ANGIOTENSIN-II INDUCES PLASMINOGEN-ACTIVATOR INHIBITOR-1 AND INHIBITOR-2 EXPRESSION IN VASCULAR ENDOTHELIAL AND SMOOTH-MUSCLE CELLS

Angiotensin II (AII)- and Arg(8)-vasopressin (AVP)-regulated gene expr ession in vascular cells has been reported to contribute to vascular h omeostasis and hypertrophy. In this report, AVP-induced expression of plasminogen activator inhibitor (PAI)-2 mRNA in rat microvessel endoth elial (RME) cells was identified using differential mRNA display. Furt her characterization of vasoactive peptide effects on PAI expression r evealed that AII stimulated a 44.8+/-25.2-fold and a 12.4+/-3.2-fold i ncrease in PAI-2 mRNA in RME cells and rat aortic smooth muscle cells (RASMC), respectively. AII also stimulated a 10- and 48-fold increase in PAI-1 mRNA in RME cells and RASMC, respectively. These AII effects mere inhibited by either Sar(1), Ile(8)-angiotensin or the AT(1) antag onist DuP 735, but mere not significantly altered in the presence of t he AT(2) antagonist PD123319. AII stimulation of RASMC and RME cells a lso significantly increased both PAI-1 protein and PAI activity releas ed to the culture medium. Inhibition of protein kinase C completely bl ocked PMA-stimulated induction of PAI-2 mRNA in both cell types and in hibited the AII-stimulated increase in RASMC by 98.6+/-2.8% In contras t, protein kinase C inhibition only partially decreased the AII-stimul ated PAI-2 expression in RME cells by 68.8+/-11.1%, suggesting that a protein kinase C-independent mechanism contributes to a 6.9+/-1.5-fold AII induction of PAI-2 expression in endothelial cells. AII and PMA a lso stimulated protein tyrosine phosphorylation in RME cells, and the tyrosine kinase inhibitor genistein partially blocked their induction of PAI-2 mRNA. These findings suggest that AII may regulate plasminoge n activation in the vasculature by inducing both PAI-1 and PAI-2 expre ssion.