Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome

Abstract

Marfan syndrome (MFS) is a multi-system connective tissue disorder that results from mutations to the gene that codes the elastin-associated glycoprotein fibrillin-1. Although elastic fibers are compromised throughout the arterial tree, the most severe phenotype manifests in the ascending aorta. By comparing biaxial mechanics of the ascending and descending thoracic aorta in a mouse model of MFS, we show that aneurysmal propensity correlates well with both a marked increase in circumferential material stiffness and an increase in intramural shear stress despite a near maintenance of circumferential stress. This finding is corroborated via a comparison of the present results with previously reported findings for both the carotid artery from the same mouse model of MFS and for the thoracic aorta from another model of elastin-associated glycoprotein deficiency that does not predispose to thoracic aortic aneurysms. We submit that the unique biaxial loading of the ascending thoracic aorta conspires with fibrillin-1 deficiency to render this aortic segment vulnerable to aneurysm and rupture.

Comparison of 10 murine models reveals a distinct biomechanical phenotype in thoracic aortic aneurysms

“…In addition to our newly collected biaxial data on Tsc1 f/f þ Tmx, ApoE 2/2 þ HT, Fbln4 SMKO , elastase-exposed and control ascending aortas, we previously reported similar data for five other models [16][17][18]20]: Myh11 R247C/R247C , Myh11 R247C/R247C þ HT, Tgfbr2 f/f þ Tmx, Fbn1 mgR/mgR and Fbln5 2/2 . Collectively, these 10 models represent diverse aortic phenotypes (table 1), ranging from normal (Control) to a stiffer and lengthened aorta without a propensity to form aneurysms (Fbln5 2/2 ), a mild phenotype (Myh11 R247C/R247C ) with little dilatation that is yet vulnerable to dissections when rendered hypertensive (Myh11 R247C/R247C þ HT), a moderate phenotype at young ages with some dilatation that develops aneurysms later in life (Tsc1 f/f þ Tmx), a dissection-prone vessel (Tgfbr2 f/f þ Tmx), a vessel with dramatic dilatation despite wall thickening (ApoE 2/2 þ HT) and ultimately ones with marked aneurysmal development (Fbn1 mgR/mgR and Fbln4 SMKO ).…”

“…Despite data confirming that the smooth muscle myosin heavy chain (MYH11) variant R247C disrupts contraction of aortic smooth muscle cells [13], this variant has minimal effects on gross anatomy (figure 1g), microstructure (figure 1q) and mechanical behaviour (figure 1a-d) of the ascending aorta in the mouse (Myh11 R247C/R247C ). Hypertension induced via a high-salt diet in combination with L-NAME can cause aortic dissections in these mice [16], but the non-dissected samples studied herein after 18 Table 1. Physiological data (mean + s.e.m.)…”

“…Similar analyses were thus carried out for models with induced hypertension (HT), including an apolipoprotein-E null (ApoE 2/2 þ HT; [15]) and the smooth muscle myosin heavy chain variant (Myh11 R247C/R247C þ HT; [16]). The experimental data for the Fbln4 SMKO , Tsc1 f/f þ Tmx and ApoE 2/2 þ HT mice are new, whereas data for the other four models were collected previously using the same methods [16][17][18]. For purposes of further comparison, we also include data from four different groups of controls ( pooled into Control; [19]) and new data for acute elastase-exposure to otherwise normal ascending aorta (Elastase).…”

Losartan Attenuates Degradation of Aorta and Lung Tissue Micromechanics in a Mouse Model of Severe Marfan Syndrome

“…However, Bellini et al recently reported differences in biaxial mechanical properties of the ascending versus descending thoracic aorta that are consistent with a propensity for aneurysms to form in the ascending segment. 5 Further studies are required to assess regional variations in vascular mechanics with losartan treatment.…”

Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models

“…Recent biomechanical analyses of Fbn1 mgR/mgR mice have raised the possibility that a structurally impaired aortic matrix may perturb AT1R mechanosignaling (72, 73). Characterization of cardiomyopathy in Fbn1 mgR/mgR mice has in dependently supported this notion (74).…”