Autocrine and paracrine up-regulation of blood-brain barrier function by plasminogen activator inhibitor-1
Autocrine and paracrine up-regulation of blood-brain barrier function by plasminogen activator inhibitor-1
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DOI：
10.1016/j.mvr.2010.10.004
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发表时间：
2011-01-01
影响因子：
3.1
通讯作者：
Kataoka, Yasufumi
中科院分区：
文献类型：
--
作者：
Dohgu, Shinya;Takata, Fuyuko;Kataoka, Yasufumi
血脑屏障（BBB）是分隔中枢神经系统（CNS）和外周循环的界面。血浆和脑中包括细胞因子在内的血源性物质的增加影响BBB功能，并且这与许多疾病的发病机制的发展相关。纤溶酶原激活物抑制剂（PAI）-1作为丝氨酸蛋白酶抑制剂调节外周和CNS中的纤溶酶原激活物/纤溶酶系统。我们研究了PAI-1是否改变BBB功能，使用由单独的大鼠原代脑内皮细胞（RBECs）和周细胞共培养的BBB体外模型。我们发现PAI-1以时间和剂量依赖性方式增加脑内皮屏障的紧密性，如跨内皮电阻（TEER）增加和荧光素钠（Na-F）渗透性降低所示。红细胞对PAI-1在面向血液和面向大脑侧的反应相同，导致Na-F渗透性降低。此外，RBEC组成性地将PAI-1释放到面向血液（管腔）和面向脑（管腔外）侧。这种释放被极化，有利于管腔侧，并促进血清。在RBEC/周细胞共培养物中，PAI-1抗体对PAI-1的中和作用比RBEC单层更强烈地降低了RBEC的TEER。这些结果表明，PAI-1来源于神经血管单位和外周血管系统参与作为一个积极的调节BBB促进内皮细胞紧密连接的屏障功能。(C)2010年爱思唯尔公司All rights reserved.
The blood-brain barrier (BBB) is the interface that separates the central nervous system (CNS) from the peripheral circulation. An increase in blood-borne substances including cytokines in plasma and brain affects BBB function, and this is associated with the development of pathogenesis of a number of diseases. Plasminogen activator inhibitor (PAI)-1 regulates the plasminogen activator/plasmin system as a serpin in the periphery and the CNS. We investigated whether PAI-1 alters BBB function using in vitro models of the BBB consisting of rat primary brain endothelial cells (RBECs) alone and co-cultured with pericytes. We found that PAI-1 increased the tightness of the brain endothelial barrier in a time- and dose-dependent manner, as shown by an increase in the transendothelial electrical resistance (TEER) and a decrease in the permeability to sodium fluorescein (Na-F). RBECs responded equally to PAI-1 in the blood-facing and brain-facing sides of the brain, leading to a decrease in Na-F permeability. In addition, RBECs constitutively released PAI-1 into the blood-facing (luminal) and brain-facing (abluminal) sides. This release was polarized in favor of the luminal side and facilitated by serum. The neutralization of PAI-1 by an antibody to PAI-1 in RBEC/pericyte co-culture more robustly reduced TEER of RBECs than in RBEC monolayers. These findings suggest that PAI-1 derived from the neurovascular unit and peripheral vascular system participates as a positive regulator of the BBB in facilitating the barrier function of the endothelial tight junctions. (C) 2010 Elsevier Inc. All rights reserved.