title: Role for substance p-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our data highlight the role of SP in reparative neovascularization. Nociceptive signaling may represent a novel target of regenerative medicine.
authors.affiliation: Laboratories of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Amadesi
authors.forename: Carlotta
authors.initials: C
authors.lastname: Reni
authors.forename: Rajesh
authors.initials: R
authors.lastname: Katare
authors.forename: Marco
authors.initials: M
authors.lastname: Meloni
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Oikawa
authors.forename: Antonio P
authors.initials: AP
authors.lastname: Beltrami
authors.forename: Elisa
authors.initials: E
authors.lastname: Avolio
authors.forename: Daniela
authors.initials: D
authors.lastname: Cesselli
authors.forename: Orazio
authors.initials: O
authors.lastname: Fortunato
authors.forename: Gaia
authors.initials: G
authors.lastname: Spinetti
authors.forename: Raimondo
authors.initials: R
authors.lastname: Ascione
authors.forename: Elisa
authors.initials: E
authors.lastname: Cangiano
authors.forename: Marco
authors.initials: M
authors.lastname: Valgimigli
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunt
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000818:Animals; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D007511:Ischemia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D059225:Nociception / Q000502:physiology*; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000502:physiology; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D013373:Substance P / Q000502:physiology*
chemical_list: D018015:Receptors, Calcitonin Gene-Related Peptide; D018040:Receptors, Neurokinin-1; D013373:Substance P