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Pathogenesis of Pulmonary Arterial Hypertension: Clues from Patients and Animal Models of Hereditary Hemorrhagic Telangiectasia

Mourad Toporsian

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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 01.04.2013

Presentation Type: Scientific Sessions

Learning Objectives:

  • Describe the clinical signs and symptoms of Hereditary Hemorrhagic Telangiectasia (HHT) and the genes mutated in this disease
  • Recall that some HHT patients can present with PAH and define how HHT and PAH share common defects in genes and signaling pathways
  • Discuss how changes in Endoglin and Alk-1-dependent cell signaling can spontaneously cause PAH in mice
  • Discuss potential therapeutic targets in the treatment of PAH

Hereditary hemorrhagic telangiectasia (HHT) is a vascular disease characterized by multiple focal telangiectases and arteriovenous malformations (AVMs) in the pulmonary, hepatic and cerebral microcirculations. Mutations in the Endoglin (ENG) and Activin-like kinase-1 receptor (ACVLR1, Alk1) genes leading to haploinsufficiency are the underlying causes of HHT type 1 and HHT type 2, respectively. Despite the very different kinds of pulmonary manifestations, recent findings indicate that individuals harboring mutations in ENG or ACVRL1, can present withpulmonary arterial hypertension (PAH) and/or HHT, suggesting that these diseases share defects in common or related signaling pathways.

TGF-β/BMP signaling and endothelial nitric oxide (NO•) synthase (eNOS) activity are critical determinants of normal endothelial function and survival, which is perturbed in PAH patients and in many animal models of this disease. We have found that Endoglin (Eng), links certain TGF-β/BMP receptors to the eNOS activation complex, and that adult Eng+/- and Alk1+/- mice spontaneously develop signs of PAH due to increased pulmonary endothelial oxidative stress and reduced NO• bioavailability. Recently, we have identified novel factors that can regulate the level/activity of endoglin and its associated signaling pathways irrespective of inborn mutations in TGF-β/BMPreceptors. Interestingly, some of these factors are elevated in sera of humans with PAH. Some of these factors may represent novel biomarkers of disease and potential therapeutic targets in the onset and progression of PAH.