Antiproliferative Effect Of Propranolol On Lymphatic Malformations
Maria Gnarra, MD, Elidona Mirashi, MD, Connie Keung, MD, Maia Reilly, Ms, June Wu, MD, Carrie Shawber, PhD.
Columbia University, New York, NY, USA.
Purpose: Lymphatic malformations (LMs) are congenital vascular lesions with severe morbidities and a high recurrence rate (up to 57%). Propranolol, a ß-adrenergic receptor (ßAR) antagonist, is effective in a subset of LM patients. We find that ß1AR and ß2AR expression is increased in lymphatic endothelial cells (LECs) in LM tissues relative to control tissues, while 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 co-stained for podoplanin (LEC marker) and Ki67 (proliferative marker). To assess propranolol effects on LEC gene expression, LM-derived LECs (LMECs) were treated with propranolol or vehicle for 48 hours and quantitative RT-PCR 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 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 (Figure 1). 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 (Figure 2).
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.
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