Enhanced Responses to Angiogenic Cues Underlie the Pathogenesis of Hereditary Hemorrhagic Telangiectasia 2

<div><p>Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic vascular disease in which arteriovenous malformations (AVMs) manifest in skin and multiple visceral organs. HHT is caused by heterozygous mutations in endoglin (<i>ENG</i>), activin receptor-like kinase 1 (<i>ALK1</i>), or <i>SMAD4</i>. ALK1 regulates angiogenesis, but the precise function of ALK1 in endothelial cells (ECs) remains elusive. Since most blood vessels of HHT patients do not produce pathological vascular lesions, <i>ALK1</i> heterozygous ECs may be normal unless additional genetic or environmental stresses are imposed. To investigate the cellular and biochemical phenotypes of <i>Alk1</i>-null versus <i>Alk1</i>-heterozygous ECs, we have generated pulmonary EC lines in which a genotype switch from the <i>Alk1</i>-conditional allele (<i>Alk1</i>^2f) to the <i>Alk1</i>-null allele (<i>Alk1</i>^1f) can be induced by tamoxifen treatment. <i>Alk1</i>-null (1 f/1 f) ECs displayed increased migratory properties <i>in vitro</i> in response to bFGF compared with <i>Alk1</i>-het (2 f/1 f) ECs. The 1 f/1 f-ECs formed a denser and more persistent tubular network as compared with their parental 2 f/1 f-ECs. Interestingly, the response to BMP-9 on SMAD1/5 phosphorylation was impaired in both 2 f/1 f- and 1 f/1 f-ECs at a comparable manner, suggesting that other factors in addition to SMADs may play a crucial role for enhanced angiogenic activity in 1 f/1 f-ECs. We also demonstrated <i>in vivo</i> that <i>Alk1</i>-deficient ECs exhibited high migratory and invasive properties. Taken together, these data suggest that enhanced responses to angiogenic cues in ALK1-deficient ECs underlie the pathogenesis of HHT2.</p></div