The
transforming growth factor β (TGFβ) superfamily consists of multipotential secreting
cytokines that mediate many key events in normal cellular growth and development, including differentiation, proliferation, motility, organization and death. TGFβs act as
ligand for 3 classes of
cell surface receptors, the transmembrane
serine-threonine kinase receptors, TGFβ receptor type I (TGFβRI) and type 2 (TGFβRII), and TGFβRIII receptors which include an ubiquitous extracellular β-
glycan and the
membrane glycoprotein endoglin (CD105). Binding of TGFβs to their receptors initiates diverse cellular responses resulting in the phosphorilation of
Smad proteins, which then translocate to the nucleus and regulate the transcription of target genes. Perturbation of TGFβ signaling has been implicated in various human disorders including
cancer,
fibrosis and auto-
immune diseases. Recently, mutations in TGFβR1 and TGFβR2 genes have been found in association with a continuum of clinical features with widespread vascular involvement. The extreme of clinical severity is represented by the
Loeys-Dietz syndrome (LDS), an autosomal dominant disorder characterized by
hypertelorism, bifid uvula, and/or
cleft palate, and aggressive arteriopathy causing arterial tortuosity as well as life-threatening complications such as vascular
aneurysms and dissections.
Elastin disarray, loss of elastic fibre architecture and increased
collagen expression in the arterial wall are the pathologic hallmark of LDS. In the present review article we will provide details on the activation of TGFβ cascade, on the clinical features of LDS, as well as on the mechanisms of TGFβ signaling perturbation leading to this condition and the potential role of the antagonism of TGFβ activity in disease management.