Hereditary Hemorrhagic Telangiectasia: A Model to Probe the Biology of the Vascular Endothelium

A decade ago, it was recognized that mutations in the ENDOGLIN ( ENG ) (1) and ACTIVIN RECEPTOR-LIKE KINASE 1 ( ACVRL1 ) (2) genes cause an autosomal dominant disorder known as hereditary hemorrhagic telangiectasia (HHT) type 1 and type 2, respectively. The predominant expression of the corresponding proteins, endoglin and ALK1, on vascular endothelial cells (ECs) and their function as transforming growth factor (TGF)-β receptors indicated that HHT is likely associated with perturbations in TGF-β signaling in ECs. Mice heterozygous for either gene develop HHT (3–6), and can be used to gain insight into the mechanisms of disease, highlighting the role of TGF-β in maintaining vascular integrity and unraveling the potential contribution of other pathways to HHT pathogenesis. Mice totally deficient in either endoglin (3–5) or ALK1 (6) do not survive past midgestation, and their analysis has revealed an essential role for these receptors in vascular development. This chapter provides an overview of HHT as a disorder of the vascular endothelium associated with the generation of abnormal structures such as telangiectases and arteriovenous malformations (AVMs), and discusses the current model of HHT pathogenesis. HISTORICAL PERSPECTIVES Over a century ago, HHT was recognized by the French physician Rendu as a syndrome associating cutaneous telangiectases with recurrent epistaxis (nosebleeds) (7).Following more specific clinical accounts of such manifestations by Osler (8) and the recognition of their familial nature by Weber (9), the new clinical entity was referred to as the Rendu-Osler-Weber syndrome. While the term hereditary hemorrhagic telangiectasia was introduced by Hanes in 1909 and is currently preferred, the early eponym is still used to designate this disorder.