Increased Endothelial Progenitor Cells and Vasculogenic Factors in Higher-Staged Arteriovenous Malformations

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Abstract
Background: Arteriovenous malformations cause significant morbidity, primarily because they expand over time and recur after treatment. The authors hypothesized that neovascularization might contribute to arteriovenous malformation progression. Methods: Arteriovenous malformation tissue was collected prospectively from 12 patients after resection. Schobinger stage was determined by clinical history. Neovascularization in stage II lesions (n = 7) was compared with stage III arteriovenous malformations (n = 5) that had progressed. Specimens were analyzed using immunohistochemistry for CD31, Ki67, and CD34/CD133. Quantitative real-time reverse-transcriptase polymerase chain reaction was used to determine mRNA expression of factors that recruit endothelial progenitor cells: vascular endothelial growth factor (VEGF), stromal cell–derived factor-1α (SDF-1α), and hypoxia-inducible factor-1α (HIF-1α). VEGF receptors (VEGFR1, VEGFR2, neuropilin 1, and neuropilin 2) also were quantified using quantitative real-time reverse-transcriptase polymerase chain reaction. Results: Stage III arteriovenous malformations showed greater microvessel density (5.8 percent) than stage II lesions (1.3 percent) (p = 0.004); no difference in proliferating endothelial cells was noted (p = 0.67). CD133+CD34+ endothelial progenitor cells were elevated in stage III (0.53 percent) compared with stage II arteriovenous malformations (0.25 percent) (p = 0.03). HIF-1α and SDF-1α were increased 7.6- and 7.9-fold in stage III compared with stage II lesions (1.7-fold and 3.3-fold), respectively (p = 0.02). Neuropilin 1 and neuropilin 2 expression was greater in stage III (5.8-fold and 4.6-fold) than stage II arteriovenous malformations (3.0-fold and 2.4-fold) (p = 0.03). Conclusions: Higher-staged arteriovenous malformations exhibit increased expression of endothelial progenitor cells and factors that stimulate their recruitment. Neovascularization by vasculogenesis may be involved in progression of arteriovenous malformation.

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