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

Jérémy H. Thalgott, Damien Dos-Santos-Luis, Anna E. Hosman, Sabrina Martin, Noël Lamandé, Diane Bracquart, Samly Srun, Georgios Galaris, Hetty C. de Boer, Simon Tual-Chalot, Steven Kroon, Helen M. Arthur, Yihai Cao, Repke J. Snijder, Frans Disch, Johannes J. Mager, Ton J. Rabelink, Christine L. Mummery, Karine Raymond, Franck Lebrin (Corresponding Author)

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)2698-2712
Number of pages15
JournalCirculation
Volume138
Issue number23
DOIs
Publication statusPublished - 4 Dec 2018
Externally publishedYes

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Vascular Endothelial Growth Factor Receptor-1
Blood Vessels
Mycoplasma pulmonis
Pathologic Neovascularization
Haploinsufficiency
Endothelial Cells
Embryonic Stem Cells
Cell Line
Vascular Endothelial Growth Factor A
Retina
Osler-rendu-weber syndrome 2
Mycoplasma Infections
Telangiectasis
Inborn Genetic Diseases
Vascular Malformations
Blocking Antibodies
Trachea
Alleles
Hemorrhage
Inflammation

Keywords

  • UT-Hybrid-D
  • arteriovenous malformation
  • hereditary hemorrhagic telangiectasia
  • vascular endothelial growth factors
  • angiogenesis, pathological

Cite this

Thalgott, J. H., Dos-Santos-Luis, D., Hosman, A. E., Martin, S., Lamandé, N., Bracquart, D., ... Lebrin, F. (2018). Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2. Circulation, 138(23), 2698-2712. https://doi.org/10.1161/CIRCULATIONAHA.117.033062
Thalgott, Jérémy H. ; Dos-Santos-Luis, Damien ; Hosman, Anna E. ; Martin, Sabrina ; Lamandé, Noël ; Bracquart, Diane ; Srun, Samly ; Galaris, Georgios ; de Boer, Hetty C. ; Tual-Chalot, Simon ; Kroon, Steven ; Arthur, Helen M. ; Cao, Yihai ; Snijder, Repke J. ; Disch, Frans ; Mager, Johannes J. ; Rabelink, Ton J. ; Mummery, Christine L. ; Raymond, Karine ; Lebrin, Franck. / Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2. In: Circulation. 2018 ; Vol. 138, No. 23. pp. 2698-2712.
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title = "Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2",
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.",
keywords = "UT-Hybrid-D, arteriovenous malformation, hereditary hemorrhagic telangiectasia, vascular endothelial growth factors, angiogenesis, pathological",
author = "Thalgott, {J{\'e}r{\'e}my H.} and Damien Dos-Santos-Luis and Hosman, {Anna E.} and Sabrina Martin and No{\"e}l Lamand{\'e} and Diane Bracquart and Samly Srun and Georgios Galaris and {de Boer}, {Hetty C.} and Simon Tual-Chalot and Steven Kroon and Arthur, {Helen M.} and Yihai Cao and Snijder, {Repke J.} and Frans Disch and Mager, {Johannes J.} and Rabelink, {Ton J.} and Mummery, {Christine L.} and Karine Raymond and Franck Lebrin",
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Thalgott, JH, Dos-Santos-Luis, D, Hosman, AE, Martin, S, Lamandé, N, Bracquart, D, Srun, S, Galaris, G, de Boer, HC, Tual-Chalot, S, Kroon, S, Arthur, HM, Cao, Y, Snijder, RJ, Disch, F, Mager, JJ, Rabelink, TJ, Mummery, CL, Raymond, K & Lebrin, F 2018, 'Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2' Circulation, vol. 138, no. 23, pp. 2698-2712. https://doi.org/10.1161/CIRCULATIONAHA.117.033062

Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2. / Thalgott, Jérémy H.; Dos-Santos-Luis, Damien; Hosman, Anna E.; Martin, Sabrina; Lamandé, Noël; Bracquart, Diane; Srun, Samly; Galaris, Georgios; de Boer, Hetty C.; Tual-Chalot, Simon; Kroon, Steven; Arthur, Helen M.; Cao, Yihai; Snijder, Repke J.; Disch, Frans; Mager, Johannes J.; Rabelink, Ton J.; Mummery, Christine L.; Raymond, Karine; Lebrin, Franck (Corresponding Author).

In: Circulation, Vol. 138, No. 23, 04.12.2018, p. 2698-2712.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2

AU - Thalgott, Jérémy H.

AU - Dos-Santos-Luis, Damien

AU - Hosman, Anna E.

AU - Martin, Sabrina

AU - Lamandé, Noël

AU - Bracquart, Diane

AU - Srun, Samly

AU - Galaris, Georgios

AU - de Boer, Hetty C.

AU - Tual-Chalot, Simon

AU - Kroon, Steven

AU - Arthur, Helen M.

AU - Cao, Yihai

AU - Snijder, Repke J.

AU - Disch, Frans

AU - Mager, Johannes J.

AU - Rabelink, Ton J.

AU - Mummery, Christine L.

AU - Raymond, Karine

AU - Lebrin, Franck

N1 - Lippincott WW deal

PY - 2018/12/4

Y1 - 2018/12/4

N2 - 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.

AB - 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.

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KW - arteriovenous malformation

KW - hereditary hemorrhagic telangiectasia

KW - vascular endothelial growth factors

KW - angiogenesis, pathological

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U2 - 10.1161/CIRCULATIONAHA.117.033062

DO - 10.1161/CIRCULATIONAHA.117.033062

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JO - Circulation

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