Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Vascular Endothelial Growth Factor Signaling is Affected by Changes in the ß-Adrenergic Receptor Pathways in Hemangioma Stem Cells
Alison Kitajewski, BA, Justin Kung, BA; Andrew K. Edwards, PhD; Carrie J. Shawber, PhD; Jan K. Kitajewski, PhD; June K. Wu, MD.
Columbia University, New York, NY, USA.

PURPOSE:
Vascular endothelial growth factor receptor 2 (VEGFR2) signaling has been shown to be constitutively activated in hemangioma endothelial cells (HemECs). Propranolol, a pan beta-adrenergic receptor (βAR) antagonist, has been shown to inhibit VEGFR2 signaling in HemECs. However, the effects of propranolol on VEGFR activity on hemangioma stem cells (HemSC’s)_believed to be the originator of infantile hemangiomas (IHs)_is not well understood. Propranolol has been shown to be anti-proliferative and cytotoxic to HemSCs in vitro. In vivo, propranolol treatment resulted in loss of Dopplerable signals and decreased vessel caliber in a murine IH model. We hypothesize that these propranolol effects on HemSCs and IH development in vitro and in vivo is mediated, at least in part, by inhibition of VEGFR signaling in HemSCs.
METHODS:
HemSCs were isolated from human specimens using CD133 magnetic bead selection. Immunofluorescence staining was performed to probe for VEGFR2 expression. HemSCs were treated with propranolol (50 µM, 100 µM or 200 µM), or the βAR specific agonist, isoprenaline (0.1 nM, 1nM or 10nM), for 24 hours in culture. Quantitative RT-PCR was performed to measure transcript levels of VEGFR2, and the VEGFR ligands vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor C (VEGF-C). ELISA was used to quantify protein levels.
RESULTS:
Cultured HemSCs expressed VEGFR2 (Fig. 1). Treatment with Isoprenaline resulted in a statistically significant increase in VEGFR2 transcripts (2.5 fold at 10 nM isoprenaline, p<0.05), VEGF-A (1.5 fold at 10 nM isoprenaline, p<0.05) and VEGFR-C (1.4 fold at 10 nM isoprenaline, p<0.05). Propranolol treatment resulted in a significant decrease in VEGF-C transcripts (5 fold decrease at 200 µM propranolol, p<0.05) (Fig. 2).
CONCLUSION:
VEGFR2 was expressed in HemSCs. Activation of βAR by isoprenaline increased transcripts of VEGFR2 and VEGFR ligands VEGF-A and VEGF-C, while inhibition of βAR signaling with propranolol decreased VEGF-C transcripts. These results suggest that alterations in βAR signaling altered VEGF/VEGFR expression, suggesting cross talk between these 2 pathways in HemSCs pathophysiology. Propranolol’s anti-proliferative and cytotoxic effects on HemSCs may be mediated via changes in VEGFR signaling.


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