Journal of Cardiovascular Pharmacology 2014-07-01

β-Blockers promote angiogenesis in the mouse aortic ring assay.

Tonino Stati, Marco Musumeci, Sonia Maccari, Alessia Massimi, Elisa Corritore, Georgios Strimpakos, Elvira Pelosi, Liviana Catalano, Giuseppe Marano

Index: J. Cardiovasc. Pharmacol. 64(1) , 21-7, (2014)

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Abstract

Recent results indicate that the reduction of β-adrenergic signaling impairs angiogenesis under ischemic conditions. Because angiogenesis may occur in the absence of ischemia, it remains to be determined whether and how β-adrenergic signaling regulates angiogenesis, which develops under normoxic conditions. The effect of β-adrenergic ligands on angiogenesis was investigated using 3-dimensional cultures of mouse aortic rings embedded in collagen type I, in which luminized microvessels develop in response to vascular endothelial growth factor (VEGF). Under normoxic conditions, both isoproterenol, a β-adrenergic receptor (β-AR) agonist, and forskolin, an adenylate cyclase activator, were unable to influence aortic microvessel sprouting. On the contrary, treatment with propranolol, a β-AR antagonist, caused an approximately 70% increase in VEGF-mediated microvessel sprouting. This effect was abolished in rings from both double β-AR and β1-AR knockout mice, but not in rings from β2-AR knockout mice. Significant increases in microvessel sprouting were also observed when mouse aortic rings from C57BL/6 mice were treated with the β1-AR-selective antagonists metoprolol and bisoprolol or with the β2-AR-selective antagonist ICI 118,551. Conversely, carvedilol, a nonselective β-AR antagonist, was unable to affect aortic sprouting. These findings suggest that some β-blockers display proangiogenic activity through a mechanism that is independent of their ability to antagonize catecholamine action. The present results also identify a new function for β-AR signaling as a facilitator for VEGF-mediated angiogenesis and have implications for understanding the mechanisms that regulate angiogenic responses under normoxic conditions.