β 2 -Adrenergic Receptor Stimulation Improves Endothelial Progenitor Cell–Mediated Ischemic Neoangiogenesis

• DOI: 10.1161/circresaha.111.300152
• Publication Date: 2013-02-16T05:59:51Z
• Authors: Gennaro Galasso; Roberta De Rosa; Michele Ciccarelli; Daniela Sorriento; Carmine Del Giudice; Teresa Strisciuglio; Chiara De Biase; Rossella Luciano; Raffaele Piccolo; Adele Pierri; Giuseppe Di Gioia; Nella Prevete; Bruno Trimarco; Federico Piscione; Guido Iaccarino
• Keywords: Male; Mice, Knockout; 0301 basic medicine; Isoproterenol; Neovascularization, Physiologic; Cell Differentiation; Adrenergic beta-Agonists; Hematopoietic Stem Cells; Rats, Inbred WKY; Hindlimb; Rats; Adrenergic beta-Agonists; Animals; Cell Differentiation; Cell Movement; Cell Proliferation; Cells, Cultured; Chronic Disease; Disease Models, Animal; Endothelium, Vascular; Hematopoietic Stem Cells; Hindlimb; Ischemia; Isoproterenol; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Physiologic; Rats; Rats, Inbred WKY; Receptors, Adrenergic, beta-2; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Cell Movement; Ischemia; Chronic Disease; Animals; Endothelium, Vascular; Cells, Cultured; Cell Proliferation

Rationale:

Endothelial progenitor cells (EPCs) are present in the systemic circulation and home to sites of ischemic injury where they promote neoangiogenesis. β 2 -Adrenergic receptor (β 2 AR) plays a critical role in vascular tone regulation and neoangiogenesis.

Objective:

We aimed to evaluate the role of β 2 AR on EPCs’ function.

Methods and Results:

We firstly performed in vitro analysis showing the expression of β 2 AR on EPCs. Stimulation of wild-type EPCs with β-agonist isoproterenol induced a significant increase of Flk-1 expression on EPCs as assessed by fluorescence-activated cell sorter. Moreover, β 2 AR stimulation induced a significant increase of cell proliferation, improved the EPCs migratory activity, and enhanced the EPCs’ ability to promote endothelial cell network formation in vitro. Then, we performed in vivo studies in animals model of hindlimb ischemia. Consistent with our in vitro results, in vivo EPCs’ treatment resulted in an improvement of impaired angiogenic phenotype in β 2 AR KO mice after induction of ischemia, whereas no significant amelioration was observed when β 2 AR knock out (KO) EPCs were injected. Indeed, wild-type–derived EPCs’ injection resulted in a significantly higher blood flow restoration in ischemic hindlimb and higher capillaries density at histological analysis as compared with not treated or β 2 AR KO EPC-treated mice.

Conclusions:

The present study provides the first evidence that EPCs express a functional β 2 AR. Moreover, β 2 AR stimulation results in EPCs proliferation, migration, and differentiation, enhancing their angiogenic ability, both in vitro and in vivo, leading to an improved response to ischemic injury in animal models of hindlimb ischemia.