Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2

Autor: 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
Přispěvatelé: Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Rok vydání: 2018
Předmět:
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
Zdroj: Circulation
Circulation, American Heart Association, 2018, 138 (23), pp.2698-2712. ⟨10.1161/CIRCULATIONAHA.117.033062⟩
Circulation, 138(23), 2698-2712
Circulation, 2018, 138 (23), pp.2698-2712. ⟨10.1161/CIRCULATIONAHA.117.033062⟩
ISSN: 1524-4539
0009-7322
Popis: 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.
Databáze: OpenAIRE