Captopril treatment during development alleviates mechanically induced aortic remodeling in newborn elastin knockout mice

Abstract

Deposition of elastin and collagen in the aorta correlate with increases in blood pressure and flow during development, suggesting that the aorta adjusts its mechanical properties in response to hemodynamic stresses. Elastin knockout (Eln −/− ) mice have high blood pressure, pathological remodeling of the aorta, and die soon after birth. We hypothesized that decreasing blood pressure in Eln −/− mice during development may reduce hemodynamic stresses and alleviate pathological remodeling of the aorta. We treated Eln +/+ and Eln −/− mice with the anti-hypertensive medication captopril throughout embryonic development and then evaluated left ventricular (LV) pressure and aortic remodeling at birth. We found that captopril treatment decreased Eln −/− LV pressure to values near Eln +/+ mice and alleviated the wall thickening and changes in mechanical behavior observed in untreated Eln −/− aorta. The changes in thickness and mechanical behavior in captopriltreated Eln −/− aorta were not due to alterations in measured elastin or collagen amounts, but may have been caused by alterations in smooth muscle cell (SMC) properties. We used a constitutive model to understand how changes in stress contributions of each wall component could explain the observed changes in composite mechanical behavior. Our modeling results show that alterations in the collagen natural configuration and SMC properties in the absence of elastin may explain untreated Eln −/− aortic behavior and that partial rescue of the SMC properties may account for captopril-treated Eln −/− aortic behavior.

Multiparametric MRI identifies subtle adaptations for demarcation of disease transition in murine aortic valve stenosis

“…Again, the restrictions caused by pixel size and partial volume effects lead to a systematic overassessment as compared to histology [ 56 ]. Nevertheless, our results were quite robust for the individual groups investigated and the magnitude of the observed increase in wall thickness (~ 30%) is in the same order as in histologic examinations of a hypertensive mouse model with pathological remodelling of the aorta [ 28 ]. Furthermore, also circumferential strains derived from those measures were in pretty good agreement with a previous reference study on morphometry and strain distribution of the C57BL/6 mouse aorta by ultrasound [ 18 ].…”

Influence of shape-memory stent grafts on local aortic compliance

“…However, we show in (Concannon et al 2020) that in the native aorta exhibits an area change between 15 and 65% from the start of systole to the end of systole. Other studies report similar levels of in vivo area change during a cardiac cycle (Sonesson et al 1994;Sugitani et al 2012;Ferruzzi and Humphrey 2013;Kim et al 2019) providing substantial evidence that clinicians cannot be certain that a 10% oversized device will maintain contact with the aortic wall throughout the entire cardiac cycle. Further uncertainty is introduced through the routine use of non-cardiac-gated imaging modalities for preoperative planning and device sizing, in that it is not known whether the pre-intervention imaging of the vessel shows the configuration at diastole or at peak systole, or at an unknown intermediate lumen pressure.…”

Developmental origins of mechanical homeostasis in the aorta

“…Given the importance of elastic fiber development in the aorta, others have appropriately used genetically modified mice (eg, Eln −/− , Eln +/− , Fbn1 −/− , Fbn1 +/− , and Fbln5 −/− ) and gestational pharmacological treatments to examine developmental consequences of particular structural contributors and defects. 10,[39][40][41][42] Again, such information is vitally important, but we focused on the natural history of geometric, compositional, and biomechanical metrics in normal thoracic aorta. Understanding normalcy is a critical first step toward understanding disease.…”