1. Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2
- Author
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Franck Lebrin, Simon Tual-Chalot, Helen M. Arthur, Steven Kroon, Frans Disch, Noël Lamandé, Christine L. Mummery, Damien Dos-Santos-Luis, Jérémy H. Thalgott, Johannes J. Mager, Ton J. Rabelink, Repke J. Snijder, Georgios Galaris, Karine Raymond, Anna E Hosman, Yihai Cao, Samly Srun, Sabrina Martin, Hetty C. de Boer, Diane Bracquart, Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
- Subjects
Adult ,Male ,0301 basic medicine ,Heterozygote ,Activin Receptors, Type II ,[SDV]Life Sciences [q-bio] ,arteriovenous malformation ,Neovascularization, Physiologic ,Antibodies ,Mycoplasma pulmonis ,Arteriovenous Malformations ,Pathogenesis ,Mice ,angiogenesis ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Animals ,Humans ,hereditary hemorrhagic telangiectasia ,Medicine ,vascular endothelial growth factors ,Telangiectasia ,Skin ,Vascular Endothelial Growth Factor Receptor-1 ,business.industry ,Genetic disorder ,Retinal Vessels ,Mouse Embryonic Stem Cells ,ACVRL1 ,Arteriovenous malformation ,Middle Aged ,medicine.disease ,Mice, Inbred C57BL ,Platelet Endothelial Cell Adhesion Molecule-1 ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,cardiovascular system ,Cancer research ,Female ,Telangiectasia, Hereditary Hemorrhagic ,pathological ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Haploinsufficiency ,Activin Receptors, Type I ,Signal Transduction - Abstract
Background: Hereditary Hemorrhagic Telangiectasia type 2 (HHT2) is an inherited genetic disorder characterized by vascular malformations and hemorrhage. HHT2 results from ACVRL1 haploinsufficiency, the remaining wild-type allele being unable to contribute sufficient protein to sustain endothelial cell function. Blood vessels function normally but are prone to respond to angiogenic stimuli, leading to the development of telangiectasic lesions that can bleed. How ACVRL1 haploinsufficiency leads to pathological angiogenesis is unknown. Methods: We took advantage of Acvrl1 +/− mutant mice that exhibit HHT2 vascular lesions and focused on the neonatal retina and the airway system after Mycoplasma pulmonis infection, as physiological and pathological models of angiogenesis, respectively. We elucidated underlying disease mechanisms in vitro by generating Acvrl1 +/− mouse embryonic stem cell lines that underwent sprouting angiogenesis and performed genetic complementation experiments. Finally, HHT2 plasma samples and skin biopsies were analyzed to determine whether the mechanisms evident in mice are conserved in humans. Results: Acvrl1 +/− retinas at postnatal day 7 showed excessive angiogenesis and numerous endothelial “tip cells” at the vascular front that displayed migratory defects. Vascular endothelial growth factor receptor 1 (VEGFR1; Flt-1) levels were reduced in Acvrl1 +/− mice and HHT2 patients, suggesting similar mechanisms in humans. In sprouting angiogenesis, VEGFR1 is expressed in stalk cells to inhibit VEGFR2 (Flk-1, KDR) signaling and thus limit tip cell formation. Soluble VEGFR1 (sVEGFR1) is also secreted, creating a VEGF gradient that promotes orientated sprout migration. Acvrl1 +/− embryonic stem cell lines recapitulated the vascular anomalies in Acvrl1 +/− (HHT2) mice. Genetic insertion of either the membrane or soluble form of VEGFR1 into the ROSA26 locus of Acvrl1 +/− embryonic stem cell lines prevented the vascular anomalies, suggesting that high VEGFR2 activity in Acvrl1 +/− endothelial cells induces HHT2 vascular anomalies. To confirm our hypothesis, Acvrl1 +/− mice were infected by Mycoplasma pulmonis to induce sustained airway inflammation. Infected Acvrl1 +/− tracheas showed excessive angiogenesis with the formation of multiple telangiectases, vascular defects that were prevented by VEGFR2 blocking antibodies. Conclusions: Our findings demonstrate a key role of VEGFR1 in HHT2 pathogenesis and provide mechanisms explaining why HHT2 blood vessels respond abnormally to angiogenic signals. This supports the case for using anti-VEGF therapy in HHT2.
- Published
- 2018