β3整合素而非β1整合素在损伤后平滑肌细胞迁移所涉及的整合素-基质相互作用中起主导作用。

Beta3-integrins rather than beta1-integrins dominate integrin-matrix interactions involved in postinjury smooth muscle cell migration.

作者信息

Slepian M J, Massia S P, Dehdashti B, Fritz A, Whitesell L

机构信息

University Heart Center, University of Arizona, Tuscon 85724, USA.

出版信息

Circulation. 1998 May 12;97(18):1818-27. doi: 10.1161/01.cir.97.18.1818.

DOI:10.1161/01.cir.97.18.1818

PMID:9603537

Abstract

BACKGROUND

Smooth muscle cell (SMC) migration is a vital component in the response of the arterial wall to revascularization injury. Cell surface integrin-extracellular matrix interactions are essential for cell migration. SMCs express both beta1- and beta3-integrins. In this study, we examined the relative functional roles of beta1- and beta3-integrin-matrix interactions in postinjury SMC migration.

METHODS AND RESULTS

Flow cytometry and fluorescence microscopy of migrating SMCs immunostained with anti-beta1 and anti-alpha(v)beta3/5 antibodies (Abs) revealed expression of both beta1- and beta3-integrins, with beta1 observed as linear streaks and beta3 found in focal contacts. In a scrape-wound migration assay, anti-beta1 Abs (92.0+/-10.7% of control, P=.1) and 0.5 mmol/L linear RGD (105+/-5% of control, P=.2) did not alter SMC migration at 48 hours after injury. Beta3-blockade, however, via Abs (anti-beta3/5 35.7+/-4.5% of control, anti-beta3 61+/-12% of control, both P<.001) and cyclic RGD (0.5 mmol/L) (12+/-10% of control, P<.001) decreased migration. Neither beta1- nor beta3-inhibition altered postinjury [3H]thymidine incorporation. In the rat carotid injury model, local adventitial polymer-based delivery of radiolabeled linear or cyclic RGD led to uptake and retention of label, for both peptides, over a 72-hour period after injury. Local arterial wall beta1-blockade via polymer-based delivery of linear RGD had no effect on SMC migration at 4.5 days (11.5+/-3.2 versus 12.8 SMCs per x600 field [control], P=.6) or on neointimal thickening at 14 days (I/M area ratio, 0.664+/-0.328 versus 1.179+/-0.324 [control], P=.6) after injury. In contrast, local beta3-blockade via cRGD limited migration (0.8+/-0.8 versus 12.8+/-4.4 SMCs per x600 field [control], P<.01) and thickening (I/M area ratio, 0.004+/-0.008 versus 1.179+/-0.324 [control], P<.01).

CONCLUSIONS

In postinjury migrating SMCs, beta3- rather than beta1-integrin-matrix interactions are of greater functional significance in adhesive processes essential for SMC migration in vitro and in vivo. Blockade of dominant SMC integrin (beta3)-matrix interactions may be a valuable approach for limiting injury-induced SMC migration and late arterial renarrowing.

摘要

背景

平滑肌细胞（SMC）迁移是动脉壁对血管再通损伤反应的重要组成部分。细胞表面整合素-细胞外基质相互作用对细胞迁移至关重要。平滑肌细胞同时表达β1和β3整合素。在本研究中，我们检测了β1和β3整合素-基质相互作用在损伤后平滑肌细胞迁移中的相对功能作用。

方法与结果

用抗β1和抗α(v)β3/5抗体（Abs）免疫染色的迁移平滑肌细胞的流式细胞术和荧光显微镜检查显示β1和β3整合素均有表达，β1呈线性条纹状，β3见于粘着斑。在划痕损伤迁移试验中，抗β1抗体（为对照的92.0±10.7%，P = 0.1）和0.5 mmol/L线性RGD（为对照的105±5%，P = 0.2）在损伤后48小时未改变平滑肌细胞迁移。然而，通过抗体（抗β3/5为对照的35.7±4.5%，抗β3为对照的61±12%，均P<0.001）和环RGD（0.5 mmol/L）（为对照的12±10%，P<0.001）阻断β3可减少迁移。β1或β3抑制均未改变损伤后[3H]胸腺嘧啶核苷掺入。在大鼠颈动脉损伤模型中，损伤后72小时内，基于聚合物的局部外膜放射性标记线性或环RGD递送导致两种肽的标记摄取和保留。基于聚合物的线性RGD局部动脉壁β1阻断在损伤后4.5天对平滑肌细胞迁移（每x600视野11.5±3.2对12.8个平滑肌细胞[对照]，P = 0.6）或14天内膜增厚（I/M面积比，0.664±0.328对1.179±0.324[对照]，P = 0.6）无影响。相反，通过cRGD进行局部β3阻断限制了迁移（每x600视野0.8±0.8对12.8±4.4个平滑肌细胞[对照]，P<0.01）和增厚（I/M面积比，0.004±0.008对1.179±0.324[对照]，P<0.01）。