PRS PSRC Podium Proofs 2016
Maria Gnarra, MD, Elidona Mirashi, MD, Connie Keung, MD, Maia Reilly, MS, June Wu, MD, Carrie Shawber, PhD
From the Columbia University, New York, N.Y.
PURPOSE: Lymphatic malformations (LMs) are congenital vascular lesions with severe morbidities and a high recurrence rate (up to 57%). Propranolol, a β-adrenergic receptor (βAR) antagonist, is effective in a subset of LM patients. We find that β1AR and β2AR expression is increased in lymphatic endothelial cells (LECs) in LM tissues relative to control tissues, whereas propranolol inhibits proliferation of LM-derived LECs. We hypothesized that LECs in LMs have increased proliferation that is targeted by propranolol.
METHODS: LM tissues (n = 9) or neonatal foreskins (control; n = 3) were costained for podoplanin (LEC marker) and Ki67 (proliferative marker). To assess propranolol effects on LEC gene expression, LM-derived LECs were treated with propranolol or vehicle for 48 hours and quantitative reverse transcription polymerase chain reaction performed for LEC genes. To assess in vivo, LM cells in Matrigel were implanted in nude mice; half were treated with propranolol or vehicle (n = 4) for 5 weeks. Sections were stained for podoplanin, and lymphatic phenotype was assessed. Significance was determined by two-tailed Student’s t test.
RESULTS: LM tissues displayed increased LEC proliferation associated with abnormal lumen dilation relative to controls. Propranolol increased expression of LEC proteins, podoplanin, LYVE1, VEGFR-2, and VEGFR-3. In the in vivo model, propranolol reduced lymphatic vessel density and dilation.
CONCLUSIONS: We demonstrate that LMs, which have been considered quiescent lesions, have increased LEC proliferation that may contribute to abnormal vessel dilation and dysfunction. In LM patients, propranolol may reduce abnormal LEC proliferation and increase LEC differentiation to normalize lymphatic vessel phenotype.