Exp Ther Med. 2012 Oct;4(4):594-604. doi: 10.3892/etm.2012.654. Epub 2012 Aug 03.

Propranolol treatment of infantile hemangioma endothelial cells: A molecular analysis.

Experimental and therapeutic medicine

Jessica Stiles, Clarissa Amaya, Robert Pham, Rebecca K Rowntree, Mary Lacaze, Arlynn Mulne, Joyce Bischoff, Victor Kokta, Laura E Boucheron, Dianne C Mitchell, Brad A Bryan

PMID: 23170111 PMCID: PMC3501380 DOI: 10.3892/etm.2012.654

Abstract

Infantile hemangiomas (IHs) are non-malignant, largely cutaneous vascular tumors affecting approximately 5-10% of children to varying degrees. During the first year of life, these tumors are strongly proliferative, reaching an average size ranging from 2 to 20 cm. These lesions subsequently stabilize, undergo a spontaneous slow involution and are fully regressed by 5 to 10 years of age. Systemic treatment of infants with the non-selective β-adrenergic receptor blocker, propranolol, has demonstrated remarkable efficacy in reducing the size and appearance of IHs. However, the mechanism by which this occurs is largely unknown. In this study, we sought to understand the molecular mechanisms underlying the effectiveness of β blocker treatment in IHs. Our data reveal that propranolol treatment of IH endothelial cells, as well as a panel of normal primary endothelial cells, blocks endothelial cell proliferation, migration, and formation of the actin cytoskeleton coincident with alterations in vascular endothelial growth factor receptor-2 (VEGFR-2), p38 and cofilin signaling. Moreover, propranolol induces major alterations in the protein levels of key cyclins and cyclin-dependent kinase inhibitors, and modulates global gene expression patterns with a particular affect on genes involved in lipid/sterol metabolism, cell cycle regulation, angiogenesis and ubiquitination. Interestingly, the effects of propranolol were endothelial cell-type independent, affecting the properties of IH endothelial cells at similar levels to that observed in neonatal dermal microvascular and coronary artery endothelial cells. This data suggests that while propranolol markedly inhibits hemangioma and normal endothelial cell function, its lack of endothelial cell specificity hints that the efficacy of this drug in the treatment of IHs may be more complex than simply blockage of endothelial function as previously believed.

References

1. Pharmacogenomics J. 2007 Feb;7(1):29-37 - PubMed
2. Auton Neurosci. 2005 Aug 31;121(1-2):33-9 - PubMed
3. J Cell Biochem. 1997 Dec 1;67(3):353-66 - PubMed
4. Anticancer Res. 2011 Nov;31(11):3645-57 - PubMed
5. Vascul Pharmacol. 2010 Nov-Dec;53(5-6):200-8 - PubMed
6. Eur J Pharmacol. 2008 Jun 10;587(1-3):85-9 - PubMed
7. Arch Dermatol. 2003 Jul;139(7):869-75 - PubMed
8. N Engl J Med. 2008 Dec 25;359(26):2846; author reply 2846-7 - PubMed
9. Ophthalmic Plast Reconstr Surg. 2012 Mar-Apr;28(2):103-6 - PubMed
10. Hepatogastroenterology. 2012 Mar-Apr;59(114):584-8 - PubMed
11. Arch Dermatol. 2012 Feb;148(2):197-202 - PubMed
12. J Clin Invest. 2001 Mar;107(6):745-52 - PubMed
13. Mol Vis. 2006 May 22;12:511-7 - PubMed
14. J Cell Physiol. 1985 Jun;123(3):337-42 - PubMed
15. In Vitro Cell Dev Biol Anim. 2002 May;38(5):298-304 - PubMed
16. Arch Otolaryngol Head Neck Surg. 2011 Aug;137(8):757-60 - PubMed
17. Nat Med. 2008 Nov;14(11):1236-46 - PubMed
18. Plast Reconstr Surg. 2008 Dec;122(6):1690-1699 - PubMed
19. Clin Exp Pharmacol Physiol. 2006 May-Jun;33(5-6):421-30 - PubMed
20. Am J Pathol. 2009 May;174(5):1638-49 - PubMed
21. J Biol Chem. 2000 May 5;275(18):13802-11 - PubMed
22. Curr Opin Hematol. 2009 May;16(3):202-8 - PubMed
23. J Clin Invest. 2008 Jul;118(7):2592-9 - PubMed
24. Invest Ophthalmol Vis Sci. 1992 Jan;33(1):42-7 - PubMed
25. Trends Cell Biol. 2002 Dec;12(12):598-605 - PubMed
26. Nature. 1998 Jun 25;393(6687):805-9 - PubMed
27. J Clin Invest. 1993 Jan;91(1):344-9 - PubMed
28. N Engl J Med. 2008 Jun 12;358(24):2649-51 - PubMed
29. Arch Otolaryngol Head Neck Surg. 2012 Feb;138(2):177-82 - PubMed
30. Nat Med. 2006 Aug;12(8):939-44 - PubMed
31. J Cardiovasc Pharmacol. 2000 Nov;36(5 Suppl 1):S401-3 - PubMed
32. Exp Dermatol. 2010 Sep;19(9):821-9 - PubMed
33. Br J Pharmacol. 2012 May;166(2):721-36 - PubMed
34. Microcirculation. 2011 Feb;18(2):118-27 - PubMed
35. Am J Physiol Endocrinol Metab. 2005 Apr;288(4):E715-22 - PubMed
36. Br J Pharmacol. 2011 Dec;164(8):1917-28 - PubMed
37. Br J Dermatol. 2010 Aug;163(2):269-74 - PubMed
38. J Burn Care Res. 2009 Nov-Dec;30(6):1013-7 - PubMed
39. J Biol Chem. 1999 Jun 11;274(24):16701-8 - PubMed
40. Eur J Pharmacol. 2009 Jun 2;611(1-3):77-84 - PubMed
41. Curr Top Med Chem. 2005;5(10):921-8 - PubMed
42. Zhonghua Zheng Xing Wai Ke Za Zhi. 2007 Jul;23(4):322-4 - PubMed
43. In Vitro. 1981 May;17(5):450-8 - PubMed
44. J Appl Physiol (1985). 1988 Sep;65(3):1251-7 - PubMed
45. Brain Behav Immun. 2010 Mar;24(3):427-37 - PubMed
46. Circ Res. 2005 Nov 25;97(11):1182-9 - PubMed
47. Ann Surg. 2012 Jul;256(1):146-56 - PubMed
48. Recenti Prog Med. 2012 Jan;103(1):11-6 - PubMed
49. Cancer. 2012 Aug 15;118(16):3911-9 - PubMed
50. Cytometry A. 2003 Jul;54(1):8-18 - PubMed
51. Wound Repair Regen. 2009 Mar-Apr;17(2):230-9 - PubMed

Publication Types

• Journal Article

Grant support

• P01 AR048564/AR/NIAMS NIH HHS/United States
• R15 HL098931/HL/NHLBI NIH HHS/United States