Role of Epidermal Growth Factor Receptor and Endoplasmic Reticulum Stress in Vascular Remodeling Induced by Angiotensin II

Abstract

The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage appear 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 metalloprotease 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 was 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.

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

“…In line with this, therapies which are known to reduce oxidative stress, such as mineralocorticoid antagonists, or angiotensin-converting enzyme inhibitors, are known to improve vascular stiffness acceleration. 23 One of the key novel mechanisms linking oxidative stress to fibrosis involves small GTPbinding protein dissociation stimulator. Its upregulation by statins results in Rac1 degradation and reduced oxidative stress 24 and may reduce cardiac and possibly vascular fibrosis.…”

Novel Epidermal Growth Factor Receptor Inhibitor Attenuates Angiotensin II-Induced Kidney Fibrosis

“…Ang II injection could increase the blood pressure of mice. However, a recent study demonstrated that treatment with EGFR inhibitor erlotinib attenuated Ang II-induced vascular remodeling and cardiac hypertrophy but not hypertension in mice, indicating that the mechanisms by which Ang II elevates blood pressure and enhances end-organ damage may be distinct (Takayanagi et al, 2015). Another independent group found that Ang II-induced hypertrophy in cerebral arterioles involves EGFR signaling, which is independent of blood pressure (Chan et al, 2015).…”

Deleting Vascular ADAM17 Sheds New Light on Hypertensive Cardiac Hypertrophy

“…In a study that appeared last year in Hypertension, Eguchi's group reported that inhibiting EGFR or endoplasmic reticulum stress attenuated vascular remodeling and cardiac hypertrophy in mice infused with Ang II, without affecting the increase in blood pressure. 1 In the current issue, these investigators extend these observations further by showing that knockout of ADAM17 specifically in vascular smooth muscle cells prevents cardiac hypertrophy, vascular medial hypertrophy, and perivascular fibrosis in mice treated with Ang II, again without affecting the induced hypertension.…”

“…In a study that appeared last year in Hypertension, Eguchi's group reported that inhibiting EGFR or endoplasmic reticulum stress attenuated vascular remodeling and cardiac hypertrophy in mice infused with Ang II, without affecting the increase in blood pressure. 1 In the current issue, these investigators extend these observations further by showing that knockout of ADAM17 specifically in vascular smooth muscle cells prevents cardiac hypertrophy, vascular medial hypertrophy, and perivascular fibrosis in mice treated with Ang II, again without affecting the induced hypertension.2 ADAM17 deficiency also diminished EGFR activation and endoplasmic reticulum stress in the vasculature, and a similar outcome was achieved by treatment of Ang II-infused mice with a human cross-reactive ADAM17 inhibitory antibody ( Figure).These new findings are remarkable for several reasons. First, they provide additional support for the contention that increased blood pressure and adverse cardiovascular remodeling, which contributes to end-organ damage, are independent phenomena that can be targeted separately.…”