Peptidergic regulation of plasminogen activator inhibitor‐1 gene expression in vivo

Abstract

The mechanisms by which PAI-1 biosynthesis is altered during stress have not been fully elucidated. Studies suggest a major role for neuro-peptidergic modulation of the stress response by PACAP (pituitary adenylate cyclase-activating polypeptide), a member of the VIP/secretin/glucagon family. We tested the hypothesis that PACAP regulates PAI-1 biosynthesis during stress in vivo. PAI-1 gene expression was monitored by RT-PCR in adrenal glands harvested from C57BL/6J mice that were unstressed, or subjected to restraint stress for 2h, or treated with PACAP. PAI-1 mRNA expression was markedly increased in adrenals from stressed mice. Restraint stress resulted in much smaller increments in adrenal tPA mRNA, suggesting that local adrenal tPA/PAI-1 biosynthetic balance is markedly altered by stress. The observed increases in PAI-1mRNA during stress were substantially blunted (55±4%, P<0.001) by pretreatment with the specific PACAP receptor antagonist, PACAP6-38, compared with pretreatment with vehicle. Administration of the agonist PACAP1-38 alone resulted in a dose-dependent increase in tissue PAI-1 mRNA. PACAP1-38 administration also resulted in substantial increases in plasma PAI-1 antigen and active PAI-1 concentrations that were significantly greater in male mice than in female mice. We conclude that adrenal PAI-1 mRNA expression is markedly increased by stress, and that the PACAP peptidergic signaling pathway plays a major role in mediating the stress-induced increase in PAI-1 biosynthesis.