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.