Role of vascular cell adhesion molecule-1 and fibronectin connecting segment-1 in monocyte rolling and adhesion on early atherosclerotic lesions
Role of vascular cell adhesion molecule-1 and fibronectin connecting segment-1 in monocyte rolling and adhesion on early atherosclerotic lesions
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DOI：
10.1161/01.res.87.2.153
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发表时间：
2000-07-21
影响因子：
20.1
通讯作者：
Ley, K
中科院分区：
文献类型：
--
作者：
Huo, YQ;Hafezi-Moghadam, A;Ley, K
动脉粥样硬化病变的发展在本质上似乎是炎症性的，涉及到单核细胞向血管壁的募集。在这项研究中，我们研究了血管细胞粘附分子-1 （VCAM-1）和纤维连接蛋白（FN）连接含有氨基酸序列ILDV的片段-1，作为α (4) β(1)整合素（vla4）的功能配体，在单核细胞早期动脉粥样硬化病变的旋转和粘附中的作用。分离载脂蛋白e缺陷小鼠颈动脉，用单核细胞或U937细胞灌注。单克隆抗体HP1/2和HP2/1阻断了VCAM-1和FN连接片段-1与VCAM-1的结合，使细胞粘附降低95+/-4%。单抗HP1/3优先阻断VCAM-1与FN的相互作用，降低黏着率30+/-8%。相比之下，通过向离体颈动脉灌注mAb MK-2.7阻断VCAM-1可使粘连降低75+/-12%。在EILDVPST存在的情况下，单个核细胞对早期动脉粥样硬化内皮的粘附受到68+/-10%的抑制，而在对照肽EIDVLPST存在的情况下则没有。当阻断vca -4或VCAM-1时，更多的单核细胞以更高（约两倍）的滚动速度在早期病变上滚动。这些数据表明：(1)阻断VCAM-1可以消除大部分（75+/-12%）vcam -4依赖性单核细胞对早期动脉粥样硬化内皮的粘附；(2)ILDV肽干扰vcam -4与VCAM-1和FN的结合，可能有助于限制单核细胞对动脉粥样硬化病变的粘附。
Atherosclerotic lesion development seems to be inflammatory in nature and involves the recruitment of monocytes to the vessel wall. In this study, we investigated the role of vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (FN) connecting segment-1 containing the amino acid sequence ILDV as functional ligands for alpha(4)beta(1) integrin (VLA-4) in monocyte rolling and adherence to early atherosclerotic lesions. Carotid arteries of apolipoprotein E-deficient mice were isolated and perfused with monocytes or U937 cells. Cell adhesion was reduced 95+/-4% by monoclonal antibodies HP1/2 and HP2/1, which block VLA-4 binding to both VCAM-1 and FN connecting segment-1. mAb HP1/3 preferentially blocked interaction of VLA-4 with FN but not VCAM-1 and decreased adhesion by 30+/-8%. In contrast, blocking VCAM-1 by perfusing the isolated carotid artery with mAb MK-2.7 reduced adhesion by 75+/-12%. Mononuclear cell adhesion to the early atherosclerotic endothelium was inhibited by 68+/-10% in the presence of EILDVPST but not in the presence of control peptide EIDVLPST. When VLA-4 or VCAM-1 was blocked, more mononuclear cells rolled on early lesions at significantly higher (approximately doubled) rolling velocities. These data demonstrate that (I) blockade of VCAM-1 can abrogate the majority (75+/-12%) of VLA-4-dependent monocyte adhesion on early atherosclerotic endothelia and (2) ILDV peptide interferes with VLA-4 binding to both VCAM-1 and FN and may be useful in limiting monocyte adhesion to atherosclerotic lesions.