Caveolin 1 is critical for abdominal aortic aneurysm formation induced by angiotensin II and inhibition of lysyl oxidase

Abstract

Although angiotensin II (Ang II) and its receptor AT1 have been implicated in abdominal aortic aneurysm (AAA) formation, the proximal signaling events primarily responsible for AAA formation remain uncertain. Caveolae are cholesterol-rich membrane microdomains that serve as a signaling platform to facilitate the temporal and spatial localization of signal transduction events including those stimulated by Ang II. Caveolin-1 (Cav1) enriched caveolae in vascular smooth muscle cells mediate ADAM17-dependent epidermal growth factor receptor (EGFR) transactivation, which is linked to vascular remodeling induced by Ang II. Here, we have tested our hypothesis that Cav1 plays a critical role for development of AAA at least in part via its specific alteration of Ang II signaling within caveolae. Cav1−/− mice and the control wild-type mice were co-infused with Ang II and β-aminopropionitrile to induce AAA. We found that Cav1−/− mice with the co-infusion did not develop AAA compared to control mice in spite of hypertension. We found an increased expression of ADAM17 and enhanced phosphorylation of EGFR in AAA. These events were markedly attenuated in Cav1−/− aortae with the co-infusion. Furthermore, Cav1−/− mice aortae with the co-infusion showed less endoplasmic reticulum stress, oxidative stress and inflammatory responses compared to aortae from control mice. Cav1 silencing in cultured vascular smooth muscle cells prevented Ang II-induced ADAM17 induction and activation. In conclusion, Cav1 appears to play a critical role in the formation of AAA and associated endoplasmic reticulum/oxidative stress presumably through the regulation of caveolae compartmentalized signals induced by Ang II.

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

“…While BAPN treatment alone does not promote AAA, it causes AAA development and rupture when combined with AngII via degeneration of elastic lamina 12 . In VSMCs, both ADAM17 and EGFR co-localize at caveolae, and AAA formation induced by AngII plus BAPN was attenuated in caveolin-1 deficient mice 13 . Moreover, we have recently reported that pharmacological inhibition of EGFR prevents AAA development induced by AngII plus BAPN, which was associated with suppression of ER stress, oxidative stress, and interleukin-6 and MMP-2 expression 10 .…”

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

“…Overexpression of caveolin-1 (Cav1), the major structural protein of caveolae, prevents ANG II-induced hypertrophy and migration of VSMCs through suppression of HB-EGF shedding, EGFR transactivation, and ERK activation (534). However, Cav1 silencing is also protective against EGFR transactivation, suggesting a tight regulatory component via Cav1/caveolae may be critical for EGFR transactivation (535).…”

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…Nonetheless, caveolin-1 also appears essential in EGFR transactivation: silencing caveolin-1 expression inhibits Ang II-induced EGFR transactivation in vascular tissue (Takayanagi et al, 2014); caveolin-1 deletion inhibits EGFR transactivation by TGF- in hepatocytes, in association with failed TACE/ADAM17 activation (Moreno-Caceres et al, 2014); and caveolin-1 deletion or caveolar disruption abolishes stretch-dependent EGFR transactivation and Akt signalling in mesangial cells (Zhang et al, 2007). Caveolin-1 may thus act to limit EGFR activity in the basal state whilst promoting EGFR transactivation.…”