Importance of β₂AR elevation for re-endothelialization capacity mediated by late endothelial progenitor cells in...

Dysfunction of late endothelial progenitor cells (EPCs) has been suggested to be associated with hypertension. β₂-Adrenergic receptor (β₂AR) is a novel and key target for EPC homing. Here, we proposed that attenuated β₂AR signaling contributes to EPCs dysfunction, whereas enhanced β₂AR signaling restores EPCs' functions in hypertension. EPCs derived from hypertensive patients exhibited reduced cell number, impaired in vitro migratory and adhesion abilities, and impaired re-endothelialization after transplantation in nude mice with carotid artery injury. β₂AR expression of EPCs from hypertensive patients was markedly downregulated, whereas the phosphorylation of the p38 mitogen-activated protein kinase (p38-MAPK) was elevated. The cleaved caspase-3 levels were elevated in EPCs. The overexpression of β₂AR in EPCs from hypertensive patients inhibited p38-MAPK signaling, whereas it enhanced in vitro EPC proliferation, migration, and adhesion and in vivo re-endothelialization. The β₂AR-mediated effects were attenuated by treating the EPCs with a neutralizing monoclonal antibody against β₂AR, which could be partially antagonized by the p38-MAPK inhibitor SB203580. Moreover, shear stress stimulation, a classic nonpharmacological intervention, increased the phosphorylation levels of β₂AR and enhanced the in vitro and in vivo functions of EPCs from hypertensive patients. Collectively, the current investigation demonstrated that impaired β₂AR/p38-MAPK/caspase-3 signaling at least partially reduced the re-endothelialization capacity of EPCs from hypertensive patients. Restoration of β₂AR expression and shear stress treatment could improve their endothelial repair capacity by regulating the p38-MAPK/caspase-3 signaling pathway. The clinical significance of β₂AR in endothelium repair still requires further investigation.NEW & NOTEWORTHY Impaired β₂-adrenergic receptor (β₂AR) expression with an elevation of p38-MAPK/caspase-3 signaling at least partially contributes to the decline of re-endothelialization capacity of late endothelial progenitor cells (EPCs) from hypertensive patients. β₂AR gene transfer and shear stress treatment improve the late EPC-mediated enhancement of the re-endothelialization capacity in hypertensive patients through activating β₂AR/p38-MAPK/caspase-3 signaling. The present study is the first to reveal the potential molecular mechanism of the impaired endothelium-reparative capacity of late EPCs in hypertension after vascular injury and strongly suggests that β₂AR is a novel and crucial therapeutic target for increasing EPC-mediated re-endothelialization capacity in hypertension.