No abstract

Aortic fibronectin (FN) expression is augmented in hypertension. Increasing evidence suggests that both angiotensin II (Ang II) and mechanical 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 existence of a link between the effects of pressure and Ang II and to explore the mechanisms underlying such a relationship, we quantified the effect of Ang II and Ang II inhibitors on the pressure-dependent FN expression in a 3-day organ culture model of rabbit aorta using immunolabeling analysis and detected FN mRNAs by in situ hybridization. A dose-dependent effect of Ang II on FN expression was observed at both 80 and 150 mm Hg but not at 0 mm Hg (relaxed vessels). One mumol/L Ang II increased the media cross-sectional surface, showing FN expression from 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 expression. Losartan, an AT1 antagonist, not only blocked the Ang II effect but also inhibited the transmural pressure effect. Angiotensin-converting enzyme inhibition abolished the pressure-dependent FN expression and significantly diminished the effect of pressure in the presence of Ang II. The effect of renin-angiotensin system inhibitors was specific 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 local renin-angiotensin system, resulting in a net Ang II production in the culture medium, (2) transmural pressure and Ang II act synergistically to enhance vascular FN expression, (3) AT1 receptors mediate both the effects of pressure and of exogenous Ang II, and (4) the effect of Ang II on FN expression is regulated at a pretranslational level.

An experimental model of in situ isolated carotid arteries has been used to evaluate the static mechanical properties of the arterial wall in 12-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The effects of endothelium removal and of local incubation with the converting enzyme inhibitor lisinopril (ICI Pharma 209000) on the carotid compliance (CC) were compared with the effects of total abolition of the vascular smooth muscle tone by potassium cyanide. CC measured for pressures ranging from 50 to 175 mm Hg had maximal values (0.22±0.07 iul/mm Hg and 0.13 ±0.03 ,ul/mm Hg, respectively, for WKY and SHR, p<0.001) for pressure values close to the operating pressures in both groups. Maximal values of CC were increased by 35% and 45% in WKY and SHR, respectively, after potassium cyanide poisoning (p<0.01). The endothelium removal induced a significant increase in CC compared with their control values (+37%, p<0.01, and +25%, p<0.01, respectively, in WKY and SHR). CC measured after endothelium removal did not significantly differ from its values measured after potassium cyanide poisoning in normotensive animals. In contrast, in hypertensive animals, CC was significantly lower after endothelium removal than after potassium cyanide poisoning (p<0.01). In the presence of intact endothelium, local incubation with converting enzyme inhibitor increased CC by 23% (p<0.05) in WKY rats and by 14% (p<0.01) in SHR. In contrast, after endothelium removal, converting enzyme inhibitors did not significantly increase further CC in either strain. The present results suggest that the mechanical properties of the wall of the carotid artery are endothelium dependent. The relative constricting role of the endothelium seems to be more predominant in normotensive than in genetically hypertensive rats. The vascular converting enzyme seems to be involved in the endothelium dependent wall properties because endothelium removal and local application of converting enzyme inhibitors had similar effects on CC. (Circulation Research 1990;66:321-328