van Royen N, Voskuil M, Hoefer I, Jost M, de Graaf S, Hedwig F, Andert J-P, Wormhoudt T A M, Hua J, Hartmann S, Bode C, Buschmann I, Schaper W, van der Neut R, Piek J J, Pals S T
Department of Cardiology, Room B2-114, Academic Medical Center, University of Amsterdam, Meibergdreef 9 1105 AZ, Amsterdam, The Netherlands.
Circulation. 2004 Apr 6;109(13):1647-52. doi: 10.1161/01.CIR.0000124066.35200.18. Epub 2004 Mar 15.
Arteriogenesis refers to the development of collateral conductance arteries and is orchestrated by circulating monocytes, which invade growing collateral arteries and act as suppliers of cytokines and growth factors. CD44 glycoproteins are involved in leukocyte extravasation but also in the regulation of growth factor activation, stability, and signaling. Here, we explored the role of CD44 during arteriogenesis.
CD44 expression increases strongly during collateral artery growth in a murine hind-limb model of arteriogenesis. This CD44 expression is of great functional importance, because arteriogenesis is severely impaired in CD44-/- mice (wild-type, 54.5+/-14.9% versus CD44-/-, 24.1+/-9.2%, P<0.001). The defective arteriogenesis is accompanied by reduced leukocyte trafficking to sites of collateral artery growth (wild-type, 29+/-12% versus CD44-/-, 18+/-7% CD11b-positive cells/square, P<0.01) and reduced expression of fibroblast growth factor-2 and platelet-derived growth factor-B protein. Finally, in patients with single-vessel coronary artery disease, the maximal expression of CD44 on activated monocytes is reduced in case of impaired collateral artery formation (poor collateralization, 1764+/-572 versus good collateralization, 2817+/-1029 AU, P<0.05).
For the first time, the pivotal role of CD44 during arteriogenesis is shown. The expression of CD44 increases during arteriogenesis, and the deficiency of CD44 severely impedes arteriogenesis. Maximal CD44 expression on isolated monocytes is decreased in patients with a poor collateralization compared with patients with a good collateralization.
动脉生成是指侧支传导动脉的发育，由循环单核细胞协调，这些单核细胞侵入正在生长的侧支动脉，并作为细胞因子和生长因子的供应者。CD44糖蛋白不仅参与白细胞渗出，还参与生长因子的激活、稳定性和信号传导的调节。在此，我们探讨了CD44在动脉生成过程中的作用。
在小鼠后肢动脉生成模型中，侧支动脉生长期间CD44表达显著增加。这种CD44表达具有重要的功能意义，因为在CD44基因敲除小鼠中动脉生成严重受损（野生型，54.5±14.9% 对比CD44基因敲除型，24.1±9.2%，P<0.001）。动脉生成缺陷伴随着白细胞向侧支动脉生长部位的迁移减少（野生型，29±12% 对比CD44基因敲除型，18±7% CD11b阳性细胞/平方，P<0.01）以及成纤维细胞生长因子-2和血小板衍生生长因子-B蛋白的表达降低。最后，在单支冠状动脉疾病患者中，侧支动脉形成受损时（侧支循环不良，1764±572对比侧支循环良好，2817±1029 AU，P<0.05），活化单核细胞上CD44的最大表达降低。
首次表明了CD44在动脉生成过程中的关键作用。动脉生成过程中CD44表达增加，而CD44缺陷严重阻碍动脉生成。与侧支循环良好的患者相比，侧支循环不良患者分离的单核细胞上CD44的最大表达降低。
