This multi-PI R01 proposal is built upon an ongoing collaboration between two PIs with related but distinct sets of expertise. Hashimoto has expertise in the translational research of intracranial aneurysm. Eguchi is an expert in the renin-angiotensin system (RAS) in cardiovascular diseases. Combining two sets of expertise, we will study the mechanisms for the development of intracranial aneurysm rupture. Hypertension is considered a risk factor for the rupture of intracranial aneurysm (i.e., aneurysmal subarachnoid hemorrhage). However, a mechanism by which hypertension promotes aneurysmal rupture is unclear. There may be common signaling pathways that mediate both aneurysmal rupture and hypertensive- vascular remodeling that leads to end-organ damage. Efficacy of anti-hypertensive treatment for the prevention of aneurysmal rupture has not been established in humans. As simple reduction of blood pressure does not completely reverse end-organ damage associated with hypertension, the prevention of aneurysmal rupture may require pharmacological therapies that target down-stream events triggered by hypertension. Local production of angiotensin II (AngII) in the vascular wall is emerging as a key mechanism for the promotion of vascular inflammation, excessive remodeling, and end-organ damages that are associated with hypertension. Clinical studies suggest a potential link between the local RAS and the rupture of intracranial aneurysms. Hashimoto has shown the increased AngII levels in the aneurysmal walls of a mouse model of intracranial aneurysm. Moreover, the pharmacological blockade of local AngII prevented aneurysmal rupture. Eguchi has shown that the activation of ADAM17 by AngII leads to the activation of epidermal growth factor receptor (EGFR) in vascular smooth muscle cells. Our collaborative papers have shown that the activation of ADAM17 and EGFR leads to pathological vascular remodeling through the induction of ER stress. Based on these findings, we propose that the activation of ADAM17 by the local AngII leads to EGFR activation and TNFa production, both of which increase ER stress and promote aneurysm rupture. We also propose that there is a signaling loop composed of the feed-forward and feed-back signaling pathways that involve ADAM17 and ER stress. This signaling loop causes the sustained inflammation and wall damage that leads to aneurysmal rupture.
Aim 1 is to test whether the activation of ADAM17 promotes aneurysmal rupture through the activation of EGFR, production of TNFa, and subsequent induction of ER stress.
Aim 2 is to test whether the EGFR activation leads to aneurysmal rupture through induction of ER stress.
Aim 3 is to test whether there is a signaling loop composed of ADAM17 activation, activation of EGFR / TNFa, and ER stress. The proposed studies will establish EGFR trans-activation and TNFa production following ADAM17 activation as key pathways that promote ER stress and subsequent aneurysm rupture. Molecular steps within the pathways represent potential therapeutic targets for the prevention of aneurysm rupture.
We will study a novel mechanism for the development of intracranial aneurysm rupture. We propose that the activation of a protease, ADAM17, by a local hormone, angiotensin II, leads to the activation of growth factor receptor and the production of a cytokine, TNFa, promoting aneurysm rupture. Molecular steps within these pathways represent potential therapeutic targets for the prevention of aneurysm rupture.
