Role for substance P-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects

Silvia Amadesi, Carlotta Reni, Rajesh Katare, Marco Meloni, Atsuhiko Oikawa, Antonio P. Beltrami, Elisa Avolio, Daniela Cesselli, Orazio Fortunato, Gaia Spinetti, Raimondo Ascione, Elisa Cangiano, Marco Valgimigli, Stephen P. Hunt, Costanza Emanueli, Paolo Madeddu

Research output: Contribution to journalArticle

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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. Methods and 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.

Original languageEnglish
Pages (from-to)1774-1786
Number of pages13
JournalCirculation
Volume125
Issue number14
DOIs
Publication statusPublished - Apr 10 2012

Fingerprint

Substance P
Stem Cells
Ischemia
Bone Marrow
Extremities
Transplantation
Myocardial Infarction
Nociceptors
Regenerative Medicine
Opioid Receptors
Neuropeptides
Morphine
Antigens
Pain

Keywords

  • Limb ischemia
  • Myocardial infarction
  • Neovascularization
  • Stem cells

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Role for substance P-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects. / Amadesi, Silvia; Reni, Carlotta; Katare, Rajesh; Meloni, Marco; Oikawa, Atsuhiko; Beltrami, Antonio P.; Avolio, Elisa; Cesselli, Daniela; Fortunato, Orazio; Spinetti, Gaia; Ascione, Raimondo; Cangiano, Elisa; Valgimigli, Marco; Hunt, Stephen P.; Emanueli, Costanza; Madeddu, Paolo.

In: Circulation, Vol. 125, No. 14, 10.04.2012, p. 1774-1786.

Research output: Contribution to journalArticle

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 2012, 'Role for substance P-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects', Circulation, vol. 125, no. 14, pp. 1774-1786. https://doi.org/10.1161/CIRCULATIONAHA.111.089763
Amadesi, Silvia ; Reni, Carlotta ; Katare, Rajesh ; Meloni, Marco ; Oikawa, Atsuhiko ; Beltrami, Antonio P. ; Avolio, Elisa ; Cesselli, Daniela ; Fortunato, Orazio ; Spinetti, Gaia ; Ascione, Raimondo ; Cangiano, Elisa ; Valgimigli, Marco ; Hunt, Stephen P. ; Emanueli, Costanza ; Madeddu, Paolo. / Role for substance P-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects. In: Circulation. 2012 ; Vol. 125, No. 14. pp. 1774-1786.
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AU - Amadesi, Silvia

AU - Reni, Carlotta

AU - Katare, Rajesh

AU - Meloni, Marco

AU - Oikawa, Atsuhiko

AU - Beltrami, Antonio P.

AU - Avolio, Elisa

AU - Cesselli, Daniela

AU - Fortunato, Orazio

AU - Spinetti, Gaia

AU - Ascione, Raimondo

AU - Cangiano, Elisa

AU - Valgimigli, Marco

AU - Hunt, Stephen P.

AU - Emanueli, Costanza

AU - Madeddu, Paolo

PY - 2012/4/10

Y1 - 2012/4/10

N2 - 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. Methods and 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.

AB - 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. Methods and 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.

KW - Limb ischemia

KW - Myocardial infarction

KW - Neovascularization

KW - Stem cells

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