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Comparative Study
. 2015 Jun;65(6):1349-55.
doi: 10.1161/HYPERTENSIONAHA.115.05344. Epub 2015 Apr 27.

Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II

Takehiko Takayanagi  1 , Tatsuo Kawai  1 , Steven J Forrester  1 , Takashi Obama  1 , Toshiyuki Tsuji  1 , Yamato Fukuda  1 , Katherine J Elliott  1 , Douglas G Tilley  1 , Robin L Davisson  1 , Joon-Young Park  1 , Satoru Eguchi  2
Affiliations
Comparative Study

Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II

Takehiko Takayanagi et al. Hypertension. 2015 Jun.

Abstract

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.

Keywords: angiotensin II; fibrosis; hypertension; hypertrophy; muscle, smooth, vascular; signal transduction.

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Figures

Figure 1
Figure 1
Effects of EGFR inhibitor, erlotinib, on cardiovascular remodeling induced by AngII. C57Bl/6 mice were infused with saline (n=8) for 2 weeks, or AngII (1 µg/kg/min) for 2 weeks with (n=8) or without (n=8) treatment of erlotinib (10 mg/kg/day intraperitoneal injection). Hearts and kidneys were stained with Sirius red and aortas were stained with Masson trichrome (Mean±SEM). A: Representative staining (200x) is presented. B: Quantification of medial area to internal arterial area of the coronary and renal arteries, and quantification of perivascular fibrosis area to vascular area of these arteries. C: Quantification of medial thickness of the thoracic aorta. D: Heart weight (HW) body weight (BW) ratio. E: Mean arterial pressure (MAP) was evaluated by telemetry. F: Heart sections were immuno-stained with antibodies as indicated (n=4). Antibodies against KDEL and CHOP were used to assess ER stress. Antibody against nitro-tyrosine (nTyr) was used to assess oxidative stress. *p<0.05 compared with control saline infusion. †p<0.05 compared with AngII infusion.
Figure 2
Figure 2
EGFR inhibitor attenuated induction of ADAM17 and GRP78 in response to AngII in VSMCs. Rat VSMCs were pretreated with or without Erlotinib (1 µmol/L for 30 min) and stimulated with AngII (100 nmol/L) for 18 hours. The cell lysates were analyzed by immunoblotting as indicated (means ± SEM, n=4 in each group). *p<0.05 compared with basal. †p<0.05 compared with AngII stimulation.
Figure 3
Figure 3
Effects of ER stress inhibitor, PBA, on cardiovascular remodeling induced by AngII. C57Bl/6 mice were infused with saline (n=8) for 2 weeks, or AngII for 2 weeks with (n=6) or without (n=8) PBA treatment (1g/kg/day in drinking water). Hearts and kidneys were stained with Sirius red and aortas were stained with Masson trichrome (Mean±SEM). A: Representative staining (200×) is presented. B: Quantification of medial area to internal arterial area of the coronary and renal arteries, and quantification of perivascular fibrosis area to vascular area of these arteries. C: Quantification of medial thickness of the thoracic aorta. D: Heart weight (HW) body weight (BW) ratio. E: Mean arterial pressure (MAP) was evaluated by telemetry. *p<0.05 compared with control saline infusion. †p<0.05 compared with AngII infusion.
Figure 4
Figure 4
Inhibition of ER stress attenuated AngII-induced ADAM17 induction in VSMCs. A. Rat VSMCs were pretreated with or without PBA (1 – 10 mmol/L for 30 min) and were stimulated with AngII (100 nmol/L) for 18 h. The cell lysates were analyzed by immunoblotting as indicated (means ± SEM, n=4 in each group). B. Rat VSMC infected with adenovirus encoding GRP78 or control LacZ (100 moi) were stimulated with AngII (100 nmol/L) for 24 h. The cell lysates were analyzed by immunoblotting as indicated (means ± SEM, n=4 in each group). *p<0.05 compared with basal. †p<0.05 compared with AngII stimulation.
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