The beta 2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms.
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 beta2-adrenergic receptors (beta2-AR) and cutaneous keratinocytes can synthesize beta-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 beta2-AR activation modulates keratinocyte migration, essential for wound re-epithelialization. Here we describe an investigation of the effects of beta2-AR activation on the dermal component of wound healing. We examined beta2-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 beta2-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. beta2-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 beta2-AR agonist responses in cutaneous cells may generate novel therapeutic approaches for the control of wound healing.
Pullar
Christine E
CE
Department of Dermatology, University of California, Davis, TB 192, One Shields Avenue, CA 95616, USA. cepullar@ucdavis.edu
Isseroff
R Rivkah
RR
D000199:Actins / Q000378:metabolism; D000322:Adrenergic Agonists / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D022001:Focal Adhesions / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
D000199:Actins; D000322:Adrenergic Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2; D019061:src-Family Kinases