A role for the sensory neuropeptide calcitonin gene-related peptide in endothelial cell proliferation in vivo
A role for the sensory neuropeptide calcitonin gene-related peptide in endothelial cell proliferation in vivo
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DOI：
10.1111/j.1476-5381.2012.01848.x
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发表时间：
2012-06-01
影响因子：
7.3
通讯作者：
Walsh, David A.
中科院分区：
文献类型：
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作者：
Mapp, Paul I.;McWilliams, Daniel F.;Walsh, David A.
背景与目的我们验证了降钙素基因相关肽（CGRP）是辣椒素诱导血管生成的介质的假设。实验方法采用CGRP、辣椒素、对照三种方法对大鼠膝关节进行连续注射。各组动物（n = 6）用CGRP受体拮抗剂BIBN4096BS和/或NK1受体拮抗剂SR140333处理。24 h后用免疫组化方法鉴定滑膜内内皮细胞、增殖内皮细胞核和巨噬细胞，并用图像分析方法定量。采用RT-PCR方法在正常、炎症大鼠和人滑膜中寻找CGRP和肾上腺髓质素受体mRNA。关键结果：关节内注射CGRP增加了内皮细胞增殖指数，而巨噬细胞浸润和膝关节直径与注射盐水的对照组相似。BIBN4096BS剂量依赖性地抑制cgrp诱导的内皮细胞增殖。在正常和炎症的人和大鼠滑膜中检测肾上腺髓质素和CGRP受体亚单位的mRNA。在辣椒素诱导的滑膜炎中，单独给药NK1或CGRP拮抗剂可部分阻断内皮细胞增殖指数的增加，同时给药两种受体拮抗剂可将内皮细胞增殖指数降低到生理盐水对照组的水平。结论和意义这些数据支持CGRP通过激活CGRP受体直接刺激体内血管生成的假设。CGRP和NK1受体拮抗剂可完全阻断辣椒素诱导的内皮细胞增殖，表明CGRP和P物质可能都有助于滑膜炎模型的血管生成。
BACKGROUND AND PURPOSE We have tested the hypothesis that calcitonin gene-related peptide (CGRP) is a mediator of capsaicin-induced angiogenesis in vivo. EXPERIMENTAL APPROACH In a series of experiments, the knee joints of rats were injected with CGRP, capsaicin or vehicle control. Groups of animals (n = 6) were treated with the CGRP receptor antagonist BIBN4096BS and/or the NK1 receptor antagonist SR140333. Endothelium, proliferating endothelial cell nuclei and macrophages were identified 24 h later in the synovium by immunohistochemistry and quantified by image analysis. mRNA for the receptors for CGRP and adrenomedullin were sought in normal and inflamed rat and human synovia using RT-PCR. KEY RESULTS Intra-articular CGRP injection increased the endothelial cell proliferation index, whereas macrophage infiltration and knee joint diameters were similar to saline-injected controls. CGRP-induced endothelial cell proliferation was dose-dependently inhibited by BIBN4096BS. mRNA for adrenomedullin and the CGRP receptor subunits were detected in normal and inflamed human and rat synovia. In capsaicin-induced synovitis, the increased endothelial cell proliferation index was partially blocked by administration of NK1 or CGRP antagonists individually and was reduced to the level of saline controls by coadministration of both receptor antagonists. CONCLUSIONS AND IMPLICATIONS These data support the hypothesis that CGRP stimulates angiogenesis in vivo directly by activating CGRP receptors. Capsaicin-induced endothelial cell proliferation was completely blocked by coadministration of CGRP and NK1 receptor antagonists, indicating that both CGRP and substance P may contribute to angiogenesis in this model of synovitis.