Knockdown of P120 catenin aggravates endothelial injury under an impinging flow by inducing breakdown of adherens junctions.
Knockdown of P120 catenin aggravates endothelial injury under an impinging flow by inducing breakdown of adherens junctions.
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DOI：
10.3892/mmr.2018.9657
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发表时间：
2018-11
影响因子：
3.4
通讯作者：
Jianlan Zhao;Zhi-Peng Xiao;Nian-Zu Yu;Jin-wen Jiang;Mei-Hua Li
中科院分区：
文献类型：
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作者：
Jianlan Zhao;Zhi-Peng Xiao;Nian-Zu Yu;Jin-wen Jiang;Mei-Hua Li
目前，颅内动脉瘤（IA）发展的机制尚不清楚，然而，血流动力学被认为是诱导IA的关键因素。为了阐明血流动力学与内皮细胞（EC）功能之间的关系，设计了一种改进的T室系统来模拟动脉分叉处的可调节血流动力学条件。将正常人脐静脉EC（HUVEC）和P120连环蛋白（P120 ctn）敲低的HUVEC在盖玻片上培养并置于室中。以250或500 ml/min的流速冲击细胞层。随后，检测P120 ctn和其他蛋白的表达水平以及EC形态学改变。在正常HUVECs中，在500 ml/min的流速下3 h后，P120 ctn、血管内皮（VE）-钙粘蛋白、Kaiso和α-连环蛋白的表达水平降低，而基质金属蛋白酶-2（MMP-2）的表达水平升高。在P120 ctn敲低的HUVECs中，当流速为500 ml/min时，ECs粘附于盖玻片的时间缩短至1 h。此外，1 h后，ECs中VE‑Cadherin、Kaiso和α‑catenin的表达水平降低，而MMP‑2的表达水平升高;与250 ml/min流速相比，在500 ml/min流速下检测到更显著的变化。粘附连接（AJs）是维持血管壁正常形态和EC功能的关键，P120 ctn是AJs的重要调节因子。血流动力学改变可引起P120 ctn的丢失。作为对血流动力学条件变化的响应，P120 ctn的缺失可能会加重EC之间的AJs，从而诱导血管壁的炎症。临床上，血流动力学改变可导致P120 ctn丢失和内皮损伤;因此，P120 ctn可能在诱发颅内动脉瘤中起关键作用。
At present, the mechanisms underlying intracranial aneurysm (IA) development remain unclear; however, hemodynamics is considered a crucial factor in the induction of IA. To elucidate the association between hemodynamics and endothelial cell (EC) functions, a modified T chamber system was designed to simulate the adjustable hemodynamic conditions of an artery bifurcation. Normal human umbilical vein ECs (HUVECs) and HUVECs with P120 catenin (P120ctn) knockdown were cultured on coverslips and placed in the chamber. A flow rate of 250 or 500 ml/min impinged on the cell layer. Subsequently, the expression levels of P120ctn and other proteins, and EC morphological alterations, were examined. In normal HUVECs, after 3 h under a flow rate of 500 ml/min, the expression levels of P120ctn, vascular endothelial (VE)‑Cadherin, Kaiso and α‑catenin were decreased, whereas matrix metalloproteinase‑2 (MMP‑2) was increased. In HUVECs with P120ctn knockdown, the period during which ECs adhered to the coverslip was reduced to 1 h under a flow rate of 500 ml/min. In addition, the expression levels of VE‑Cadherin, Kaiso and α‑catenin in ECs were decreased, whereas those of MMP‑2 were increased after 1 h; more prominent alterations were detected under a 500 ml/min flow rate compared with a 250 ml/min flow rate. Adherens junctions (AJs) are critical to the maintenance of normal morphology and EC functioning in the vascular wall, and P120ctn is an important regulator of AJs. Loss of P120ctn may be induced by hemodynamic alterations. In response to changes in hemodynamic conditions, a loss of P120ctn may aggravate AJs between ECs, thus inducing inflammation in the vascular wall. Clinically, hemodynamic alterations may result in a loss of P120ctn and endothelial injury; therefore, P120ctn may have a critical role in inducing intracranial aneurysms.