Role for Substance P–Based Nociceptive Signaling in Progenitor Cell Activation and Angiogenesis During Ischemia in Mice and in Human Subjects
Open accessAbstract
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.
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SP mobilizes mesenchymal stem cells and endothelial progenitor cells in bone marrow and induces them to migrate into injured peripheral tissues where they are involved in tissue regeneration.
“Furthermore, SP mobilizes mesenchymal stem cells52 and endothelial progenitor cells (EPCs)53 in the bone marrow, and induces them to migrate into the injured peripheral tissues where they are involved in tissue regeneration.”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [53]
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- Authors
- Amadesi, S., Reni, C., Katare, R., Meloni, M., Oikawa, A., Beltrami, A. P., Avolio, E., Cesselli, D., Fortunato, O., Spinetti, G., Ascione, R., Cangiano, E., Valgimigli, M., Hunt, S. P., Emanueli, C., & Madeddu, P.
- Affiliations
- University of Udine (IT)
- ORCID
- Venue
- Circulation
- Published
- 2012-04-10
- Volume
- 125
- Issue
- 14
- Pages
- 1774-1786
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC3616366
- OpenAlex
- W2053495327
- Cited by
- 100
- References
- 45
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 6 · 2020: 7 · 2019: 9 · 2018: 7 · 2017: 10 · 2016: 13 · 2015: 10 · 2014: 7 · 2013: 10 · 2012: 2
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CentAUR (University of Reading) (submittedVersion)
- Institutional Research Information System (University of Udine) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- British Heart Foundation (FS/10/001/27959, PG/09/099/28122)
- University of Bristol
- Medical Research Council (MR/J002593/1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- substance P, neurokinin-1 receptor, nociceptive signaling, progenitor cell mobilization, angiogenesis, ischemia, acute myocardial infarction, limb ischemia, bone marrow, neovascularization, morphine, regenerative medicine, CXCR4, CD34, KDR
- MeSH terms
- Animals, Humans, Ischemia, Male, Mice, Inbred C57BL, Stem Cells, Substance P, Signal Transduction, Receptors, Calcitonin Gene-Related Peptide, Receptors, Neurokinin-1, Neovascularization, Physiologic, Hematopoietic Stem Cell Mobilization, Mice, Nociception
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