Autocrine and paracrine up-regulation of blood-brain barrier function by plasminogen activator inhibitor-1

作者：Dohgu Shinya; Takata Fuyuko; Matsumoto Junichi; Oda Masatoshi; Harada Eriko; Watanabe Takuya; Nishioku Tsuyoshi; Shuto Hideki; Yamauchi Atsushi; Kataoka Yasufumi^*

来源：Microvascular Research, 2011, 81(1): 103-107.

DOI：10.1016/j.mvr.2010.10.004

• Blood-brain barrier
• Plasminogen activator inhibitor-1
• Brain endothelial cells
• Pericytes
• Permeability
• Transendothelial electrical resistance
• Co-culture

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.

• 出版日期2011-1