M-CSF Accelerates Neointimal Formation in the Early Phase After Vascular Injury in Mice

Abstract

Objective-Since the macrophage colony-stimulating factor (M-CSF) has been shown to stimulate differentiation and proliferation of monocyte/macrophage lineage and to be involved in the process of neointimal formation after vascular injury, we tested the effects of M-CSF on the recruitment of bone marrow-derived progenitor cells in neointimal formation after vascular injury in mice. Methods and Results-Wire-mediated vascular injury was produced in the femoral artery of C57BL/6 mice. Recombinant human M-CSF [500 g/(kg⅐day)] or saline (control) was administered for 10 consecutive days, starting 4 days before the injury. Treatment with M-CSF accelerated neointimal formation in the early phase after injury, and this neointimal lesion mainly consisted of bone marrow-derived cells. M-CSF treatment had no effect on the mobilization of endothelial progenitor cells (EPCs: CD34 ϩ /Flk-1 ϩ ) and reendothelialization after injury. The stromal cell-derived factor-1 (SDF-1) was markedly expressed in the neointima and media after injury, whereas CXCR4 ϩ cells were observed in the neointima. Further, a novel CXCR4 antagonist, AMD3100, significantly attenuated the M-CSF-induced neointimal formation. Conclusions-These findings suggest that M-CSF accelerated neointimal formation after vascular injury via the SDF-1-CXCR4 system, and the inhibition of this system has therapeutic potential for the treatment of cardiovascular diseases. Key Words: angioplasty Ⅲ cytokines Ⅲ inflammation Ⅲ restenosis Ⅲ vascular biology T he vascular endothelium forms a biological interface between circulating blood components and various tissues in the body. This monolayer of endothelial cells locally monitors systemically generated stimuli, and alters the functional state of the vessels. This adaptive mechanism contributes to normal homeostasis; however, nonadaptive changes in the endothelial structure and function, provoked by pathophysiological stimuli, may induce "endothelial dysfunction," which plays an important role in the initiation and progression of cardiovascular diseases. In particular, the loss of endothelial cells because of vascular injury leads to the migration and proliferation of vascular smooth muscle cells (SMCs), resulting in neointimal formation. Further, the vascular injury initiates an inflammatory healing response that involves the expression of growth factors and cytokines and promotes neointimal formation. The resultant neointimal formation is the pathological basis of atherosclerosis and restenosis following percutaneous coronary intervention (PCI) such as angioplasty and stenting. See page 263The recruitment, activation, and proliferation of monocytes/macrophages in the vessel wall make important contribution to the process of atherosclerosis and restenosis. The presence of activated monocytes/macrophages at the site of the vascular injury leads to the release of vasoactive molecules, cytokines, and growth factors, which can induce the migration and proliferation of SMCs. However, recent evidence indicates that a part of the po...

A novel role for platelet secretion in angiogenesis: mediating bone marrow–derived cell mobilization and homing

“…CXCR4 ϩ proangiogenic cells represent a heterogeneous population and have been described as endothelial progenitor cells, smooth muscle progenitors, mesenchymal stem cells, hematopoietic stem cells, fibroblasts, or tumor-associated myeloid cells. 2,7,28,30,[39][40][41] Based on our previously published studies, we think that the use of CXCR4 as a marker allows for tracking of the majority of recruited BMDCs. 1 Regardless of the presence of additional markers, these BMDCs are crucial for angiogenesis and vascular maturation in various models.…”

“…Several factors associated with BMDC mobilization were found to be tumor-produced and present within platelet lysates ( Figure 6). Among these were granulocyte colony-stimulating factor, macrophage colony-stimulating factor, matrix metalloproteinase-9, and granulocyte-macrophage colony-stimulating factor, which are known to be associated with the release of stem cells from the BM niche into the circulation 8,[28][29][30] and ranged from 25 to 335 pg/mL in platelets ( Figure 6A). While in the BM and circulation, thrombopoietin and IL-6 support stem cell survival and expansion 29,31 and were found at the highest levels within platelets (thrombopoietin, 13 798.81 Ϯ 3292.31 pg/mL; IL-6, 8500.57 Ϯ 2356.11 pg/mL; Figure 6B).…”

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

“…SDF-1 is upregulated in damaged tissues, such as the liver [9], arteries [10] or irradiated BM [11] (Table 1). Indeed, hypoxic and/ or apoptotic conditions are the trigger to induce expression of cytokines and chemokines.…”

“…In tumor models, inhibition of the SDF-1-CXCR4 pathway with chronic administration of AMD3100 leads to efficient reduction of tumor growth and angiogenesis by targeting (i) proliferation of CXCR4-expressing tumor cells, (ii) diminishing recruitment of CXCR4 + angiogenic cells and (iii) promoting CXCR4-dependent metastasis [27,58,63]. In addition, CXCR4 antagonists might prevent vascular neointima formation and atherosclerosis [10].…”

Endothelial progenitors in pulmonary hypertension: new pathophysiology and therapeutic implications

“…Once in the bloodstream, EPCs constitute a pool of circulating cells able to form a cellular patch at sites of endothelial denudation, in order to restore endothelial integrity [16]. This action has been demonstrated in several experimental models and is accomplished through the expression of surface adhesion molecules and chemokines receptors [17,18]. EPCs are also involved in physiological and pathological stimulation of new vessel growth, both de novo (neo-vasculogenesis) or sprouting from pre-existing vessels (neo-angiogenesis), especially in ischaemic tissues.…”