Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs such as lungs, liver, and brain. Mutations in ENG (endoglin), ACVRL1 (ALK1), and MADH4 (Smad4) genes account for over 95% of HHT. Localized telangiectases and AVMs are present in different organs, with frequencies which differ among affected individuals. By itself, HHT gene heterozygosity does not account for the focal nature and varying presentation of the vascular lesions leading to the hypothesis of a "second-hit" that triggers the lesions. Accumulating research has identified a variety of triggers that may synergize with HHT gene heterozygosity to generate the vascular lesions. Among the postulated second-hits are: mechanical trauma, light, inflammation, vascular injury, angiogenic stimuli, shear stress, modifier genes, and somatic mutations in the wildtype HHT gene allele. The aim of this review is to summarize these triggers, as well as the functional mechanisms involved.

Keywords: ALK1; Smad4; angiogenesis; arteriovenous malformation (AVM); cell adhesion; endoglin; hereditary hemorrhagic telangiectasia (HHT), second-hit; inflammation; shear stress; somatic mutation; transforming growth factor beta (TGF-β); vascular endothelial growth factor (VEGF); vascular injury.

Figure 1

Hereditary hemorrhagic telangiectasia (HHT) and the transforming growth factor beta (TGF-β) signaling pathway in endothelial cells. Heterodimers of bone morphogenetic protein 9 (BMP9) and BMP10, among other members of the TGF-β family, bind to an endothelial cell surface receptor complex composed by the type I (R-I) receptor named ALK1 and the type II (R-II; BMPR2, ActR2A, ActR2B) receptor, both serine/threonine kinases, as well as the auxiliary receptor endoglin. The heterodimeric association between different R-I and R-II determines the specificity of the ligand signaling. Upon ligand binding, the R-II transphosphorylates ALK1, which subsequently propagates the signal by phosphorylating the receptor-regulated Smad (R-Smad) family of proteins, Smad1/5/8. Once phosphorylated (P-), R-Smads form heteromeric complexes with a cooperating homologue named Smad4 and translocate into the nucleus, where they regulate the transcriptional activity of different target genes, in turn modulating endothelial cell function. The involvement of other components of the TGF-β pathway has been omitted for simplification [32]. BMP9, Endoglin, ALK1, and Smad4 proteins are encoded by GDF2, ENG, ACVRL1, and MADH4 genes, whose pathogenic mutations give rise to HHT5, HHT1, HHT2, and JPHT, respectively. BMP, bone morphogenetic protein; GTM, general transcription machinery. Adapted from Ruiz-Llorente et al. [34].

Figure 2

Hypothetical second-hit model in hereditary hemorrhagic telangiectasia (HHT). The germline heterozygous mutation in the HHT gene leads to a monoallelic loss of the encoded HHT protein in endothelial cells (First-hit). A subsequent environmental stimulus like inflammation, hypoxia, neoangiogenesis, vascular injury, radiation, shear stress, or trauma (environmental second-hit; E2H), can induce the expression/activation of mediators, which generate a microenvironment where HHT protein levels are below the needed functional threshold. This drop in the HHT functional protein can also be generated by a somatic mutation in the normal allele (genetic second-hit; G2H), leading to a focal protein loss in lesions. One possible cause of somatic mutation is sunlight radiation, especially in skin telangiectases. A somatic mutation could also synergize with an environmental third-hit (E3H). Modifier genes (G2H) could also contribute to focal vascular lesions by affecting HHT protein level and activity. In all cases, the result is an impaired endothelial cell function, leading to the generation of telangiectases or arteriovenous malformations (AVMs).