Abstract
Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibition attenuates the progression of pre-established AAA and potential implications. Pharmacological Notch inhibitor (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester; DAPT) was administered subcutaneously three times a week starting at day 28 of angiotensin II (AngII) infusion. Progressive increase in pulse wave velocity (PWV), maximal intra-luminal diameter (MILD) and maximal external aortic diameter (MEAD) were observed at day 56 of the AngII. DAPT prevented such increase in MILD, PWV and MEAD (P < 0.01). Histologically, the aortae of DAPT-treated Apoe−/− mice had significant reduction in inflammatory response and elastin fragmentation. Naked collagen microfibrils and weaker banded structure observed in the aortae of Apoe−/− mice in response to AngII, were substantially diminished by DAPT. A significant decrease in the proteolytic activity in the aneurysmal tissues and vascular smooth muscle cells (vSMCs) was observed with DAPT (P < 0.01). In human and mouse AAA tissues, increased immunoreactivity of activated Notch signaling correlated strongly with CD38 expression (R2 = 0.61). Collectively, we propose inhibition of Notch signaling as a potential therapeutic target for AAA progression.
Highlights
Abdominal aortic aneurysm (AAA) is a localized dilation of the abdominal aorta exceeding the normal diameter (~20 mm) by 1.5 times (≥30 mm)[1]
We demonstrate that Notch inhibition stabilizes pre-established AAA and increases the factors of stability in an experimental model of angiotensin II (AngII)-induced AAA via a CD38 signaling dependent mechanism
Transabdominal ultrasound imaging showed a significant increase in the maximal intra-luminal diameter (MILD) (1.59 ± 0.34 vs. 0.90 ± 0.03 mm, P < 0.001), pulse wave velocity (PWV) (1.50 ± 0.28 vs. 0.93 ± 0.04 m/s, P < 0.001), and a decrease in distensibility (74.2 ± 18.8 vs. 103.7 ± 9.99 1/MPa, P < 0.001) and radial strain (24.9 ± 7.89 vs. 53.1 ± 4.2%, P < 0.001) in the Apoe−/− mice in response to AngII than controls at day 28 (Supplementary Fig. 2 and data not shown)
Summary
Abdominal aortic aneurysm (AAA) is a localized dilation of the abdominal aorta exceeding the normal diameter (~20 mm) by 1.5 times (≥30 mm)[1]. Progression of AAA is accompanied by differentiation of vSMC into a synthetic phenotype in the medial layer, their apoptotic cell death and perpetual expansion of adventitial layer[10,11]. These pathways have emphasized the contribution of aortic vSMCs to aortic wall stiffness via phenotypic changes and extracellular matrix (ECM) dysregulation[12,13]. We demonstrate that Notch inhibition stabilizes pre-established AAA and increases the factors of stability in an experimental model of AngII-induced AAA via a CD38 signaling dependent mechanism
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