Investigating the effects of methyl‐β‐cyclodextrin on aortic function & structure in a mouse model of Marfan syndrome using high frequency ultrasound imaging
Authors: Cameron Eryn L. , Hoxha Brikena , Potter Ross M. , Vallejo‐Elias Johana , Esfandiarei Mitra 
Published: June 2021

Marfan syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the fibrillin‐1 gene leading to various complications in multiple organs. However, aortic aneurysm is considered as the most life‐threatening complications that may lead to aortic dissection, rupture, and sudden death. Previous studies have shown that transforming growth factor β (TGF‐β) and angiotensin II type 1 receptor (ATII/AT1R) signaling play important roles during the progression of MFS aneurysm. Interestingly, both pathways are shown to be regulated by caveolin‐1 (Cav‐1), a structural protein within caveolae, which is highly expressed in vascular smooth muscle and endothelial cells. Studies in Cav‐1 knock‐out mice have reported that Cav‐1 is required for normal ATII/AT1R signalling, while having inhibitory effects on TGF‐β pathway and endothelial nitric oxide (eNOS) activity. Considering the complexity of caveolae and CAV‐1 regulatory functions, we propose to investigate the effects of caveolae (CAV‐1) disruption by the cholesterol depleting agent methyl‐β‐cyclodextrin (MβCD) on the progression of aortic aneurysm in a mouse model of MFS. Four‐week old MFS (Fbn1C1039G/+) and control C57BL/6 mice received intra‐peritoneal injection of MβCD (500 mg/kg) twice a week, and cardiac and aortic structure and function were measured at 3 and 6 months of age using Vevo 2100 high resolution ultra sound imaging system (FUJIFILM VisualSonics). Measurements for aortic annulus, sinus of Valsalva, sinotubular junction diameters, and pulse wave velocity showed an increase in MFS mice at 3 and 6 months of age as compared to control; all these effects were exacerbated in MFS mice treated with MβCD, indicating that disruption of caveolae structure in MFS mice has negative impact on aortic wall structure and function. Furthermore, the dimensions of the left ventricle were also evaluated by the measurements of interventricular septum in systole and diastole. Cardiac function was evaluated measuring the cardiac output, stroke volume, ejection fraction, which showed no difference in MFS and control mice in the presence or absence of MβCD treatment. Early and atrial ventricular filling velocities were decreased in MFS mice at the age of 3 and 6 months as compared to controls. However, MβCD treatment resulted in an increase in both early and atrial velocities in MFS mice. Using the tail‐cuff method we also measured the blood pressure of these animals. The measurements showed higher systolic and diastolic values in control and MFS groups treated with MβCD, confirming that caveolae has an inhibitory effect on eNOS activity in mice. This study provides insights into the role that caveolae may play during the progression of aortic aneurysm in MFS mice, and warrant further investigation into the potential value of CAV‐1 as a therapeutic target in MFS associated aortic aneurysm.Support or Funding InformationThis study is supported by funding from The Marfan Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.