title: β-Blockers promote angiogenesis in the mouse aortic ring assay.
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.
authors.affiliation: *Department of Pharmacology, National Institute of Health, Rome, Italy; †Institute of Cell Biology and Neurobiology, Consiglio Nazionale delle Ricerche, Rome, Italy; ‡Department of Hematology, Oncology, and Molecular Medicine, National Institute of Health, Rome, Italy; and §National Blood Center, Rome, Italy.
authors.forename: Tonino
authors.initials: T
authors.lastname: Stati
authors.forename: Marco
authors.initials: M
authors.lastname: Musumeci
authors.forename: Sonia
authors.initials: S
authors.lastname: Maccari
authors.forename: Alessia
authors.initials: A
authors.lastname: Massimi
authors.forename: Elisa
authors.initials: E
authors.lastname: Corritore
authors.forename: Georgios
authors.initials: G
authors.lastname: Strimpakos
authors.forename: Elvira
authors.initials: E
authors.lastname: Pelosi
authors.forename: Liviana
authors.initials: L
authors.lastname: Catalano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marano
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D018343:Receptors, Adrenergic, beta-2; D042461:Vascular Endothelial Growth Factor A