Understanding the function of endoglin through the generation and characterization of endoglin deficient mice and the study of patients with hereditary hemorrhagic telangiectasia

grantor: University of TorontoEndoglin, (CD105), an integral membrane glycoprotein, is a member of the TGF-ß receptor superfamily. It is expressed at high levels on vascular endothelium and also found in several human hematopoietic cells. Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder associated with mutations in the 'Endoglin' gene, leading to loss of a functional allele (haploinsufficiency). To define the role of endoglin in normal and pathological blood vessel formation, we first investigated its expression in vascular endothelium of HHT patients. We then generated ' Endoglin' deficient mice and analyzed their vascular and immune systems. The haploinsufficiency model proposed for HHT was first based on ' in vitro' experiments. This thesis further confirms this model. It demonstrates that all blood vessels of HHT1 patients express reduced endoglin ' in situ', and that severe lesions such as arteriovenous malformations (AVMs) are not attributed to loss of heterozygosity. To generate an animal model for BHT and ascertain the role of endoglin in development, we generated mice lacking one and two copies of the gene. We show that 'Endoglin' null embryos die at gestational day 10.0-10.5 due to defects in vessel and heart development suggesting that endoglin is critical for both angiogenesis and heart valve formation. Some mice expressing a single allele of 'Endoglin' spontaneously developed clinical signs of HHT. The analysis of disease onset and progression revealed that clinical manifestations were heterogeneous, leading to severe vascular abnormalities and fatal hemorrhages. Our results demonstrate that the HHT mouse model reproduces well the heterogeneous phenotype of the human disease. The data suggest that in addition to reduced expression of endoglin, modifier genes can contribute to heterogeneity and severity of HHT. As expression of a single allele of 'Endoglin' leads to a vascular disorder, we investigated if it could alter the immune system of ' Endoglin' heterozygous mice. We show that reduced endoglin expression either on vascular endothelium or on subsets of hematopoietic cells leads to alteration of T and B lymphocyte homeostasis.Ph.D