Background: Mutations in endoglin (ENG) and activin receptor-like kinase 1 (ALK-1 or ACVRL1) genes are the underlying basis of hereditary haemorrhagic telangiectasia (HHT) types 1 and 2, respectively. Both genes belong to the transforming growth factor-beta (TGF-beta) receptors superfamily and are expressed in endothelial cells. The current model for HHT is that ENG or ALK-1 haplo-insufficiency affects angiogenesis and predisposes to vascular dysplasia and arteriovenous malformations.
Materials and methods: Using microarray technology, we compared human umbilical vein endothelial cells (HUVEC) from newborns with ENG or ALK-1 mutations to control cells to search for gene profiles associated with early stages of the disease. Real-time polymerase chain reaction and Western blot analysis were used to validate a subset of the modulated genes and functionally related genes.
Results: Our results indicate that HHT endothelial cells in vitro display several gene expression disturbances, including genes associated with the activation phase of angiogenesis, with cell guidance and intercellular connections, and also with the TGF-beta pathway. Hierarchical clustering using modulated genes enables discrimination between affected and non-affected samples.
Conclusion: HHT HUVECs display gene modulations which can suggest that ENG and ALK-1 haplo-insufficiency induces compensatory regulatory mechanisms at the expression levels.