Src tyrosine kinases and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases mediate pressure-induced c-fos expression in cannulated rat mesenteric small arteries

Chronic hypertension is associated with remodeling of small arteries. There is evidence that the high pressure itself may cause these structural chang es, but the responsible mechanisms are: not clearly defined. Previously we showed that pressure-induced c-fos expression in intact cannulated rat mese nteric small arteries was inhibited by genistein, a general tyrosine kinase inhibitor. The purpose of this study was to further unravel the underlying signal transduction mechanisms, and we particularly tested the involvement of src tyrosine kinases and extracellular signal-regulated kinase (ERK). R at mesenteric small arteries were cannulated in a dual-vessel chamber. Afte r a 60-minute equilibration period, the pressure in I artery was increased to 140 mm Hg, while the other artery remained at 90 mm Hg. Semiquantitative reverse transcriptase-polymerase chain reaction was used to determine c-fo s expression, and Western blotting was used to examine levels of ERK phosph orylation, The involvement of src and ERK was tested with the inhibitors he rbimycin A (1 mu mol/L), PPI (10 mu mol/L), PP2 (10 mu mol/L), and PD98059 (30 mu mol/L). One-hour exposure to 140 mm Hg increased the c-fos/cyclophil in ratio 3.6-fold, from 0.29+/-0.07 to 1.06+/-0.25. All the tested inhibito rs suppressed the pressure-induced increase of c-fos expression. A 5-minute exposure period to 140 mm HE increased ERK phosphorylation, and this was a bolished in the presence of PPI. The results suggest that pressure-induced c-fos expression in intact cannulated rat mesenteric small arteries may be mediated, at least in part, by src tyrosine kinases and ERK.