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. 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. 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. 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. Children with proliferating infantile hemangioma demonstrate increased levels of mobilized EPCs and surgical specimens of infantile hemangioma are positive for progenitor-specific markers including CD34, AC133, and VEGF.
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 and may result in release of EPCs by cleavage of membrane-bound kit ligand in the bone marrow.
Recently, aberrant vasculogenesis and EPC function have been implicated in another cerebrovascular disease, moyamoya disease. Future studies are needed to enumerate circulating endothelial progenitor cells in patients with cerebrovascular disease in vivo by using fluorescence-activated cell sorting protocols 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.
Neurosurg Focus. 2009;26(5):E9 © 2009 American Association of Neurological Surgeons
Cite this: Pathogenesis and Radiobiology of Brain Arteriovenous Malformations: Implications for Risk Stratification in Natural History and Post-treatment Course - Medscape - May 01, 2009.