This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 27/12/2664    most recent ATVBAHA.107.150284v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kleinman, M. E. Articles by Gurtner, G. C. Search for Related Content PubMed PubMed Citation Articles by Kleinman, M. E. Articles by Gurtner, G. C.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2664.)
© 2007 American Heart Association, Inc.

Vascular Biology

Hypoxia-Induced Mediators of Stem/Progenitor Cell Trafficking Are Increased in Children With Hemangioma

Mark E. Kleinman; Matthew R. Greives; Samara S. Churgin; Keith M. Blechman; Eric I. Chang; Daniel J. Ceradini; Oren M. Tepper; Geoffrey C. Gurtner

From the Stanford University School of Medicine (M.E.K., E.I.C., G.C.G.), Children’s Surgical Research Program, Stanford, Calif; and New York University School of Medicine (M.R.G., S.S.C., K.M.B., D.J.C., O.M.T.), Institute of Reconstructive Plastic Surgery, New York.

Correspondence to Geoffrey C. Gurtner, MD, Stanford University, Department of Surgery, PSRL, GK-201, 257 Campus Drive West, Stanford, CA, 94305-5148. E-mail ggurtner{at}stanford.edu

Objective— The mechanism of neovascularization during the proliferative phase of infantile hemangioma is poorly understood. It is known that circulating bone marrow-derived endothelial progenitor cells (EPCs) form new blood vessels in ischemic tissues using mediators regulated by the transcription factor, HIF-1. Mobilization of EPCs is enhanced by VEGF-A, matrix metalloproteinase (MMP)-9, and estrogen, whereas homing is secondary to localized expression of stromal cell-derived factor-1 (SDF-1). We examined whether these mediators of EPC trafficking are upregulated during the proliferation of infantile hemangioma.

Methods and Results— Surgical specimens and blood samples were obtained from children with proliferating hemangioma and age-matched controls (n=10, each group). VEGF-A and MMP-9 levels were measured in blood, and tissue sections were analyzed for SDF-1, MMP-9, VEGF-A, and HIF-1. The role of estrogen as a modulator of hemangioma endothelial cell growth was also investigated. We found that all these mediators of EPC trafficking are elevated in blood and specimens from children with proliferating infantile hemangioma. In vitro, the combination of hypoxia and estrogen demonstrated a synergistic effect on hemangioma endothelial cell proliferation.

Conclusions— These findings demonstrate that proliferating hemangiomas express known mediators of vasculogenesis and suggest that this process may play a role in the initiation or progression of this disease.

The pathophysiology of infantile hemangioma is unknown, yet there is evidence to suggest that stem/progenitor cells may contribute to their rapid proliferation. We investigated the mediators of progenitor cell mobilization and recruitment in children with hemangioma and demonstrate that growth may be linked to hypoxia and activation of vasculogenic pathways.

Key Words: hemangioma • hypoxia • vasculogenesis • endothelial progenitor cells • chemokines