The paradoxical TGF-β vasculopathies

Abstract

Two new studies show that haploinsufficiency for TGFB2 causes a familial syndrome of thoracic aortic aneurysms and dissections with other clinical features that overlap the Marfan, Loeys-Dietz spectrum of syndromes. Their finding of loss-of-function mutations in yet another transforming growth factor (TGF)-β pathway gene reinforces the seeming paradox of observed increases in the downstream TGF-β signaling pathway.

Figure 1

Canonical and non-canonical TGF-β signaling pathways. This diagram shows possible routes of SMAD2 phosphorylation (pSMAD2) independent of the SMAD kinase activity of TβRI, including by TRAF6-TAK1-p38 (yellow), through Alk4 kinase activated by activin and/or myostatin (blue), by direct phosphorylation by AT1 (orange) or through excessive autocrine production of the paralogous ligand TGF-β1 (purple). Molecules in red type (fibrillin, TGF-β2, TβRII, TβRI and SMAD3) are altered by mutation in MLD syndromes. Note that TGF-β1 and Ang II are stress-response proteins, and both are known inducers of fibrosis that are reciprocally activated by each other^,. pSMAD3, phosphorylated SMAD3.