Mechanical activation of the angiotensin II type 1 receptor contributes to abdominal aortic aneurysm formation.

objectiveThe angiotensin II type 1 receptor (AT1R) can be activated under conditions of mechanical stretch in some cellular systems. Whether this activity influences signaling within the abdominal aorta to promote to abdominal aortic aneurysm (AAA) development remains unknown. We evaluated the hypothesis that mechanical AT1R activation can occur under conditions of hypertension (HTN) and contribute to AAA formation.

methodsBPH/2 mice, which demonstrate spontaneous neurogenic, low-renin HTN, and normotensive BPN/3 mice underwent AAA induction via the calcium chloride model, with or without an osmotic minipump delivering 30 mg/kg/d of the AT1R blocker Losartan. Systolic blood pressure (SBP) was measured at baseline and weekly via a tail cuff. The aortic diameter (AoD) was measured at baseline and terminal surgery at 21 days by digital microscopy. Aortic tissue was harvested for immunoblotting (phosphorylated extracellular signal-regulated kinase-1 and -2 [pERK1/2] to ERK1/2 ratio) and expressed as the fold-change from the BPN/3 control mice. Aortic vascular smooth muscle cells (VSMCs) underwent stretch with or without Losartan (1 μM) treatment to assess the mechanical stimulation of ERK1/2 activity. Statistical analysis of the blood pressure, AoD, and VSMC ERK1/2 activity was performed using analysis of variance. However, the data distribution was determined to be log-normal (Shapiro-Wilk test) for ERK1/2 activity. Therefore, it was logarithmically transformed before analysis of variance.

resultsAt baseline, the SBP was elevated in the BPH/2 mice relative to the BPN/3 mice (

conclusionsIn BPH/2 mice with spontaneous neurogenic, low-renin HTN, AAA growth was amplified compared with the normotensive control and was effectively attenuated using Losartan. ERK1/2 activity was significantly elevated in the BPH/2 mice and after AAA induction in the normotensive and hypertensive mice but was attenuated by Losartan treatment. These data suggest that AT1R activation contributes to AAA development. Therefore, further investigation into this signaling pathway could establish targets for pharmacotherapeutic engineering to slow AAA growth. (JVS-Vascular Science 2021;2:194-206.). CLINICAL RELEVANCE: Hypertension (HTN) and abdominal aortic aneurysm (AAA) have been epidemiologically linked for decades; however, a biomechanical link has not yet been identified. Using a murine model of spontaneous neurogenic HTN experimentally demonstrated to have low circulating renin, mechanical activation of the angiotensin II type 1 receptor (AT1R) was identified with elevated blood pressure and AAA induction. HTN amplified AAA growth. However, more importantly, blocking the activation of AT1R with the angiotensin receptor blocker Losartan effectively abrogated AAA development. Although inhibiting the production of angiotensin II has previously been unsuccessful in altering AAA growth, the results from the present study suggest that blocking the activation of AT1R through direct ligand binding or mechanical stimulation might alter aortic wall signaling and warrants further investigation.