A Comparison Of Beta Receptor Specificity On Infantile Hemangioma Gene Expression And Microvascular Density
James E. McCarthy, MD, Timothy W. King, MD, PhD.
University of Wisconsin-Madison, Madison, WI, USA.
Purpose: Infantile hemangiomas (IH) demonstrate involution following oral and topical beta blockers. We sought to determine: (1) administration route on tumor involution, (2) beta receptor selectivity on gene expression and (3) effect of mesenchymal cell type on gene expression.
Methods: Human IH endothelial stem cells (HemESCs) and endothelial cells (HemECs) were grown to 90% confluence and media was exchanged to 50ug/ul and 100ug/ul concentrations of metoprolol (beta-1 blocker) and propranolol (non-selective beta blocker) for 72 hours. RT-PCR was used to assess gene expression of HIF-a, VEGF-a, VEGF-a1 receptor, VEGF-a2 receptor, and PDGF-beta. The dorsum of 8-week old nude athymic mice were injected with 200uL of HemESCs and HemECs in matrigel at 1x10^6 cells/uL per cell line. Six mice per beta blocker per route were treated with 0.2mg/kg oral, local injection of 0.2mg/kg, or 1% topical preparations BID for two weeks at which time tumors were explanted. Differences in tumor volume and microvascular density were analyzed.
Results: HemESCs exposed to propranolol had a 1.5-fold reduction in expression of HIF-a and VEGF-a in a dose dependent manner (p 0.05). There were no differences in tumor volume between administration routes, however, oral administration trended toward greater reduction in microvascular density (p = 0.08).
Conclusions: Non-selective beta blockade leads to greater inhibition of HIF-a and VEGF-a compared to selective beta blockade, particularly in HemESCs. Oral administration of beta blockers appears to produce greater reduction in microvascular density.
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