Aldosterone and Angiotensin II Synergistically Stimulate Migration in Vascular Smooth Muscle Cells Through c-Src–Regulated Redox-Sensitive RhoA Pathways

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 28; no. 8; pp. 1511 - 1518
• Main Authors: Montezano, A C, Callera, G E, Yogi, A, He, Y, Tostes, R C, He, G, Schiffrin, E L, Touyz, R M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.08.2008; Hagerstown, MD Lippincott
• Subjects: Aldosterone - physiology; Angiotensin II - physiology; Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cell Movement - physiology; Cells, Cultured; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fundamental and applied biological sciences. Psychology; Male; Medical sciences; Muscle, Smooth, Vascular - physiology; Myocytes, Smooth Muscle - physiology; Rats; rhoA GTP-Binding Protein - physiology; Signal Transduction - physiology; src-Family Kinases - physiology; Vertebrates: cardiovascular system; Steroid hormone; Mineralocorticoid; Peptide hormone; Smooth muscle; Cardiovascular disease; Aldosterone; Synergism; Rho A; Vascular disease; Octapeptide; Renin angiotensin system; c-Src; Adrenal hormone; Atherosclerosis; Angiotensin II
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.108.168021

OBJECTIVE—Synergistic interactions between aldosterone (Aldo) and angiotensin II (Ang II) have been implicated in vascular inflammation, fibrosis, and remodeling. Molecular mechanisms underlying this are unclear. We tested the hypothesis that c-Src activation, through receptor tyrosine kinase transactivation, is critically involved in synergistic interactions between Aldo and Ang II and that it is upstream of promigratory signaling pathways in vascular smooth muscle cells (VSMCs). METHODS AND RESULTS—VSMCs from WKY rats were studied. At low concentrations (10 mol/L) Aldo and Ang II alone did not influence c-Src activation, whereas in combination they rapidly increased phosphorylation (P<0.01), an effect blocked by eplerenone (Aldo receptor antagonist) and irbesartan (AT1R blocker). This synergism was attenuated by AG1478 and AG1296 (inhibitors of EGFR and PDGFR, respectively), but not by AG1024 (IGFR inhibitor). Aldo and Ang II costimulation induced c-Src–dependent activation of NAD(P)H oxidase and c-Src–independent activation of ERK1/2 (P<0.05), without effect on ERK5, p38MAPK, or JNK. Aldo/Ang II synergistically activated RhoA/Rho kinase and VSMC migration, effects blocked by PP2, apocynin, and fasudil, inhibitors of c-Src, NADPH oxidase, and Rho kinase, respectively. CONCLUSIONS—Aldo/Ang II synergistically activate c-Src, an immediate signaling response, through EGFR and PDGFR, but not IGFR transactivation. This is associated with activation of redox-regulated RhoA/Rho kinase, which controls VSMC migration. Although Aldo and Ang II interact to stimulate ERK1/2, such effects are c-Src–independent. These findings indicate differential signaling in Aldo-Ang II crosstalk and highlight the importance of c-Src in redox-sensitive RhoA, but not ERK1/2 signaling. Blockade of Aldo/Ang II may be therapeutically useful in vascular remodeling associated with abnormal VSMC migration.