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First published online January 27, 2006
doi: 10.1242/10.1242/jcs.02772

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The ß2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms

Department of Dermatology, University of California, Davis, TB 192, One Shields Avenue, CA 95616, USA

^* Author for correspondence (e-mail: cepullar{at}ucdavis.edu)

Accepted 24 October 2005

Dermal fibroblasts are required for skin wound repair; they migrate into the wound bed, proliferate, synthesize extracellular matrix components and contract the wound. Although fibroblasts express ß2-adrenergic receptors (ß2-AR) and cutaneous keratinocytes can synthesize ß-AR agonists (catecholamines), the functional significance of this hormonal mediator network in the skin has not been addressed. Emerging studies from our laboratory demonstrate that ß2-AR activation modulates keratinocyte migration, essential for wound re-epithelialization. Here we describe an investigation of the effects of ß2-AR activation on the dermal component of wound healing. We examined ß2-AR-mediated regulation of biological processes in dermal fibroblasts that are critical for wound repair: migration, proliferation, contractile ability and cytoskeletal conformation.

We provide evidence for the activation of at least two divergent ß2-AR-mediated signaling pathways in dermal fibroblasts, a Src-dependent pro-migratory pathway, transduced through the epidermal growth factor receptor and extracellular signal-regulated kinase, and a PKA-dependent pro-proliferative pathway. ß2-AR activation attenuates collagen gel contraction and alters the actin cytoskeleton and focal adhesion distribution through PKA-dependent mechanisms. Our work uncovers a previously unrecognized role for the adrenergic hormonal mediator network in the cutaneous wound repair process. Exploiting these divergent ß2-AR agonist responses in cutaneous cells may generate novel therapeutic approaches for the control of wound healing.

Key words: Wound healing, EGFR transactivation, Src, cAMP, Motility, Skin

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