title: Activation of vascular p38MAPK by mechanical stretch is independent of c-Src and NADPH oxidase: influence of hypertension and angiotensin II.
abstract: Little is known about vascular MAPK regulation in response to mechanical strain. Whether mechanically-sensitive pathways are altered in hypertension is unclear. We examined effects of stretch and Ang II on activation of p38MAPK in vascular smooth muscle cells (VSMC) from WKY and SHR. The role of c-Src and redox-sensitive pathways in stretch-induced effects were examined. VSMC from mesenteric arteries were plated onto flexible silastic plates and exposed to acute or chronic cyclic stretch (10%, 1 Hz) with or without Ang II (0.1 uM). Acute stretch stimulated p38MAPK activation in WKY and SHR, independently of c-Src and reactive oxygen species (ROS), since PP2 (c-Src inhibitor) and apocynin (NADPH oxidase inhibitor), failed to alter stretch-mediated p38MAPK. Chronic stretch blunted p38MAPK phosphorylation in WKY and increased phosphorylation in SHR. Stretch, in the presence of Ang II, induced an increase in procollagen-1 expression. This was blocked by SB203580 (p38MAPK inhibitor). Accordingly, vascular p38MAPK is a mechano-sensitive MAPK, differentially regulated by acute and chronic stretch in WKY and SHR. Functionally, stretch and Ang II, amplify profibrotic responses in a p38MAPK-dependent manner, responses that are perturbed in SHR. Such molecular process may influence vascular fibrosis in hypertension and appear to be independent of c-Src and ROS.
authors.affiliation: Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Tamara M
authors.initials: TM
authors.lastname: Paravicini
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Montezano
authors.forename: Hiba
authors.initials: H
authors.lastname: Yusuf
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009097:Multienzyme Complexes / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D015398:Signal Transduction; D013314:Stress, Mechanical; D014655:Vascular Resistance / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019061:src-Family Kinases
chemical_list: D009097:Multienzyme Complexes; D000804:Angiotensin II; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases