ß3–Adrenergic Receptors Mediate Choroidal Endothelial Cell Migration, Proliferation, and Tube Formation

Abstract

Abstract: : Purpose: To determine the expression pattern and role of ß₃–adrenergic receptor signaling in human choroidal endothelial cells in culture Methods: Human choroidal endothelial cells were stained with antibodies to determine ß₃–adrenergic receptor expression using immunofluorescence. Choroidal endothelial cells were stimulated with BRL37344, a specific ß₃–adrenergic receptor agonist, and cell proliferation, migration and cord formation were measured. Cell proliferation, migration, and tube formation were also investigated in the presence of BRL37344 with pre–treatment with inhibitors to the extracellular signal–regulated kinase (ERK1/2), Src, and phosphatidylinositol–3–kinase (PI3K) cell signaling cascades. Results: ß₃–adrenergic receptor expression was greater in choroidal endothelial cells than in mesenteric endothelial cells. Stimulation of human choroidal endothelial cells with BRL37344 produced a 203% increase in cell migration relative to control values. Migration was inhibited by prior administration of inhibitors to Src, PI3K, and Akt. Cord formation was increased by 300% in BRL37344–treated cells, and was blocked by pre–treatment with Src and PI3K inhibitors. Proliferation was significantly increased following BRL37344, but not to the extent of migration or cord formation. Conclusions: These results demonstrate the presence of ß₃–adrenergic receptors in choroidal endothelial cells. These receptors mediate the three primary stages of angiogenesis in vitro of cell proliferation, cell migration, and tube formation. Thus, modulation of ß₃–adrenergic receptors may be a novel approach to address vascular growth noted in choroidal neovascularization.

Keywords: neovascularization • growth factors/growth factor receptors • signal transduction: pharmacology/physiology