Abstract 17004: Nociceptive Signalling Contributes to Progenitor Cells Activation and Mobilization in Ischemia
Background: Pain is an essential component of the alarm response to tissue injury. We hypothesised that neuropeptides substance P (SP) and Calcitonin Gene-Releated Peptide (CGRP), released from nociceptive fibres, contribute to progenitor cells (PC) mobilization in ischemia.
Methods and Results: By immunostaining, we confirmed the expression of SP and CGRP within vesicles of fibre-like structures in mouse bone marrow (BM). Moreover, we found that NK1 and CLR/RAMP-1 (SP and CGRP receptors) were expressed on cells of the osteoblastic and vascular niches and co-expressed in PC with ckit, Sca-1 and Flk1. In in vitro migration assays, SP and CGRP attracted BM PC (SP, 1 nM: 1.8±0.2 fold; CGRP, 1 nM: 1.9±0.3 fold increase in migration; p=0.04 for both comparisons vs. control; N=3). Mouse dorsal root ganglia neurons (mDRGN) or their conditioned medium (CM) had similar promigratory effects (mDRGN: 2.1±0.2 fold, p<0.001; CM: 2.4±0.7 fold, p=0.02. N=5). In a mouse model of limb ischemia, we observed a remarkable increase of RAMP-1- and NK1-expressing cells in BM at 1d post-ischemia (RAMP-1: 12.3±1.3 vs. 5.3±1.2%, p=0.01; NK1: 9.1±1.4 vs. 3.4±0.4% in controls, p=0.02. N=3-5 animals). Moreover, the cKitpos/Flk1pos PC fraction showed higher level of RAMP-1 (1.37 fold, p=0.05) and NK1 (1.11 fold, p=0.08) after ischemia. RAMP-1 and NK1 expression also increased in peripheral blood (PB) cKitpos/Flk1pos PC (1.21 and 1.24 fold). Furthermore, we found that NK1 and CLR/RAMP-1 were expressed in human PB PC and that acute myocardial infarction (aMI) and chronic angina (CA) increased CD34pos/KDRpos PC co-expressing RAMP-1 (control 0.004±0.001% of total mononuclear cells; aMI 0.008±0.001%, p<0.02; CA 0.013±0.003% p<0.01; N=8-8-3) and NK1 (control 0.004±0.001%; aMI 0.008±0.001%, p<0.04; CA 0.010±0.002%, p<0.02). Moreover, RAMP-1 and NK1 expression increased in the CD34pos/KDRpos PC fraction (RAMP-1: control 9.2±0.6%; aMI 15.5±1.8%, p<0.01; CA 22.1±8.4% p<0.02. NK1: control 8.4±0.9%; aMI 16.6±1.9%, p<0.01; CA 16.1±7.2%, p<0.02).
Conclusion: Our results suggest that neurogenic mechanisms regulate PC mobilization in ischemia. Nociceptive signalling might represent a novel target for modulation of BM-mediated reparative response.
- © 2010 by American Heart Association, Inc.