The β2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms
The β2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms
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DOI：
10.1242/jcs.02772
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发表时间：
2006-02-01
影响因子：
4
通讯作者：
Isseroff, RR
中科院分区：
文献类型：
--
作者：
Pullar, CE;Isseroff, RR
皮肤伤口修复需要真皮成纤维细胞;它们迁移到伤口床中，增殖，合成细胞外基质组分并收缩伤口。虽然成纤维细胞表达β 2-肾上腺素能受体（β 2-AR），皮肤角质形成细胞可以合成β-AR激动剂（儿茶酚胺），这种激素介质网络在皮肤中的功能意义尚未得到解决。我们实验室的新兴研究表明，β 2-AR激活调节角质形成细胞迁移，这对伤口再上皮化至关重要。在这里，我们描述了一个调查的影响β 2-AR激活皮肤伤口愈合的组成部分。我们研究了β 2-AR介导的调节真皮成纤维细胞的生物学过程，这些过程对伤口修复至关重要：迁移、增殖、收缩能力和细胞骨架构象。我们提供的证据激活至少两个不同的β 2-AR介导的信号通路在真皮成纤维细胞，Src依赖的促迁移途径，通过表皮生长因子受体和细胞外信号调节激酶，和PKA依赖的促增殖途径转导。β 2-AR激活减弱胶原凝胶收缩，并通过PKA依赖性机制改变肌动蛋白细胞骨架和粘着斑分布。我们的工作揭示了一个以前未被认识到的作用，肾上腺素能激素介质网络在皮肤伤口修复过程中。利用皮肤细胞中这些不同的β 2-AR激动剂反应可能会产生新的治疗方法来控制伤口愈合。
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 beta 2-adrenergic receptors (beta 2-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 beta 2-AR activation modulates keratinocyte migration, essential for wound re-epithelialization. Here we describe an investigation of the effects of beta 2-AR activation on the dermal component of wound healing. We examined beta 2-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 Beta 2-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. beta 2-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 beta 2-AR agonist responses in cutaneous cells may generate novel therapeutic approaches for the control of wound healing.