Pressure-induced activation of extracellular signal-regulated kinase 1/2 in small arteries.
Extracellular signal-regulated kinase 1/2 (ERK1/2) may play a central signaling role in vascular remodeling. We investigated a possible combined role for the renin-angiotensin system and platelet-derived growth factor beta-receptor (PDGF-beta-R) in pressure-induced ERK1/2 activation in intact rat mesenteric small arteries. In an organ culture model, vessels were pressurized (70 mm Hg) for 1 hour plus a 5-minute intervention period. The intervention was either a rise in intraluminal pressure (up to 140 mm Hg) or challenge with angiotensin II (Ang II, 0.1 micromol/L) or PDGF-BB (30 microg/L). ERK1/2 activation was determined by Western blotting as formation of phosphorylated ERK1/2. All interventions caused ERK1/2 activation that was inhibited by the MEK inhibitor PD98059. The response to pressure was inhibited by an ACE inhibitor (perindoprilat), an Ang II receptor type 1 (R-AT1) antagonist (candesartan), and tyrosine kinase inhibitors (genistein, herbimycin A). An R-AT2 antagonist (PD123319) had no significant effect. Both a PDGF-receptor tyrosine kinase inhibitor (RPR101511A) and a neutralizing PDGF-beta-R antibody (AF385) inhibited the activation of ERK1/2 caused by PDGF-BB, Ang II, and pressure. That the latter interventions could indeed inhibit the PDGF-beta-R was supported by experiments with unmounted vessels in which PDGF-beta-R activation was measured by Western blot; both PDGF-BB and Ang II-mediated PDGF-beta-R activation were inhibited by RPR101511A and AF385. Immunohistochemistry showed that ERK1/2 and PDGF-beta-R was located in the adventitia, tunica media, and intima. The results suggest that pressure in rat mesenteric small arteries causes acute activation of ERK1/2 through pathways involving Ang II and PDGF-beta-R.
Eskildsen-Helmond
Yvonne E G
YE
Department of Pharmacology, University of Aarhus, University Park 240, DK-8000 Aarhus C, Denmark. ye@farm.au.dk
Mulvany
Michael J
MJ
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D008638:Mesenteric Arteries / Q000033:anatomy & histology / Q000187:drug effects / Q000201:enzymology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D009924:Organ Culture Techniques; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000032:analysis / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology; D013314:Stress, Mechanical; D014655:Vascular Resistance
D004791:Enzyme Inhibitors; D000804:Angiotensin II; D020797:Receptor, Platelet-Derived Growth Factor beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases