Pro-angiogenic nature of Arteriovenous Malformations associated with Hereditary Hemorrhagic Telangiectasia
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by arteriovenous malformations (AVMs) in major organs. HHT is caused by heterozygous loss-of-function mutations in Transforming Growth Factor-beta (TGF-beta) signaling components activin receptor-like kinase 1 (ACVRL1/ALK1), endoglin (ENG), mothers against decapentaplegic homolog 4 (SMAD4), or Bone Morphogenic protein (BMP9). Current HHT mouse models are generated by homozygous deletion of Alk1, Eng, and Smad4 in endothelial cells (ECs). Retinal AVMs (rAVMs) along with other retinal vascular defects and molecular changes were thoroughly characterized after their formations. However, the critical primary causative phenotypes and molecular changes contributing to rAVMs remain largely unknown. Here, we utilized our novel Smad4-HHT mouse model to characterize the developmental process of rAVMs. Artery dilation and elevated pro-angiogenic genes were determined as potential initiating factors leading to rAVMs, while EC enlargement and increased EC proliferation contributed to the rAVM maturation process. Additionally, we previously demonstrated that Angiopoietin-2 (Ang2) is a direct downstream effector promoting HHT vascular pathologies; pharmacological inhibition of Ang2 prevented and alleviated AVMs and vessel enlargement in a retinal mouse model of Smad4-HHT. However, whether Ang2 inhibition could be utilized universally to treat AVMs and HHT associated vascular defects, and in clinically relevant organs, such as the brain, remained unclear. Therefore, we characterized the cerebrovascular defects in Alk1-, Eng- and Smad4-HHT mouse models. Comparative RNA-seq analyses revealed a common, but unique pro-angiogenic transcriptional program associated with HHT. This included a consistent upregulation of Ang2 and an overall reduction in Ang-Tek signaling. More significantly, Ang2 blockade greatly improved brain vascular pathologies in all HHT models, albeit in different aspects. Transcriptomic profiling further indicated that normalization of angiogenesis and cell migration processes were primarily responsible for the cerebrovascular improvements. Thus, ANG2-targeted therapies may represent a compelling and novel approach to treating AVMs and HHT vascular pathologies.