NRSA Fellowship for Chen: Mechanisms of Renin Angiotensin Modulation in Thoracic Aortic Aneurysms

Thoracic aortic aneurysms (TAAs) are a common, clinically silent dilatation of the aorta. Although the majority of afflicted individuals are asymptomatic, complications - such as aortic dissection and rupture - are sudden and deadly. In mice, chronic angiotensinII (AngII) infusion induces TAAs independently of increased blood pressure. Preclinical studies demonstrated efficacy of losartan - an angiotensin receptor blocker (ARB) - in treating Marfan Syndrome associated TAA, inspiring several clinical trials utilizing renin angioteinsin system (RAS) modulation as treatment. Altogether, these data suggest that RAS modulation ablates TAA in Marfans mice in an AT1aR dependent manner, but it is not known if AT1aR is necessary for TAA formation. Consequently, AT1aR inhibition through AngII depletion may or may not be sufficient to prevent Marfans associated TAA. In addition, it is unknown if these paradigms hold true for spontaneous TAAD in humans. This proposal will explore these paradoxes to determine the role of the renin angiotensin system in Marfan-associated thoracic aortic aneurysms.