A novel function of angiotensin II in skin wound healing - Induction of fibroblast and keratinocyte migration by angiotensin II via heparin-binding epidermal growth factor (EGF)-like growth factor-mediated egf receptor transactivation
A novel function of angiotensin II in skin wound healing - Induction of fibroblast and keratinocyte migration by angiotensin II via heparin-binding epidermal growth factor (EGF)-like growth factor-mediated egf receptor transactivation
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DOI：
10.1074/jbc.m509771200
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发表时间：
2006-05-12
影响因子：
4.8
通讯作者：
Hashimoto, K
中科院分区：
文献类型：
--
作者：
Yahata, Y;Shirakata, Y;Hashimoto, K
血管紧张素 II (Ang II) 在控制全身血压和容量稳态中的作用是众所周知的，并已得到广泛研究。最近，Ang II 被认为还具有皮肤伤口愈合的功能。在本研究中，使用 Ang II 1 型受体 (AT1R) 敲除小鼠研究了 Ang II 在皮肤伤口愈合中的体内功能。发现这些小鼠的伤口愈合明显延迟。角质形成细胞和成纤维细胞在伤口愈合中发挥重要作用，因此检查了 Ang II 对这些细胞迁移的影响。 Ang II 以剂量依赖性方式刺激角质形成细胞和成纤维细胞迁移。据报道，G 蛋白偶联受体 (GPCR) 激活通过肝素结合 EGF 样生长因子 (HB-EGF) 的脱落诱导表皮生长因子 (EGF) 受体 (EGFR) 反式激活。由于 AT1R 是 GPCR，因此推测 Ang II 诱导的角质形成细胞和成纤维细胞迁移是由 EGFR 反式激活介导的。 Ang II 诱导 EGFR 磷酸化，而角质形成细胞和成纤维细胞中的 EGFR 磷酸化可被 AT1R 拮抗剂、HB-EGF 中和抗体和 HB-EGF 拮抗剂抑制。此外，Ang II 诱导的角质形成细胞和成纤维细胞的迁移也被这些抑制剂阻止。总而言之，这些发现首次清楚地表明，Ang II 在皮肤伤口愈合中发挥着重要作用，并且它通过在 HB-EGF 脱落介导的过程中加速角质形成细胞和成纤维细胞迁移来发挥作用。
The role of angiotensin II ( Ang II) in the control of systemic blood pressure and volume homeostasis is well known and has been extensively studied. Recently, Ang II was suggested to also have a function in skin wound healing. In the present study, the in vivo function of Ang II in skin wound healing was investigated using Ang II type 1 receptor ( AT1R) knock-out mice. Wound healing in these mice was found to be markedly delayed. Keratinocytes and fibroblasts play important roles in wound healing, and thus the effect of Ang II on the migration of these cells was examined. Ang II stimulated keratinocyte and fibroblast migration in a dose-dependent manner. It has been reported that G protein-coupled receptor ( GPCR) activation induces epidermal growth factor ( EGF) receptor ( EGFR) transactivation through the shedding of heparin-binding EGF-like growth factor ( HB-EGF). As AT1R is a GPCR, it was hypothesized that Ang II-induced keratinocyte and fibroblast migration is mediated by EGFR transactivation. Ang II induced EGFR phosphorylation, which was inhibited by an AT1R antagonist, HB-EGF neutralizing antibody, and an HB-EGF antagonist in both keratinocytes and in fibroblasts. Moreover, Ang II-induced migration of keratinocytes and fibroblasts was also prevented by these inhibitors. Taken together, these findings clearly demonstrate, for the first time, that Ang II plays an important role in skin wound healing and that it functions by accelerating keratinocyte and fibroblast migration in a process mediated by HB-EGF shedding.