Tissue Resident Cells Play a Dominant Role in Arteriogenesis and Concomitant Macrophage Accumulation

Abstract

Abstract-Collateral growth is characterized by macrophage accumulation, suggesting an important role of circulating cells. To study origin and function of macrophages during arteriogenesis, we related the extent of macrophage accumulation to vascular proliferation and investigated the fate of fluorescently (CMFDA) labeled blood cells that were injected at the time of femoral artery occlusion. The effect of bone marrow depletion via cyclophosphamide before femoral artery occlusion on collateral proliferation and macrophage accumulation was studied, and we looked for the presence of bone marrow-derived stem cells in the vicinity of growing collateral vessels. Finally, we investigated the arteriogenic effect of macrophage activation via MCP-1 in bone marrow-depleted animals. Maximal macrophage accumulation occurred during the first 3 days after femoral artery occlusion and paralleled the extent of vascular proliferation. Fluorescently labeled leukocytes homed to spleen and wound but they were absent in proliferating collateral arteries during maximal macrophage accumulation. Depletion of circulating cells did neither affect macrophage accumulation nor collateral growth. Staining of monocyte-depleted animals for BrdUrd and ED2, ␣SMA, or VE-Cadherin demonstrated local proliferation of macrophages and vascular cells, whereas C-Kit, SSEA1, or Thy1-positive bone marrow-derived stem cells were not detectable. Enhancement of macrophage accumulation via MCP-1 was independent of circulating monocytes and promoted arteriogenesis in the absence of direct effects on vascular cells. We propose that the initial phase of vascular growth is characterized by local proliferation of tissue resident precursors rather than by migration of blood born cells.

Migration of Mononuclear Cells Expressing β-Actin Through the Adventitia into Media and Intima in Coronary Arteriogenesis and Venogenesis in Ischemic Myocardium

“…These findings are also quite different to the previous understanding that proliferation of resident cells induces venogenesis. 3,4) In the present study, β-MNCs migrated into the coronary vessel wall, not from the lumen but from outside, ie, the interstitial space, and contributed to arteriogenesis and venogenesis. This finding is also different to the previous understanding that circulating stem cells/precursor cells migrate into the vessel wall from the lumen and contribute to angiogenesis.…”

“…It was previously thought that compared to angiogenesis (capillary formation), arteriogenesis is a distinct process based on the remodeling and maturation of pre-existing arterioles and arteries, 1) characterized by proliferation of pre-existing smooth muscle cells (SMCs), endothelial cells (ECs), or their resident precursors. 2) Recent reports that arteriogenesis is augmented by bone marrow mononuclear cells [3][4][5] and endothelial progenitor cells suggest involvement in arteriogenesis of not only proliferation of resident cells, but also migration and proliferation of circulating stem cells/precursor cells. [6][7][8] Although previous studies have demonstrated capillary formation (vasculogenesis/angiogenesis) by transplanted cells, [7][8][9][10] they could not demonstrate incorporation of transplanted cells into pre-existing arterioles and arteries, inducing arteriogenesis.…”

Reticulon 4B (Nogo-B) is necessary for macrophage infiltration and tissue repair

“…The increase in Nogo-B expression in tissue is likely due to increased gene expression in vascular cells as well as the recruitment of monocytes/macrophages into tissue. In this model of severe limb ischemia, it is believed that ischemia triggers the redistribution of blood flow into preformed collaterals, and the increase in shear stress concomitant with the recruitment of macrophages and macrophage-derived cytokines such as MCP-1, TNF␣, or VEGF participate in arteriogenesis in the adductor muscles, blood flow recovery, and angiogenesis in the gastrocnemius muscle (16,17,28 (29) and local macrophages may proliferate in tissue after ischemia (30), thus, the presence of residual Nogo-positive macrophages after irradiation in WT mice may contribute to the recovery of function postischemia in mice transplanted with Nogo Ϫ/Ϫ BMM. Indeed our data suggests that skeletal muscle resident macrophages exist in irradiated mice before and after ischemia, and they contribute to cytokine gene expression.…”

Review article: Is obesity an inflammatory illness? Role of low‐grade inflammation and macrophage infiltration in human white adipose tissue

“…38 The role of macrophages in the angiogenesis may occur in rapidly expanding adipose tissue, eventually leading to some degree of hypoxia. As a consequence, macrophages could contribute to the local control of fat mass expansion and of its biology.…”