Aortic aneurysms are an important cause of mortality in the western world. Monogenic disorders such as the
Marfan syndrome (MFS) are good genetic models for the pathogenesis of
aortic aneurysm. In the MFS, progressive dilatation of the aortic root leads to
aortic aneurysm and dissection, often associated with precocious death. Early pathogenetic models for MFS focused upon structural weakness of the tissues imposed by microfibrillar deficiency. However, recent studies of transgenic mouse models have challenged this model and demonstrated a central role for the upregulation of the
TGFbeta signaling pathway. The discovery of a new
aortic aneurysm syndrome, the
Loeys-Dietz syndrome (LDS), confirmed the importance of the
cytokine TGFbeta in
aneurysm pathogenesis. The main distinguishing features between LDS and MFS include the presence of
hypertelorism,
cleft palate/bifid uvula and arterial tortuosity. LDS is caused by mutations in the genes encoding the receptors for
TGFbeta (
TGFBR1/2). This insight helped to elucidate the pathogenesis of another rare autosomal recessive connective tissue disorder, arterial tortuosity syndrome. This disease is caused by mutations in the SLC2A10 gene, coding for GLUT10, a member of the
glucose transporter family. In analogy to LDS, we demonstrated an upregulation of
TGFbeta in ATS. Finally, all these insights have also lead to new therapeutic insights. In transgenic mouse models it was shown that
losartan, an
angiotensin II type 1 receptor with known inhibiting effects on
TGFbeta, rescues the aortic phenotype. If these promising results are confirmed in human trials,
losartan might have beneficial effects in the treatment of more common nonhereditary
aortic aneurysms.