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

Abstract

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.

Adrenergic Receptor Kinase C-Terminal Peptide Gene-Therapy Improves 2-Adrenergic Receptor-Dependent Neoangiogenesis after Hindlimb Ischemia

“…It is important to underline that we cannot exclude any potential involvement of other cell types (i.e., skeletal muscle cells or smooth muscle cells) other than ECs and endothelial progenitor cells, for which a relevant role has been proposed in postischemic angiogenesis in vivo (Galasso et al, 2013). In this regard, it has been recently demonstrated that in C2C12 myoblasts GRK2 overexpression led to a significant impairment in cell differentiation, thus suggesting for this kinase a relevant role in skeletal muscle myogenesis (Garcia-Guerra et al, 2014).…”

Sympathetic predominance is associated with impaired endothelial progenitor cells and tunneling nanotubes in controlled-hypertensive patients

“…In recent years, the sympathetic nervous system was identified as a decisive determinant in progenitor cell mobilization from the bone marrow (22). In relation to this, EPC were shown to express functional ␤ 2 -adrenergic receptors that upon stimulation induce EPC migration, proliferation, and differentiation, resulting in improved neoangiogenesis in experimental hind limb ischemia (14). Interestingly, in chronic obstructive pulmonary disease patients, ␤ 2 -adrenergic receptor expression in early EPCs was higher than in healthy controls, and treatment of EPC with a ␤ 2 -adrenergic receptor antagonist (ICI-118551) increased EPC migration and proliferation compared with treatment with the agonist norepinephrine (24).…”

Recent Developments in Cardiovascular Stem Cells

“…19,29,[53][54][55][56][57][58] Equally exciting and challenging are the discovery and characterization of other CPCs that could give raise to various cardiac cells types, including smooth muscle cells, endothelial cells, and fibroblasts. [59][60][61][62][63] An important problem to overcome is the multiple comorbidities and their comedications of ischemic heart disease patients with heart failure that may affect cytoprotective signaling triggered by the different stem cell, as well as survival and differentiation properties of such stem cells in the injured tissue. [64][65][66] Clearly, the rapid face of discoveries is dazzling and a complete coverage of the recent developments in cardiovascular stem cells would be beyond the scope of this article.…”