2009 George E. Brown Memorial Lecture—Marfan Syndrome and Related Disorders: From Molecules to Medicines

Abstract

Our lab studies molecular determinants of vessel wall homeostasis, with particular emphasis on molecules and pathways that contribute to aortic aneurysm. The study of Marfan syndrome (MFS), an autosomal dominant condition with a strong predisposition for aortic root aneurysm and dissection, has provided a tractable means to gain a foothold in the pathogenesis of this complex phenotype. Our initial studies demonstrated that MFS is caused by mutations in the extracellular matrix protein fibrillin-1. Early pathogenetic models that singularly invoked inherent weakness of the tissues as the driving force in disease progression boded poorly for the development of productive treatment strategies and failed to reconcile multiple disease manifestations, including bone overgrowth, myxomatous valve changes, and muscle and fat hypoplasia. Using mouse models of MFS, we demonstrated that fibrillin-1 is not simply a structural protein but rather regulates the local bioavailability and activation of the growth factor transforming growth factor (TGF) β . Many important manifestations of MFS, including emphysema, valve degeneration, myopathy, and aortic aneurysm, could be attenuated or prevented in fibrillin-1–deficient mice upon systemic administration of TGF β antagonists. Similar protection was achieved through the use of the angiotensin II type 1 receptor blocker (ARB) losartan, which lowers both blood pressure and TGF β signaling and is in widespread clinical use for the treatment of hypertension. These observations led to the first clinical trial for MFS that is based upon a refined mechanistic understanding of disease. We now have performed comprehensive interrogation of a modifier network in mouse models of MFS. These data reveal parsing of the angiotensin II signaling cascades in the pathogenesis and prevention of aortic aneurysm. Signaling through the type 2 (AT2) receptor is protective, whereas loss of AT2 signaling accelerates disease and attenuates the protection afforded by ARBs, suggesting that losartan provides protection, at least in part, through shunting of angiotensin II signaling through AT2. We also demonstrate a predominant role of noncanonical TGF β signaling in the pathogenesis of ascending aortic aneurysm and show that the mechanism of AT2-mediated protection derives from cross-talk with this pathway. Taken together, these data explain why ARBs markedly outperform angiotensin-converting enzyme inhibitors in our mouse model of MFS. They also define noncanonical TGF β and AT2 signaling as prognostic and therapeutic modifiers of vascular disease and provide rationale and incentive for additional clinical trials in MFS and related disorders.