TARGETING ENDOTHELIAL DYSFUNCTION IN A GENETIC MOUSE MODEL OF AORTIC ANEURYSM: IMPLICATIONS FOR PREVENTION AND THERAPY - PROJECT SUMMARY
Marfan syndrome is caused by fibrillin-1 mutations and results in aortic root dilation, dissection or rupture and
death at around 35-45 years of age in absence of medical treatment and/or surgical intervention. Current
guidelines for the prophylactic treatment of aortic root enlargement rely on two medications: β-blocker Atenolol,
a cardio-selective hypotensive agent, and the more recent angiotensin II receptor type 1(ATR1) blocker (ARB)
Losartan, which reduces blood pressure with a unique anti-transforming growth factor (TGF-β) effect.
However, their mode of action and effects on aortic root enlargement are controversial. A large-scale clinical
trial has failed to reproduce the expected superiority of Losartan over Atenolol, which suggests that our
comprehension of MFS pathogenesis and patient management approaches is incomplete, and that better and
more effective options should be explored. Our research team recently reported that hypotensive MFS animals
develop aortic root enlargement identically to normotensive animals, which suggests that lowering of blood
pressure might not be the primary mechanism of action of MFS-associated medications, a concept that warrant
further investigations. Also, we have been able to show that Losartan blocks aortic root enlargement in MFS
animals lacking normal angiotensin receptor ATR1 expression, indicating an off-target effect. Our findings also
indicate that Losartan inhibition of MFS aortic root enlargement is entirely mediated via increased endothelial
function. This concept is further supported by our recent published animal data showing that chronic activation
of endothelial function by mild aerobic exercise also attenuates MFS aortic root enlargement. Therefore, we
hypothesize that optimal improvements in endothelial function using clinically relevant approaches
will attenuate MFS-associated aortic root enlargement, leading to MFS aortic root stability. To test this
hypothesis, three Specific Aims are proposed:
Aim #1: To confirm that mild aerobic exercise or combination of exercise and Losartan can confer aortic root
protection in MFS mice in an eNOS-dependent manner.
Aim #2: To identify an ARB superior to Losartan in terms of increasing endothelial function, correcting aortic
signaling and preventing MFS aortic root widening.
Aim #3: To determine whether other clinically-relevant non-ARB medications that are known to increase
endothelial function can block aortic root dilation in an eNOS-dependent fashion.
To address the aims, we utilize pharmacological (available patient-ready drugs) and genetic (by generating
new transgenic mouse models) approaches to manipulate endothelial function by increasing the activity of
endothelial nitric oxide synthase (eNOS) in the aortic tissue in MFS mice. The ultimate goal is to explore more
effective therapies that lead to better clinical outcomes in terms of aortic root remodeling and aneurysm
progression in MFS or other related vascular complications.
