Abstract
Macrophage invasion is an important event during arteriogenesis, but the underlying mechanism is still only partially understood. The present study tested the hypothesis that nitric oxide (NO) and VE-cadherin, two key mediators for vascular permeability, contribute to this event in a rat ischemic hindlimb model. In addition, the effect of NO on expression of VE-caherin and endothelial permeability was also studied in cultured HUVECs. We found that: 1) in normal arteriolar vessels (NAV), eNOS was moderately expressed in endothelial cells (EC) and iNOS was rarely detected. In contrast, in collateral vessels (CVs) induced by simple femoral artery ligation, both eNOS and iNOS were significantly upregulated (P<0.05). Induced iNOS was found mainly in smooth muscle cells, but also in other vascular cells and macrophages; 2) in NAV VE-cadherin was strongly expressed in EC. In CVs, VE-cadherin was significantly downregulated, with a discontinuous and punctate pattern. Administration of nitric oxide donor DETA NONOate (NONOate) further reduced the amounts of Ve-cadherin in CVs, whereas NO synthase inhibitor L-NAME inhibited downregulation of VE-cadherin in CVs; 3) in normal rats Evans blue extravasation (EBE) was low in the musculus gracilis, FITC-dextron leakage was not detected in the vascular wall and few macrophages were observed in perivascular space. In contrast, EBE was significantly increased in femoral artery ligation rats, FITC-dextron leakage and increased amounts of macrophages were detected in CVs, which were further enhanced by administration of NONOate, but inhibited by L-NAME supplement; 4) in vitro experiments confirmed that an increase in NO production reduced VE-cadherin expression, correlated with increases in the permeability of HUVECs. In conclusion, our data for the first time reveal the expression profile of VE-cadherin and alterations of vascular permeability in CVs, suggesting that NO-mediated VE-cadherin pathway may be one important mechanism responsible, at least in part, for macrophage invasion during arteriogenesis.
Highlights
Monocyte/macrophage plays an important part during arteriogenesis
After many years’ study, it is well-known that the mechanism for the adhesion of monocytes to the endothelial lining involves a panel of different adhesion and chemokine molecule groups produced by activated endothelial cells under increased shear stress, such as ICAM and MCP-1, but the question how monocytes transmigrate through the endothelial barrier into underlying tissue remains open
Correlated with the changes in fluorescein isothiocyanate (FITC)-dextran/ Evans blue extravasation (EBE) leakage, few macrophages were detected in sham rats, but significantly increased (P
Summary
Monocyte/macrophage plays an important part during arteriogenesis. It is because monocytes/ macrophages are the main source of growth factors and cytokines such as basic fibroblast growth factor (bFGF) or TNFα, which contribute to collateral growth and remodelling[1]. Monocyte-deficient op/op mice showed only a stunted collateral response to femoral artery occlusion, whereas intravenous injections of blood-isolated monocytes could rescue the flow recovery in 5-fluorouracil induced monocyte-deficient rabbits [2, 3]. As early as 1976 Schaper and Schaper showed that monocytes adhere, migrate into deeper parts of the vessel wall, and/or populate the adventitial space [4]. After many years’ study, it is well-known that the mechanism for the adhesion of monocytes to the endothelial lining involves a panel of different adhesion and chemokine molecule groups produced by activated endothelial cells under increased shear stress, such as ICAM and MCP-1, but the question how monocytes transmigrate through the endothelial barrier into underlying tissue remains open
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