Nicotine accelerates angiogenesis and wound healing in genetically diabetic mice
Nicotine accelerates angiogenesis and wound healing in genetically diabetic mice
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DOI：
10.1016/s0002-9440(10)64161-2
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发表时间：
2002-07-01
影响因子：
6
通讯作者：
Cooke, JP
中科院分区：
文献类型：
--
作者：
Jacobi, J;Jang, JJ;Cooke, JP
最近，我们发现了一个内源性胆碱能途径血管生成介导的内皮烟碱乙酰胆碱受体（nAChRs）。由于血管生成在伤口修复中起主要作用，我们假设用尼古丁激活nAChR将加速小鼠切除伤口模型中的伤口愈合。在遗传性糖尿病小鼠和对照小鼠中，在背部创建全层皮肤伤口（0.8 cm），并用溶剂（磷酸盐缓冲盐水，PBS）或尼古丁（10（-8）mol/L，10（-9）mol/L;各= 5）局部处理7天。在14天内测量伤口大小，然后进行切除、组织学分析和定量血管分布。在糖尿病动物中，还测试了nAChR的激动剂（地棘蛙素，10（-10）mol/L）或拮抗剂（六甲双铵，10（-4）mol/L）以及阳性对照碱性成纤维细胞生长因子（bFGF，25 μ g/kg）。为了进一步研究内皮nAChRs在血管生成中的作用，我们使用了离体血管外植体模型。糖尿病小鼠的伤口愈合明显受损。通过闭合率和组织学评分评估，尼古丁显著加速伤口愈合。尼古丁的作用与bFGF相当，可被地棘蛙素模拟，并被六甲双铵阻断。组织形态计量学显示，尼古丁治疗动物的新生血管形成增加。此外，从血管外植体的毛细血管样发芽显着增强尼古丁。总之，激动剂诱导的nAChR刺激通过促进血管生成来加速糖尿病小鼠的伤口愈合。我们已经发现了一个胆碱能途径的血管生成，参与伤口愈合，这是一个潜在的目标治疗血管生成。
Recently, we have discovered an endogenous cholinergic pathway for angiogenesis mediated by endothelial nicotinic acetylcholine receptors (nAChRs). Since angiogenesis plays a major role in wound repair, we hypothesized that activation of nAChRs with nicotine would accelerate wound healing in a murine excisional wound model. In genetically diabetic and control mice full-thickness skin wounds (0.8 cm) were created on the dorsum and topically treated over 7 days with either vehicle (phosphate-buffered saline, PBS) or nicotine (10(-8) mol/L, 10(-9) mol/L; each, it = 5). Wound size was measured over 14 days followed by resection, histological analysis, and quantitation of vascularity. In diabetic animals an agonist (epibatidine, 10(-10) mol/L) or antagonist (hexamethonium, 10(-4) mol/L) of nAChRs as well as the positive control basic fibroblast growth factor (bFGF, 25 mug/kg) were also tested. To further study the role of endothelial nAChRs in angiogenesis, we used an ex vivo vascular explant model. In diabetic mice wound healing was markedly impaired. Nicotine significantly accelerated wound healing as assessed by closure rate and histological score. The effects of nicotine were equal to bFGF and were mimicked by epibatidine and blocked by hexamethonium. Histomorphometry revealed increased neovascularization in animals treated with nicotine. Furthermore, capillary-like sprouting from vascular explants was significantly enhanced by nicotine. In conclusion, agonist-induced stimulation of nAChRs accelerates wound healing in diabetic mice by promoting angiogenesis. We have discovered a cholinergic pathway for angiogenesis that is involved in wound healing, and which is a potential target for therapeutic angiogenesis.