Vascular signal as a therapeutic target for abdominal aortic aneurysm

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 DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) is a significant cause of mortality for adults aged >60 years. No established pharmacological treatment is currently available to prevent AAA advancement and/or rupture. Accumulating evidence suggests critical roles for the renin angiotensin aldosterone system (RAAS) in AAA formation. While several downstream signals and target proteins of AT1 receptor have been identified, there is a huge void in our knowledge regarding the proximal signaling events primarily responsible for AAA. Unfortunately, efficacies of the AngII blockers for human AAA appear to be limited. It is likely that the critical AAA promoting signal inducible upon AT1 stimulation is shard by many other AAA-promoting risk factors, such as by aldosterone (Aldo), indicating that an AngII blocker alone is insufficient as a treatment. Thus, we propose to determine alternative therapeutic targets for AAA in the AngII signal transduction pathway shared with other risk factors. We recently reported that caveolae membrane microdomains in vascular smooth muscle cells (VSMC) mediate a metalloprotease ADAM17-dependent EGFR transactivation, which is linked to vascular remodeling induced by AngII. Our preliminary data showed complete failure of AngII to induce AAA in mice lacking VSMC ADAM17 suggesting that ADAM17 is a potential target to prevent AAA. EGFR activation, ER stress and oxidative stress associated with AAA formation were also attenuated in VSMC ADAM17 deficient mice. Moreover, loss or inhibition of ADAM17 associated signaling elements (knockout of the caveolae structural protein, caveolin-1 or treatment with EGFR inhibitor) prevented AngII-dependent AAA as well as ER/oxidative stress. Enhanced ADAM17 expression and EGFR activation were also confirmed in human AAA. While EGFR transactivation appears critical for Aldo/mineralocorticoid receptor (MR) signal transduction in VSMC, whether the VSMC caveolae ADAM17/EGFR axis is critical for Aldo-mediated AAA is unclear. Here, we have developed the following 2 Aims to answer our key hypotheses. Aim 1. To investigate the contribution and mechanism of VSMC ADAM17 and EGFR in AAA. Hypothesis: VSMC ADAM17 is essential for AAA development and/or rupture through induction of ER stress and subsequent AAA associated genes/proteins via the novel feed forward loop of ADAM17/EGFR activation. Aim 2. To investigate the VSMC Cav1 mechanism and its consequence for the mouse models of AAA. Hypothesis: VSMC Cav1 silencing prevents ER stress and subsequent AAA formation and/or rupture through prevention of vascular ADAM17 activation by BMX. To accomplish these 2 Aims, 3 different AAA models will be used with mice lacking VSMC ADAM17, EGFR or Cav1. For an AngII- or Aldo-dependent AAA model, the mice will be infused with AngII plus BAPN, a lysyl oxidase inhibitor or treated with DOCA salt plus BAPN, respectively. For a RAAS-independent AAA model, the mouse abdominal aorta will be treated with CaCl2 plus PBS. In addition, this RAAS-independent AAA model and cultured VSMC will be used together with adenovirus encoding miRNA-embedded siRNA targeting ADAM17, EGFR, Cav1 or BMX. Accomplishment of this proposal will explore the novel feed-forward loop mechanism initiated by vascular caveolae compartmentalized signaling molecules as a potential therapeutic target for reducing AAA development.