial
animal study has shown that in bAVM, vessel integrity is hemorrhage and brain arteriovenous malformations. Acta Neurochir
impaired. Therefore, the macrophages in bAVM could Suppl 2008;105:199‑206.
[11]
also be a response to the extravasation of blood content. 8. Choi EJ, Chen W, Jun K, Arthur HM, Young WL, Su H. Novel brain
arteriovenous malformation mouse models for type 1 hereditary
hemorrhagic telangiectasia. PLoS One 2014;9:e88511.
One limitation of the study is that we only used one 9. Moftakhar P, Hauptman JS, Malkasian D, Martin NA. Cerebral
marker for each cell‑type. Adding additional markers, arteriovenous malformations. Part 1: cellular and molecular biology.
including positive and negative controls, would make Neurosurg Focus 2009;26:E10.
our data more convincing. However, the markers we 10. Chen W, Guo Y, Walker EJ, Shen F, Jun K, Oh SP, Degos V,
Lawton MT, Tihan T, Davalos D, Akassoglou K, Nelson J,
used in this study are the most commonly used for Pile‑Spellman J, Su H, Young WL. Reduced mural cell coverage
macrophages, total lymphocytes, T‑ and B‑lymphocytes, and impaired vessel integrity after angiogenic stimulation
and plasma cells. A future study will employ more in the Alk1‑deficient brain. Arterioscler Thromb Vasc Biol
2013;33:305‑10.
markers to confirm the cell‑types we have identified 11. Chen W, Sun Z, Han Z, Jun K, Camus M, Wankhede M, Mao L,
here, and to define the subtypes of T‑ or B‑lymphocytes Arnold T, Young WL, Su H. De novo cerebrovascular malformation
or other inflammatory cells. in the adult mouse after endothelial Alk1 deletion and angiogenic
stimulation. Stroke 2014;45:900‑2.
12. Chen W, Choi EJ, McDougall CM, Su H. Brain arteriovenous
In summary, we found that the load and location of malformation modeling, pathogenesis, and novel therapeutic targets.
T‑lymphocytes were not associated with hemosiderin Transl Stroke Res 2014;5:316‑29.
and macrophages. Macrophages are present in 13. Chen Y, Zhu W, Bollen AW, Lawton MT, Barbaro NM, Dowd CF,
unruptured and previously untreated bAVMs, and Hashimoto T, Yang GY, Young WL. Evidence of inflammatory cell
their load was greater when hemosiderin is present. involvement in brain arteriovenous malformations. Neurosurgery
2008;62:1340‑9.
However, the presence of macrophages is not uniquely 14. Chen Y, Fan Y, Poon KY, Achrol AS, Lawton MT, Zhu Y,
driven by hemosiderin, because they were also found in McCulloch CE, Hashimoto T, Lee C, Barbaro NM, Bollen AW,
hemosiderin‑negative specimens. Future studies need Yang GY, Young WL. MMP‑9 expression is associated with leukocytic
but not endothelial markers in brain arteriovenous malformations.
to be conducted to determine (1) how macrophages Front Biosci 2006;11:3121‑8.
and lymphocytes contribute to the pathogenesis 15. Chen Y, Pawlikowska L, Yao JS, Shen F, Zhai W, Achrol AS,
and progression of the disease, and (2) whether the Lawton MT, Kwok PY, Yang GY, Young WL. Interleukin‑6
burden of these cell loads is causally related to the involvement in brain arteriovenous malformations. Ann Neurol
2006;59:72‑80.
development of micro‑hemorrhage, and ultimately, 16. Hashimoto G, Inoki I, Fujii Y, Aoki T, Ikeda E, Okada Y. Matrix
clinically symptomatic hemorrhage. metalloproteinases cleave connective tissue growth factor and
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ACKNOWLEDGMENTS 17. Storer KP, Tu J, Karunanayaka A, Morgan MK, Stoodley MA.
Inflammatory molecule expression in cerebral arteriovenous
The authors would like to thank Voltaire Gungab for assistance malformations. J Clin Neurosci 2008;15:179‑84.
with manuscript preparation, and members of the UCSF 18. Hasan DM, Amans M, Tihan T, Hess C, Guo Y, Cha S, Su H,
bAVM Study Project (http://avm.ucsf.edu.) for their support. Martin AJ, Lawton MT, Neuwelt EA, Saloner DA, Young WL.
Ferumoxytol‑enhanced MRI to image inflammation within human
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