Key result
Ischemic muscle microparticles increase ~3.5-fold and stimulate postnatal neovascularization.
Why the study?
Microparticles released after ischemia are hypothesized to act as endogenous signals promoting postischemic vasculogenesis, but their role and mechanisms remain unclear.
Effect estimate: 3.5-fold higher
Absolute Event Rate: 1392% vs 394%
p-value: p=<0.001
Microparticles released during tissue ischemia stimulate progenitor cell differentiation and promote postnatal neovascularization, suggesting a novel endogenous mechanism for postischemic vasculogenesis.
Hypothesis-generating in murine ischemia; leaves open translation to human postischemic vasculogenesis.
BACKGROUND: We hypothesized that microparticles (MPs) released after ischemia are endogenous signals leading to postischemic vasculogenesis. METHODS AND RESULTS: MPs from mice ischemic hind-limb muscle were detected by electron microscopy 48 hours after unilateral femoral artery ligation as vesicles of 0.1- to 1-microm diameter. After isolation by sequential centrifugation, flow cytometry analyses showed that the annexin V(+) MP concentration was 3.5-fold higher in ischemic calves than control muscles (1392+/-406 versus 394+/-180 annexin V(+) MPs per 1 mg; P<0.001) and came mainly from endothelial cells (71% of MPs are CD(144+)). MPs isolated from ischemic muscles induced more potent in vitro bone marrow-mononuclear cell (BM-MNC) differentiation into cells with endothelial phenotype than those isolated from control muscles. MPs isolated from atherosclerotic plaques were ineffective, whereas those isolated from apoptotic or interleukin-1beta-activated endothelial cells also promoted BM-MNC differentiation. Interestingly, MPs from ischemic muscles produced more reactive oxygen species and expressed significantly higher levels of NADPH oxidase p47 (6-fold; P<0.05) and p67 subunits (16-fold; P<0.001) than controls, whereas gp91 subunit expression was unchanged. BM-MNC differentiation was reduced by 2-fold with MPs isolated from gp91-deficient animals compared with wild-type mice (P<0.05). MP effects on postischemic revascularization were then examined in an ischemic hind-limb model. MPs isolated from ischemic muscles were injected into ischemic legs in parallel with venous injection of BM-MNCs. MPs increased the proangiogenic effect of BM-MNC transplantation, and this effect was blunted by gp91 deficiency. In parallel, BM-MNC proangiogenic potential also was reduced in ABCA1 knockout mice with impaired vesiculation. CONCLUSIONS: MPs produced during tissue ischemia stimulate progenitor cell differentiation and subsequently promote postnatal neovascularization.
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Leroyer et al. (2009) studied Tissue ischemia. Microparticles from ischemic muscle vs. Microparticles from control muscles was evaluated on Annexin V(+) MP concentration (3.5-fold higher, p=<0.001). Microparticles released from ischemic muscle were significantly higher than in controls (1392 vs 394 per 1 mg; P<0.001) and stimulated progenitor cell differentiation and postnatal neovascularization.
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