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

Abstract

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-1α. 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-1α (SDF-1α). 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-1α, MMP-9, VEGF-A, and HIF-1α. 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.

Treatment of infantile hemangiomas: therapeutic options in regard to side effects and adverse events – a review of the literature

“…[14] It is both effective during the proliferative and the involution phase of IH growth. The mechanism of action of propranolol in IH is not yet completely understood, but it is thought to originate from several effects, like vasoconstriction, [2,15] inhibition of angiogenesis, [16][17][18][19][20][21][22][23] stimulation of apoptosis [24] and inhibition of the reninangiotensin system (RAS). [25,26] IL: intralesional; IV: intravenous; MESNA: sodium-2-mercaptoethane sulfonate.…”

Receptor Tyrosine Kinase-Mediated Angiogenesis

“…However, infantile hemangiomas regress spontaneously within several years and treatment is reserved for cases of significant cosmetic and functional interference and complications (North et al 2006). Although their pathogenesis is still poorly understood, local dysregulation of angiogenesis involving hypoxia-mediated changes in VEGF and VEGFR expression seem to have an important etiological role in hemangiomas (Kleinman et al 2007;Przewratil et al 2010). Lymphangiomas, on the other hand, are vascular malformations involving lymphatic vessels, and they seem to be exclusively sporadic unlike capillary and venous malformations, which exist in both sporadic and hereditary forms (Brouillard and Vikkula 2007).…”

Clinical and Molecular Biology of Angiosarcoma

“…These lesions are common in newborns as strawberry patches or port wine stains. The causative mechanism of growth is unknown, but serum levels of VEGFA and HIF-1alpha are elevated in children with hemangiomas (Kleinman et al 2007) suggesting hypoxic signals may be driving AS growth. Hemangiomas have been successfully treated with the beta-blocking agent propranolol (Leaute-Labreze et al 2008;Sans et al 2009).…”