Aortic Remodeling After Transverse Aortic Constriction in Mice Is Attenuated With AT ₁ Receptor Blockade

Abstract

Objective Although hypertension is the most common risk factor for thoracic aortic diseases, it is not understood how increased pressures on the ascending aorta lead to aortic aneurysms. We investigated the role of Ang II type 1 (AT1) receptor activation in ascending aortic remodeling in response to increased biomechanical forces using a transverse aortic constriction (TAC) mouse model. Approach and Results Two weeks after TAC, the increased biomechanical pressures led to ascending aortic dilatation, aortic wall thickening and medial hypertrophy. Significant adventitial hyperplasia and inflammatory responses in TAC ascending aortas were accompanied by increased adventitial collagen, elevated inflammatory and proliferative markers, and increased cell density due to accumulation of myofibroblasts and macrophages. Treatment with losartan significantly blocked TAC induced vascular inflammation and macrophage accumulation. However, losartan only partially prevented TAC induced adventitial hyperplasia, collagen accumulation and ascending aortic dilatation. Increased Tgfb2 expression and phosphorylated-Smad2 staining in the medial layer of TAC ascending aortas was effectively blocked with losartan. In contrast, the increased Tgfb1 expression and adventitial phospho-Smad2 staining were only partially attenuated by losartan. In addition, losartan significantly blocked Erk activation and ROS production in the TAC ascending aorta. Conclusions Inhibition of the AT1 receptor using losartan significantly attenuated the vascular remodeling associated with TAC but did not completely block the increased TGF- β1 expression, adventitial Smad2 signaling and collagen accumulation. These results help to delineate the aortic TGF-β signaling that is dependent and independent of the AT1 receptor after TAC.

FOXE3 mutations predispose to thoracic aortic aneurysms and dissections

“…TAC also induces an inflammatory reaction characterized by increased expression of matrix metalloproteinases (Mmp2, Mmp9) and inflammatory mediators (Il6) and infiltration of macrophages in the adventitia (20). Induction of Mmp2, Mmp9, and Il6 expression as well as adventitial macrophage infiltration (positively stained anti-MOMA2 or anti-Mac2 cells) after TAC were significantly attenuated in Foxe3 -/-aortae (Supplemental Figure 4, A and B; P < 0.01).…”

“…Written informed consent was received from all participants prior gradient that was more than 5-to 10-fold higher by Doppler, indicating successful transverse constriction, were used for the studies (39). High-resolution ultrasound was performed with a Vevo 770 imaging system using a 40-MHz 704 probe (VisualSonics) as described previously (20). All scanning and analysis were performed by an experienced ultrasound technician who was blinded to the mouse genotype.…”

“…TAC induces thickening of the media and adventitia of the ascending aortic wall in WT mice (20), but the Foxe3 -/-aortae showed significantly less thickening, with reduced medial and adventitial areas, compared with WT aortae 2 weeks after TAC (P < 0.05; Figure 5F and Supplemental Figure 3C). TAC also induces an inflammatory reaction characterized by increased expression of matrix metalloproteinases (Mmp2, Mmp9) and inflammatory mediators (Il6) and infiltration of macrophages in the adventitia (20).…”

“…To determine whether Foxe3 -/-aortae were more sensitive to risk factors for aortic disease, we used the established model of transverse aortic constriction (TAC) to increase biomechanical force on the ascending aorta (19,20). After TAC, Foxe3 expression was significantly induced in WT mice, and immunostaining detected FOXE3 protein in the nuclei of medial cells in the ascending aorta ( Figure 5, A and B).…”

“…-/-and WT mice by staff at the Mouse Phenotype Core Laboratory at the Baylor College of Medicine using a standard surgical protocol (20). Studies were performed 2 weeks after TAC, prior to the maladaptive cardiac failure that is associated with TAC (38).…”