Pathogenesis and Radiobiology of Brain Arteriovenous Malformations: Implications for Risk Stratification in Natural History and Post-treatment Course

Achal S. Achrol, B.S.; Raphael Guzman, M.D.; Monika Varga, B.S.; John R. Adler, M.D.; Gary K. Steinberg, M.D.; Ph.D.; Steven D. Chang, M.D.

Disclosures

Neurosurg Focus. 2009;26(5):E9 

In This Article

Endothelial Progenitor Cells and Aberrant Vasculogenesis

Most BAVM research has focused on abnormal angiogenesis, that is, endothelial cell sprouting from existing vessels, in the underlying pathogenesis of a BAVM.[100] However, adult vasculogenesis is increasingly being understood as the pathway for adult neovascularization.[3,12,13] Vasculogenesis differs from angiogenesis in that new blood vessels arise from circulating bone marrow-derived EPCs rather than from sprouting of local endothelial cells.[3] During tissue ischemia, vasculogenesis is initiated via increased expression of the transcription factor HIF-1, which promotes local production of SDF-1 and VEGF-A by hypoxic endothelial cells.[12,13] It is hypothesized that release of SDF-1 ligand results in reversal of a marrow/periphery gradient that normally inhibits EPC migration.[13] As a result, EPCs now mobilize to the periphery where they are preferentially recruited to SDF-1 expressing ischemic tissue.[12,13,41,57,99]

Aberrant vasculogenesis and EPC trafficking have recently been implicated in the development of other vascular abnormalities, including infantile hemangioma[52,53] and moyamoya disease.[47] Children with proliferating infantile hemangioma demonstrate increased levels of mobilized EPCs[53] and surgical specimens of infantile hemangioma are positive for progenitor-specific markers including CD34, AC133, and VEGF.[52]

Consistent with aberrant vasculogenesis as a factor in the etiology of BAVM, increased expression of HIF-1, VEGF, and VEGF receptors are detected in BAVM tissue.[35,36,37,38,40] Expression of matrix metelloproteinase-9 is also increased in BAVM tissue[15,17,39] and has been shown to be hypoxia responsive[45] and may result in release of EPCs by cleavage of membrane-bound kit ligand in the bone marrow.[42]

Recently, aberrant vasculogenesis and EPC function have been implicated in another cerebrovascular disease, moyamoya disease.[47] Future studies are needed to enumerate circulating endothelial progenitor cells in patients with cerebrovascular disease in vivo by using fluorescence-activated cell sorting protocols[24] and to perform blood genomic analysis on these and other circulating cell populations, as previously described.[62,84] Such studies would aid in the understanding of vascular stem cell biology, validate the utility of EPCs as a marker of cerebrovascular disease progression, and shed new light on novel therapeutic strategies for the medical management of cerebrovascular disease.

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