Role for Substance-P Based Nociceptive Signaling in Progenitor Cell Activation and Angiogenesis during Ischemia in Mice and in Human Subjects
Background—Pain triggers homeostatic alarm reaction to injury. It remains unknown however if 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.
Methods and Results—The mouse bone marrow contains sensory fibers and PC that express SP. Moreover, SP-induced migration enriches for PC that express NK1 and promote reparative angiogenesis following 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 following ischemia. We next asked if SP is instrumental to PC mobilization and homing in patients with ischemia. Human PC express NK1 and SP-induced migration enriches for pro-angiogenic PC. Patients with acute myocardial infarction show high circulating levels of SP and NK1-positive cells that co-express PC antigens, like CD34, KDR and CXCR4. Moreover, NK1-expressing PC are abundant in infarcted hearts, but not in hearts that developed an infarct after transplantation.
Conclusions—Our data highlight the role of SP in reparative neovascularization. Nociceptive signaling may represent a novel target of regenerative medicine.
- Received December 27, 2011.
- Accepted February 27, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited