Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II.
The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage seem to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by disintegrin and metalloproteinase domain 17 (ADAM17), and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with erlotinib as well as 4-phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation, and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells were also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension.
From the Department of Physiology, Cardiovascular Research Center (T. Takayanagi, T.K., S.J.F., T.O., T. Tsuji, Y.F., K.J.E., J.-Y.P., S.E.) and Department of Pharmacology, Center for Translational Medicine (D.G.T.), Temple University School of Medicine, Philadelphia, PA; Department of Kinesiology, Temple University College of Public Health, Philadelphia, PA (S.J.F., J.-Y.P.); and Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY (R.L.D.).
Takehiko
T
Takayanagi
From the Department of Physiology, Cardiovascular Research Center (T. Takayanagi, T.K., S.J.F., T.O., T. Tsuji, Y.F., K.J.E., J.-Y.P., S.E.) and Department of Pharmacology, Center for Translational Medicine (D.G.T.), Temple University School of Medicine, Philadelphia, PA; Department of Kinesiology, Temple University College of Public Health, Philadelphia, PA (S.J.F., J.-Y.P.); and Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY (R.L.D.).
Tatsuo
T
Kawai
From the Department of Physiology, Cardiovascular Research Center (T. Takayanagi, T.K., S.J.F., T.O., T. Tsuji, Y.F., K.J.E., J.-Y.P., S.E.) and Department of Pharmacology, Center for Translational Medicine (D.G.T.), Temple University School of Medicine, Philadelphia, PA; Department of Kinesiology, Temple University College of Public Health, Philadelphia, PA (S.J.F., J.-Y.P.); and Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY (R.L.D.).
Steven J
SJ
Forrester
From the Department of Physiology, Cardiovascular Research Center (T. Takayanagi, T.K., S.J.F., T.O., T. Tsuji, Y.F., K.J.E., J.-Y.P., S.E.) and Department of Pharmacology, Center for Translational Medicine (D.G.T.), Temple University School of Medicine, Philadelphia, PA; Department of Kinesiology, Temple University College of Public Health, Philadelphia, PA (S.J.F., J.-Y.P.); and Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY (R.L.D.).
Takashi
T
Obama
From the Department of Physiology, Cardiovascular Research Center (T. Takayanagi, T.K., S.J.F., T.O., T. Tsuji, Y.F., K.J.E., J.-Y.P., S.E.) and Department of Pharmacology, Center for Translational Medicine (D.G.T.), Temple University School of Medicine, Philadelphia, PA; Department of Kinesiology, Temple University College of Public Health, Philadelphia, PA (S.J.F., J.-Y.P.); and Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY (R.L.D.).
Toshiyuki
T
Tsuji
From the Department of Physiology, Cardiovascular Research Center (T. Takayanagi, T.K., S.J.F., T.O., T. Tsuji, Y.F., K.J.E., J.-Y.P., S.E.) and Department of Pharmacology, Center for Translational Medicine (D.G.T.), Temple University School of Medicine, Philadelphia, PA; Department of Kinesiology, Temple University College of Public Health, Philadelphia, PA (S.J.F., J.-Y.P.); and Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY (R.L.D.).
Yamato
Y
Fukuda
From the Department of Physiology, Cardiovascular Research Center (T. Takayanagi, T.K., S.J.F., T.O., T. Tsuji, Y.F., K.J.E., J.-Y.P., S.E.) and Department of Pharmacology, Center for Translational Medicine (D.G.T.), Temple University School of Medicine, Philadelphia, PA; Department of Kinesiology, Temple University College of Public Health, Philadelphia, PA (S.J.F., J.-Y.P.); and Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY (R.L.D.).
Katherine J
KJ
Elliott
From the Department of Physiology, Cardiovascular Research Center (T. Takayanagi, T.K., S.J.F., T.O., T. Tsuji, Y.F., K.J.E., J.-Y.P., S.E.) and Department of Pharmacology, Center for Translational Medicine (D.G.T.), Temple University School of Medicine, Philadelphia, PA; Department of Kinesiology, Temple University College of Public Health, Philadelphia, PA (S.J.F., J.-Y.P.); and Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY (R.L.D.).
Douglas G
DG
Tilley
From the Department of Physiology, Cardiovascular Research Center (T. Takayanagi, T.K., S.J.F., T.O., T. Tsuji, Y.F., K.J.E., J.-Y.P., S.E.) and Department of Pharmacology, Center for Translational Medicine (D.G.T.), Temple University School of Medicine, Philadelphia, PA; Department of Kinesiology, Temple University College of Public Health, Philadelphia, PA (S.J.F., J.-Y.P.); and Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY (R.L.D.).
Robin L
RL
Davisson
From the Department of Physiology, Cardiovascular Research Center (T. Takayanagi, T.K., S.J.F., T.O., T. Tsuji, Y.F., K.J.E., J.-Y.P., S.E.) and Department of Pharmacology, Center for Translational Medicine (D.G.T.), Temple University School of Medicine, Philadelphia, PA; Department of Kinesiology, Temple University College of Public Health, Philadelphia, PA (S.J.F., J.-Y.P.); and Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY (R.L.D.).
Joon-Young
JY
Park
From the Department of Physiology, Cardiovascular Research Center (T. Takayanagi, T.K., S.J.F., T.O., T. Tsuji, Y.F., K.J.E., J.-Y.P., S.E.) and Department of Pharmacology, Center for Translational Medicine (D.G.T.), Temple University School of Medicine, Philadelphia, PA; Department of Kinesiology, Temple University College of Public Health, Philadelphia, PA (S.J.F., J.-Y.P.); and Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY (R.L.D.). seguchi@temple.edu.
Satoru
S
Eguchi
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006973:Hypertension / Q000503:physiopathology; D006984:Hypertrophy / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D011897:Random Allocation; D012380:Role; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D066253:Vascular Remodeling / Q000187:drug effects* / Q000502:physiology
D010654:Phenylbutyrates; D011799:Quinazolines; D000804:Angiotensin II; C075773:4-phenylbutyric acid; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
angiotensin II; fibrosis; hypertension; hypertrophy; muscle, smooth, vascular; signal transduction