Implications of Genetic Manipulation of Caveolin‐1 Protein Expression in a Mouse Model of Marfan Syndrome‐Associated Aortic Aneurysm
Authors: Curry Tala , Hoxha Brikena , Johnson Nathan , Broderick Tom L , Vallejo‐Elias Johana , Esfandiarei Mitra 
Published: June 2021

Marfan Syndrome (MFS), a connective tissue disorder, resulting from mutations in the Fibrillin‐1 gene, is associated with several clinical manifestations with the most life‐threatening being aortic aneurysm, dissection, and rupture. The mechanism underlying MFS pathogenesis seems to result from crosstalk between the Angiotensin‐II (AngII) pathway and over activation of transforming growth factor‐beta (TGF‐b) signaling. Studies show that Losartan, an angiotensin II receptor type I (ATRI) blocker, can block progression of aortic aneurysm in mice, partially due to its inhibitory effects on TGF‐b signaling. It has been established that caveolin‐1 (Cav1), a coat protein of caveolae that is highly expressed in endothelial and smooth muscle, regulates AngII and TGF‐β signaling pathways, through its interactions with ATR1 and TGF‐β receptors. Interestingly, Cav1 knockout (Cav1KO) animal models illustrated increased elastin synthesis and nitric oxide (NO) production. Our previous study in the MFS mouse model reported reduced NO production in the aortic wall, proposing a potential link between Cav‐1 activation and aneurysm progression in MFS mice. Hence, in this study, we aimed to investigate the effects of genetic manipulation of Cav1 expression on the progression of aortic aneurysm in a well‐established mouse model of MFS‐associated aortic aneurysm, by generating MFS mice lacking Cav1 expression (MFS/Cav1KO).

In vivo analysis of biophysical properties in 3‐ and 6‐ month old wild type, MFS, Cav1KO, and MFS/Cav1KO mice was performed using Vevo 2100 high‐resolution ultrasound imaging system (FUJIFILM VisualSonics). Aortic diameters at the aortic annulus, sinus of Valsalva, and sinotubular junction were significantly increased in MFS and MFS/CAV1KO mice as compared to control and Cav1KO groups at 3, and 6 months in systole and diastole. Pulse wave velocity (PWV), a reliable indicator of aortic wall stiffness, was significantly increased in MFS as compared to control and Cav1KO mice, with no significant changes observed between MFS and MFS/Cav1KO groups at 3 months of age. Interestingly, at 6 months of age, MFS/Cav1KO mice presented higher values for PWV as compared to MFS groups, indicating that deletion of Cav1 gene in MFS mice may have detrimental effects on aortic wall structure as MFS mice age.

Cardiac parameters were also measured. Our data showed that at 3 months of age, a marked increase in heart rate, ejection fraction, and fractional shortening were detectable in MFS mice as compared to control subjects. Measurements of cardiac output and stroke volume revealed no significant differences among experimental groups. Interestingly, left ventricular mass was significantly greater in MFS/CAV1KO compared to wild type and MFS mice, suggesting that Cav1 plays a protective role in maintaining normal cardiac structure in MFS mice. At this point, our collected data suggest that Cav1 may have some protective effects on aortic and cardiac structure and function during the development of aortic aneurysm in the mouse model of MFS.

Support or Funding Information

This study was funded by The Marfan Foundation (M.E.), and a Midwestern University Graduate Fund (T.C.).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.