Vascular ADAM17 (a Disintegrin and Metalloproteinase Domain 17) Is Required for Angiotensin II/β-Aminopropionitrile–Induced Abdominal Aortic Aneurysm

Abstract

Angiotensin II (AngII)-activated epidermal growth factor receptor (EGFR) has been implicated in abdominal aortic aneurysm (AAA) development. In vascular smooth muscle cells (VSMC), AngII activates EGFR via a metalloproteinase, a disintegrin and metallopeptidase domain 17 (ADAM17). We hypothesized that AngII-dependent AAA development would be prevented in mice lacking ADAM17 in VSMCs. To test this concept, control and VSMC ADAM17 deficient mice were co-treated with AngII and a lysyl oxidase inhibitor, β-aminopropionitrile, to induce AAA. We found that 52.4% of control mice did not survive due to aortic rupture. All other surviving control mice developed AAA and demonstrated enhanced expression of ADAM17 in the AAA lesions. In contrast, all AngII and β-aminopropionitrile-treated VSMC ADAM17 deficient mice survived and showed reduction in external/internal diameters (51%/28%, respectively). VSMC ADAM17 deficiency was associated with lack of EGFR activation, interleukin-6 induction, ER/oxidative stress and matrix deposition in the abdominal aorta of treated mice. However, both VSMC ADAM17 deficient and control mice treated with AngII and β-aminopropionitrile developed comparable levels of hypertension. Treatment of C57Bl/6 mice with an ADAM17 inhibitory antibody but not with control IgG also prevented AAA development. In conclusion, VSMC ADAM17 silencing or systemic ADAM17 inhibition appears to protect mice from AAA formation. The mechanism appears to involve suppression of EGFR activation.

Role of Endothelial ADAM17 in Early Vascular Changes Associated with Diabetic Retinopathy

“…For example, previous studies have implicated ADAM17 in the regulation of several substrates involved in the pathogenesis of DR including TNFα, TNFRI/II, IL-6R, p75NTR, and ICAM-1 [9,10,[12][13][14][15][16]. Our data are consistent with previous reports showing that ADAM17 contributes to multiple vascular pathologies [28][29][30]. In particular, studies in brain microvascular endothelial cells demonstrated an important contribution of ADAM17 to vascular barrier impairment in response to hypoxia [32].…”

Factor XII blockade inhibits aortic dilatation in angiotensin II-infused apolipoprotein E-deficient mice

“…Expression of ADAM-17 is elevated in human AAA tissue and its deletion inhibits experimental AAA [28]. Pharmacological inhibition of ADAM-17 or vascular smooth muscle cell deficiency of ADAM-17 attenuates AAA formation and rupture induced by AngII [29]. In the current study, both FXII deficiency and FXIIa neutralisation significantly reduced SRA ADAM-17 activity.…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…Building upon this, deletion of Cav1, which is required for ANG II-induced ADAM17 activation, prevents AAA development in mice (1033). In line with these observations, deletion of VSMC ADAM17 attenuated AAA formation in mice, which is associated with reduction in aortic EGFR activation, oxidative stress, ER stress, and immune cell accumulation (471). An ER stress inhibitor is also effective in preventing ANG II-induced AAA (848).…”

“…ApoEϪ/Ϫ mice overexpressing SMC-specific catalase are also protected from early aortic structural remodeling that underlies AAA development, further highlighting the role of SMC-related ROS production in AAA pathophysiology (635). As described below, VSMC ADAM17-deficient mice are also protected from ANG II-induced AAA, and this was associated with reduced oxidative and ER stress in abdominal aorta (471). VSMC KLF4-deficient mice are also protected from ANG II-dependent AAA development.…”