β2-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, while hyperpigmentation negatively impacts scar quality. Over 100 million patients heal with a scar every year. To investigate the role of the β2-adrenoceptor (β2AR) in wound scarring, the ability of β2AR agonists (β2ARag) to alter HDF differentiation and function, wound inflammation, angiogenesis and wound scarring was explored in HDFs, zebrafish, chick allantoic membranes (CAM) and a porcine skin wound model, respectively. Here we identify a β2AR-mediated mechanism for scar reduction. β2ARag significantly reduced HDF differentiation, via multiple cAMP and/or FGF2-dependent mechanisms, in the presence of TGFβ1, reduced contractile function and inhibited mRNA expression of a number of pro-fibrotic markers. β2ARag also reduced inflammation and angiogenesis in zebrafish and CAMs in vivo, respectively. In Red Duroc pig full-thickness wounds, β2ARag 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 β2ARag-treated porcine scars in vivo. Both macrophage infiltration and angiogenesis were initially decreased, while DF function was impaired in the β2ARag-treated porcine wound bed. These data collectively reveal the potential of β2ARag to improve skin scarring.