PRESSURE AND ANGIOTENSIN-II SYNERGISTICALLY INDUCE AORTIC FIBRONECTINEXPRESSION IN ORGAN-CULTURE MODEL OF RABBIT AORTA - EVIDENCE FOR A PRESSURE-INDUCED TISSUE RENIN-ANGIOTENSIN SYSTEM

Aortic fibronectin (FN) expression is augmented in hypertension. Incre asing evidence suggests that both angiotensin II (Ang II and mechanica l factors may induce vascular remodeling in response to hypertension. We have previously shown that, in vitro, increased transmural pressure enhances FN expression in rabbit aortic media. To investigate the exi stence of a link between the effects of pressure and Ang II and to exp lore the mechanisms underlying such a relationship, we quantified the effect of Ang II and Ang II inhibitors on the pressure-dependent FN ex pression in a 3-day organ culture model of rabbit aorta using immunola beling analysis and detected FN mRNAs by in situ hybridization. A dose -dependent effect of Ang II on FN expression was observed at both 80 a nd 150 mm Hg but not at 0 mm Hg (relaxed vessels). One mu mol/L Ang II increased the media cross-sectional surface, showing FN expression fr om 7.9+/-0.7% (n=9) to 18.9+/-1.1% (n=4) at 80 mm Hg (P<.01) and from 17.4+/-1.8% (n=9) to 56.6%+/-3.6 (n=4) at 150 mm Hg (P<.001). In situ hybridization revealed that Ang II and pressure upregulated FN mRNA ex pression. Losartan, an AT(1) antagonist, not only blocked the Ang II e ffect but also inhibited the transmural pressure effect. Angiotensin-c onverting enzyme inhibition abolished the pressure-dependent FN expres sion and significantly diminished the effect of pressure in the presen ce of Ang II. The effect of renin-angiotensin system inhibitors was sp ecific for FN, since neither bFGF nor laminin expression was affected by these agents. Taken together, the results demonstrate that (1) the effect of transmural pressure is mediated by the stimulation of a loca l renin-angiotensin system, resulting in a net Ang II production in th e culture medium, (2) transmural pressure and Ang II act synergistical ly to enhance vascular FN expression, (3) AT(1) receptors mediate both the effects of pressure and of exogenous Ang II, and (4) the effect o f Ang II on FN expression is regulated at a pretranslational level.