内皮素-1 促进血管平滑肌细胞穿过血管壁迁移：一种导致巨细胞动脉炎血管重塑和内膜增生的机制。

Endothelin-1 promotes vascular smooth muscle cell migration across the artery wall: a mechanism contributing to vascular remodelling and intimal hyperplasia in giant-cell arteritis.

机构信息

Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CRB-CELLEX, Barcelona, Spain.

Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona and CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Barcelona, Spain.

出版信息

Ann Rheum Dis. 2017 Sep;76(9):1624-1634. doi: 10.1136/annrheumdis-2016-210792. Epub 2017 Jun 12.

DOI:10.1136/annrheumdis-2016-210792

PMID:28606962

Abstract

BACKGROUND

Giant-cell arteritis (GCA) is an inflammatory disease of large/medium-sized arteries, frequently involving the temporal arteries (TA). Inflammation-induced vascular remodelling leads to vaso-occlusive events. Circulating endothelin-1 (ET-1) is increased in patients with GCA with ischaemic complications suggesting a role for ET-1 in vascular occlusion beyond its vasoactive function.

OBJECTIVE

To investigate whether ET-1 induces a migratory myofibroblastic phenotype in human TA-derived vascular smooth muscle cells (VSMC) leading to intimal hyperplasia and vascular occlusion in GCA.

METHODS AND RESULTS

Immunofluorescence/confocal microscopy showed increased ET-1 expression in GCA lesions compared with control arteries. In inflamed arteries, ET-1 was predominantly expressed by infiltrating mononuclear cells whereas ET receptors, particularly ET-1 receptor B (ETR), were expressed by both mononuclear cells and VSMC. ET-1 increased TA-derived VSMC migration in vitro and α-smooth muscle actin (αSMA) expression and migration from the media to the intima in cultured TA explants. ET-1 promoted VSMC motility by increasing activation of focal adhesion kinase (FAK), a crucial molecule in the turnover of focal adhesions during cell migration. FAK activation resulted in Y397 autophosphorylation creating binding sites for Src kinases and the p85 subunit of PI3kinases which, upon ET-1 exposure, colocalised with FAK at the focal adhesions of migrating VSMC. Accordingly, FAK or PI3K inhibition abrogated ET-1-induced migration in vitro. Consistently, ET-1 receptor A and ETR antagonists reduced αSMA expression and delayed VSMC outgrowth from cultured GCA-involved artery explants.

CONCLUSIONS

ET-1 is upregulated in GCA lesions and, by promoting VSMC migration towards the intimal layer, may contribute to intimal hyperplasia and vascular occlusion in GCA.

摘要

背景

巨细胞动脉炎（GCA）是一种大/中动脉的炎症性疾病，常累及颞动脉（TA）。炎症引起的血管重塑导致血管闭塞事件。在有缺血并发症的 GCA 患者中，循环内皮素-1（ET-1）增加，表明 ET-1 在血管闭塞中的作用超出了其血管活性功能。

目的

研究 ET-1 是否在人类 TA 来源的血管平滑肌细胞（VSMC）中诱导迁移性肌成纤维细胞表型，导致 GCA 中的内膜增生和血管闭塞。

方法和结果

免疫荧光/共聚焦显微镜显示，与对照动脉相比，GCA 病变中 ET-1 的表达增加。在炎症动脉中，ET-1 主要由浸润的单核细胞表达，而 ET 受体，特别是 ET-1 受体 B（ETR），则由单核细胞和 VSMC 共同表达。ET-1 增加了体外 TA 来源的 VSMC 迁移，以及培养的 TA 外植体中从中膜向内膜迁移的α-平滑肌肌动蛋白（αSMA）表达。ET-1 通过增加粘着斑激酶（FAK）的激活来促进 VSMC 的迁移，FAK 是细胞迁移过程中粘着斑周转的关键分子。FAK 激活导致 Y397 自身磷酸化，为Src 激酶和 PI3 激酶的 p85 亚基创造了结合位点，在暴露于 ET-1 后，这些激酶和 p85 亚基与迁移的 VSMC 的粘着斑共定位。因此，FAK 或 PI3K 抑制消除了体外 ET-1 诱导的迁移。一致地，ET-1 受体 A 和 ETR 拮抗剂减少了αSMA 的表达，并延迟了培养的 GCA 受累动脉外植体中 VSMC 的生长。