The Pathogenic Transforming Growth Factor-β Overdrive Hypothesis in Aortic Aneurysms and Dissections: A Mirage?

Abstract

For >10 years ago, an unexpected role for the transforming growth factor-β cytokine pathway has been put forward in driving thoracic aortic aneurysms and dissections. Here, we reassess the evidence for a detrimental transforming growth factor-β overdrive in thoracic aortic aneurysms and dissections. In our view, most of the available mechanistic data argue against this theory. Syndromic thoracic aortic aneurysms and dissections (TAADs) develop in patients with connective tissue disorders because of genetic mutations that affect structural components of the extracellular matrix and the cell contractile machinery. Early pathogenic hypotheses attributed the aortopathy to structural failure of the aortic tissue. Over 14 years ago, Neptune et al,1 Habashi et al,2 and Lindsay and Dietz3 proposed a novel hypothesis to explain how fibrillin-1 ( FBN1 ) mutations in Marfan syndrome (MFS) lead to pulmonary emphysema and aortic aneurysm and pointed to increased transforming growth factor-β (TGFβ) activation as the culprit mechanism. This constituted a major paradigm shift, and a new hope emerged that the life-threatening manifestations of MFS might be prevented by a simple medical treatment, losartan, shown to prevent the disease in mice through its TGFβ-antagonizing properties.2 In 2010, we serendipitously discovered that TGFβ neutralization in mice treated with AngII (angiotensin II) unexpectedly induced fatal aortic dissections.4 Despite differences in the mouse models, the critical vasculoprotective role of TGFβ in our experiments highly contrasted with the reported pathogenic role of TGFβ in MFS and Loeys–Dietz syndrome (LDS), leading us to question the validity of the previous assumptions. Moreover, recent clinical testing of the concept in MFS patients failed to show any benefit of losartan over placebo or β-blockade.5 Thus, the time has come for a reassessment of the scientific evidence that supports a causal role for increased TGFβ signaling in TAADs. ### Marfan Syndrome The paradigm stipulates that FBN1 …