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

OBJECTIVE: The 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. METHODS: BPH/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. RESULTS: At baseline, the SBP was elevated in the BPH/2 mice relative to the BPN/3 mice (P < .05). Losartan treatment significantly reduced the SBP in both mouse strains (P < .05). AAA induction did not affect the SBP. At 21 days after induction, the percentage of increase in the AoD from baseline was significantly greater in the BPH/2 mice than in the BPN/3 mice (101.28% ± 4.19% vs 75.59% ± 1.67% above baseline; P < .05). Losartan treatment significantly attenuated AAA growth in both BPH/2 and BPN/3 mice (33.88% ± 2.97% and 43.96% ± 3.05% above baseline, respectively; P < .05). ERK1/2 activity was increased approximately fivefold in the BPH/2 control mice relative to the BPN/3 control mice (P < .05). In the BPH/2 and BPN/3 mice with AAA, ERK1/2 activity was significantly increased relative to the respective baseline control (P < .05) and effectively reduced by concomitant Losartan therapy (P < .05). Biaxial stretch of the VSMCs in the absence of angiotensin II demonstrated increased ERK1/2 activation (P < .05 vs static control), which was significantly inhibited by Losartan. CONCLUSIONS: In 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.

Lipid Keratopathy: A Review of Pathophysiology, Differential Diagnosis, and Management.

Lipid keratopathy is a disease in which fat deposits accumulate in the cornea, leading to opacification and decrease of visual acuity. This condition can be idiopathic without signs of previous corneal disease or secondary to ocular or systemic diseases. Lipid keratopathy is usually associated with abnormal vascularization of the cornea, and the lipid classically deposits adjacent to these vessels. Treatment of this condition usually aims to eliminate or prevent abnormal vessel formation, and several modalities have been described. In this review we summarize the etiology, pathophysiology, and clinical presentation of lipid keratopathy and describe current and emerging treatment regimens.

Collagenolytic Activity Is Associated with Scar Resolution in Zebrafish Hearts after Cryoinjury.

Myocardial infarction is the major cause of cardiac injury in western countries and can result in a massive loss of heart cells, leading eventually to heart failure. A fibrotic collagen-rich scar may prevent ventricular wall rupture, but also may result in heart failure because of its stiffness. In zebrafish, cardiac cryoinjury triggers a fibrotic response and scarring. Unlike with mammals, zebrafish heart has the striking ability to regenerate and to resolve the scar. Thus, understanding the mechanisms of scar resolution in zebrafish heart might facilitate the design of new therapeutic approaches to improve the recovery of patients. To visualize the collagenolytic activity within the zebrafish heart following cryoinjury, we used an in situ collagen zymography assay. We detected expression of mmp2 and mmp14a and these matrix metalloproteinases might contribute to the collagenase activity. Collagenolytic activity was present in the wound area, but decreased as the myocardium regenerated. Comparison with neonatal mouse hearts that failed to regenerate after transmural cryoinjury revealed a similar collagenolytic activity in the scar. These findings suggest that collagenolytic activity may be key to how the zebrafish heart resolves its scar; however, it is not sufficient in mouse hearts that lack efficient myocardial regeneration.