Propranolol adrenergic blockade inhibits human brain endothelial cells tubulogenesis and matrix metalloproteinase-9 secretion

Pharmacol Res. 2009 Nov;60(5):438-45. doi: 10.1016/j.phrs.2009.05.005. Epub 2009 May 23.

Abstract

In recent clinical observation, the growth of endothelial tumors, such as hemangiomas of infancy, was repressed by the non-selective beta-adrenergic antagonist propranolol possibly through targeting of the vascular endothelial compartment. As human brain microvascular endothelial cells (HBMEC) play an essential role as structural and functional components in tumor angiogenesis, we assessed whether propranolol could target HBMEC's in vitro angiogenic properties. We found that biopsies from human glioblastoma as well as from experimental brain tumor-associated vasculature expressed high levels of the beta2-adrenergic receptor, suggesting adrenergic adaptative processes could take place during tumor vascularization. We observed that in vitro tubulogenesis was significantly reduced by propranolol when HBMEC were seeded on Matrigel. Propranolol, as much as 100microM, did not reduce cell viability and did not alter HBMEC migration as assessed with Boyden chambers. Secretion of the key angiogenic and extracellular matrix degrading enzymes MMP-2 and MMP-9 was assessed by zymography. Propranolol significantly reduced MMP-9 secretion upon treatment with the tumor-promoting agent phorbol 12-myristate 13-acetate, while secretion of MMP-2 remained unaffected. This was correlated with a decrease in MMP-9 gene expression which is, in part, explained by a decrease in the nucleocytoplasmic export of the mRNA stabilizing factor HuR. Our data are therefore indicative of a selective role for propranolol in inhibiting MMP-9 secretion and HBMEC tubulogenesis which could potentially add to propranolol's anti-angiogenic properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology*
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Brain / drug effects
  • Brain Neoplasms / metabolism
  • Cell Line
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / metabolism
  • Humans
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic / drug therapy*
  • Propranolol / pharmacology*
  • Receptors, Adrenergic, beta / genetics
  • Receptors, Adrenergic, beta / metabolism

Substances

  • Adrenergic beta-Antagonists
  • Angiogenesis Inhibitors
  • Receptors, Adrenergic, beta
  • Propranolol
  • Matrix Metalloproteinase 9