Role for substance p-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects.
Role for substance p-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects.
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DOI：
10.1161/circulationaha.111.089763
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发表时间：
2012-04-10
期刊：
影响因子：
37.8
通讯作者：
Madeddu P
中科院分区：
文献类型：
--
作者：
Amadesi S;Reni C;Katare R;Meloni M;Oikawa A;Beltrami AP;Avolio E;Cesselli D;Fortunato O;Spinetti G;Ascione R;Cangiano E;Valgimigli M;Hunt SP;Emanueli C;Madeddu P
疼痛会触发对损伤的稳态警报反应。然而，目前尚不清楚缺血激活的伤害性信号是否与祖细胞(PC)从骨髓中释放有关。为此，我们研究了神经肽P物质(SP)和同源神经激肽1(NK1)伤害性感受器在小鼠和人类缺血时PC激活和血管生成中的作用。小鼠骨髓中含有表达SP的感觉神经纤维和PC。此外，在肢体缺血的小鼠模型中，SP诱导的迁移为表达NK1的PC提供了丰富，并促进了移植后的修复性血管生成。急性心肌梗死和肢体缺血增加了外周血中的SP水平，降低了骨髓中的SP水平，并刺激了表达NK1的PC的动员，这些作用可被阿片受体激动剂吗啡全身给药所消除。此外，NK1基因敲除细胞的骨髓重建导致PC动员受抑，血流恢复延迟，缺血后新生血管减少。接下来，我们询问SP是否有助于脑缺血患者的PC动员和归巢。人PC表达NK1，SP诱导的迁移为前血管生成PC提供了丰富的物质基础。急性心肌梗死患者循环中高水平的SP和NK1阳性细胞共表达PC抗原，如CD34、KDR和CXCR4。此外，NK1表达的PC在梗死的心脏中大量存在，但在移植后发生梗塞的心脏中则不表达。我们的数据强调了SP在修复性新生血管中的作用。伤害性信号可能代表了再生医学的一个新靶点。
Pain triggers a homeostatic alarm reaction to injury. It remains unknown, however, whether nociceptive signaling activated by ischemia is relevant for progenitor cells (PC) release from bone marrow. To this end, we investigated the role of the neuropeptide substance P (SP) and cognate neurokinin 1 (NK1) nociceptor in PC activation and angiogenesis during ischemia in mice and in human subjects. The mouse bone marrow contains sensory fibers and PC that express SP. Moreover, SP-induced migration provides enrichment for PC that express NK1 and promote reparative angiogenesis after transplantation in a mouse model of limb ischemia. Acute myocardial infarction and limb ischemia increase SP levels in peripheral blood, decrease SP levels in bone marrow, and stimulate the mobilization of NK1-expressing PC, with these effects being abrogated by systemic administration of the opioid receptor agonist morphine. Moreover, bone marrow reconstitution with NK1-knockout cells results in depressed PC mobilization, delayed blood flow recovery, and reduced neovascularization after ischemia. We next asked whether SP is instrumental to PC mobilization and homing in patients with ischemia. Human PC express NK1, and SP-induced migration provides enrichment for proangiogenic PC. Patients with acute myocardial infarction show high circulating levels of SP and NK1-positive cells that coexpress PC antigens, such as CD34, KDR, and CXCR4. Moreover, NK1-expressing PC are abundant in infarcted hearts but not in hearts that developed an infarct after transplantation. Our data highlight the role of SP in reparative neovascularization. Nociceptive signaling may represent a novel target of regenerative medicine.