2 Hypertension May 2018 acknowledged in VSMCs, whether it has any significance in vascular pathophysiology linked to angiotensin II had not been studied. Recently, our group was able to demonstrate the critical roles the cascade play in angiotensin II–induced hypertensive cardiovascular remodeling. On 2-week angiotensin II infusion in mice, activation of EGFR is mainly observed in coronary arteries in the cardiac section. Erlotinib is a clinically used selective EGF receptor kinase inhibitor. Treatment with erlotinib markedly attenuated vascular EGFR activation, vascular medial hypertrophy, and perivascular fibrosis induced by angiotensin II infusion, whereas angiotensin II–induced hypertension was unaltered. Interestingly, angiotensin II–induced cardiac hypertrophy was also prevented by the EGFR inhibitor. 32 These data suggest that vascular EGFR transactivation mediate cardiovascular remodeling induced by angiotensin II independently of hypertension. In addition, erlotinib prevented development of abdominal aortic aneurysm induced by cotreatment of angiotensin II and a lysyl oxidase inhibitor, β-aminopropionitrile. 33 Others also demonstrated that in EGFR-inactivated mutant mice, angiotensin II–induced cerebral arteriolar hypertrophy but not hypertension was attenuated. 34 In smooth muscle–targeted and inducible EGFR silencing mice, vascular hypertrophy and fibrosis induced by angiotensin II infusion were also attenuated, and development of hypertension was partially inhibited. However, angiotensin II–induced cardiac hypertrophy was not prevented. 35 Taken together, these data suggest that EGFR transactivation is critical for angiotensin II–mediated cardiovascular complications and that distinct cell types including VSMC and cardiac myocytes may be involved in the EGFR-dependent pathophysiology. In vitro studies have demonstrated that a metalloprotease, ADAM17 (a disintegrin and metalloprotease 17), mediates angiotensin II–induced EGFR transactivation via generation of mature form of heparin-binding EGF-like growth factor. 36, 37

AT1 receptor activates ADAM17 via Tyr702 phosphorylation through unidentified kinase. 38 Src family kinase is the potential candidate because it phosphorylates and activates ADAM17 in response to mechanical stretch in rat myoblasts. 39 In addition, several Ser/Thr kinases are implicated in ADAM17 activation in other cell systems. 40 We have used SM22α (smooth muscle 22 α)-mediated conditional ADAM17-knockout mice to ask what role VSMC ADAM17 plays in hypertension and associated cardiovascular remodeling induced by angiotensin II. Compared with wild-type littermate control mice, vascular hypertrophy, perivascular fibrosis, and cardiac hypertrophy but not hypertension induced by angiotensin II infusion were blunted in the ADAM17-silenced mice. The phenotype is associated with inhibition of vascular EGFR activation. Systemic ADAM17 inhibition by neutralizing antibody also attenuated angiotensin II–induced cardiovascular remodeling but not hypertension in wild-type mice. 41 In addition, development of abdominal aortic aneurysm induced by angiotensin II plus β-aminopropionitrile was also blunted in VSMC ADAM17-silenced mice or wildtype mice treated with ADAM17 antibody. 42 Although SM22αmediated ADAM17 knockdown could partially reduce cardiac myocyte ADAM17 expression, 41 others have reported that angiotensin II–induced cardiac hypertrophy was not altered in cardiomyocyte-targeted ADAM17-silenced mice. 43 These data further support the concept that the VSMC ADAM17/EGFR transactivation mainly mediates cardiovascular pathology including …