beta 2-Adrenoceptor Activation Modulates Skin Wound Healing Processes to Reduce Scarring

During wound healing, excessive inflammation, angiogenesis, and differentiated human dermal fibroblast (HDF) function contribute to scarring, whereas hyperpigmentation negatively affects scar quality. Over 100 million patients heal with a scar every year. To investigate the role of the beta 2 adrenergic receptor (beta 2AR) in wound scarring, the ability of beta 2 adrenergic receptor agonist (beta 2ARag) to alter HDF differentiation and function, wound inflammation, angiogenesis, and wound scarring was explored in HDFs, zebrafish, chick chorioallantoic membrane assay (CAM), and a porcine skin wound model, respectively. Here we identify a PAR-mediated mechanism for scar reduction. beta 2ARag significantly reduced HDF differentiation, via multiple cAMP and/or fibroblast growth factor 2 or basic FGF (FGF2)-dependent mechanisms, in the presence of transforming growth factor beta beta 1, reduced contractile function, and inhibited mRNA expression of a number of profibrotic markers. beta 2ARag also reduced inflammation and angiogenesis in zebrafish and CAMs in vivo, respectively. In Red Duroc pig full-thickness wounds, beta 2ARag reduced both scar area and hyperpigmentation by almost 50% and significantly improved scar quality. Indeed, mechanisms delineated in vitro and in other in vivo models were evident in the beta 2ARag-treated porcine scars in vivo. Both macrophage infiltration and angiogenesis were initially decreased, whereas DF function was impaired in the beta 2ARag-treated porcine wound bed. These data collectively reveal the potential of beta 2ARag to improve skin scarring.