Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases

Abstract

ABSTRACTOBJECTIVEHereditary aortic diseases (hADs) increase the risk of aortic dissections and ruptures. Recently, we have established an objective approach to measure the rupture force of the murine aorta, thereby explaining the outcomes of clinical studies and assessing the added value of approved drugs in vascular Ehlers-Danlos syndrome (vEDS). Here, we applied our approach to six additional mouse hAD models.APPROACH AND RESULTWe used two mouse models of Marfan syndrome (MFS) as well as one smooth-muscle-cell-specific knockout (SMKO) ofEfemp2and three CRISPR/Cas9-engineered knock-in models (Ltbp1,Mfap4, andTimp1). One of the two MFS models was subjected to 4-week-long losartan treatment. Per mouse, three rings of the thoracic aorta were prepared, mounted on a tissue puller, and uniaxially stretched until rupture. The aortic rupture force of the SMKO and both MFS models was significantly lower compared with wild-type mice but in both MFS models higher than in mice modeling vEDS. In contrast, theLtbp1,Mfap4, andTimp1knock-in models presented no impaired aortic integrity. As expected, losartan treatment reduced aneurysm formation but surprisingly had no impact on the aortic rupture force of our MFS mice.CONCLUSIONSOur read-out system can characterize the aortic biomechanical integrity of mice modeling not only vEDS but also related hADs, allowing the aortic-rupture-force- focused comparison of mouse models. Furthermore, aneurysm progression alone may not be a sufficient read-out for aortic rupture, as antihypertensive drugs reducing aortic dilatation might not strengthen the weakened aortic wall. Our results may enable identification of improved medical therapies of hADs.HighlightsAssay to measure the aortic rupture force as read-out for the biomechanical integrity identified weakened murine thoracic aorta prior to micro- and macroscopic changes inFbn1+/C1041Gmice.Despite reducing aneurysm growth, losartan treatment did not have any impact on the aortic rupture force ofFbn1mgR/mgRmice modeling MFS.Smooth-muscle-cell-knock-out ofEfemp2significantly impaired the rupture force of the murine ascending aorta.Aortic rupture force measurements could clarify the causality of novel candidate gene(s)/variant(s) in mouse models of aortic diseases.Graphical Abstract