Genetic and molecular pathogenesis of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by vascular dysplasia and hemorrhage. The pathogenesis regarding heterogeneity of vascular malformations in patients with HHT has been obscure, although it has become possible to partially explain the pathogenesis from the identification of two distinct genes, endoglin and ALK-1. Endoglin and ALK-1 are type III and type I TGF-beta receptors, respectively, and are exclusively expressed on vascular endothelial cells. Binding of TGF-beta to the type II TGF-beta receptor on endothelial cells, which is accelerated in the presence of endoglin, phosphorylates type I TGF-beta receptors, ALK-5 and ALK-1, and phosphorylated ALK-5 and ALK-1 activate the downstream proteins Smad2/3 and Smad1/5, respectively. These activated Smad proteins dissociate from the type I TGF-beta receptor, bind to Smad4, and enter the nucleus to transmit TGF-beta signaling by regulating transcription from specific gene promoters involved in angiogenesis. Therefore, a balance between these two signaling pathways via ALK-5 and ALK-1 plays an important role in determining the properties of endothelial cells during angiogenesis. Mutations of endoglin and ALK-1 genes are genetic pathogenesis of HHT type 1 and HHT type 2, respectively. To date, at least 29 and 17 different kinds of mutations in endoglin and ALK-1, respectively, have been found, including missense, nonsense, frameshift, and deletion mutations. The precise mechanisms of vascular abnormalities elicited by these mutations observed in HHT patients are still uncertain, although elucidation of the mechanism of intracellular signal transduction and the change in targeted gene expressions using mutant recombinant endoglin or ALK-1 proteins and knockout mice will enable us to understand the genetic and molecular pathogenesis of HHT and to effectively treat patients with HHT.