{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T13:24:21Z","timestamp":1793193861652,"version":"4.5.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"23","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2018,12,4]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Hereditary Hemorrhagic Telangiectasia type 2 (HHT2) is an inherited genetic disorder characterized by vascular malformations and hemorrhage. HHT2 results from\n              <jats:italic>ACVRL1<\/jats:italic>\n              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\n              <jats:italic>ACVRL1<\/jats:italic>\n              haploinsufficiency leads to pathological angiogenesis is unknown.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              We took advantage of\n              <jats:italic>Acvrl1<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              mutant mice that exhibit HHT2 vascular lesions and focused on the neonatal retina and the airway system after\n              <jats:italic>Mycoplasma pulmonis<\/jats:italic>\n              infection, as physiological and pathological models of angiogenesis, respectively. We elucidated underlying disease mechanisms in vitro by generating\n              <jats:italic>Acvrl1<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              <jats:italic>Acvrl1<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              retinas at postnatal day 7 showed excessive angiogenesis and numerous endothelial \u201ctip cells\u201d at the vascular front that displayed migratory defects. Vascular endothelial growth factor receptor 1 (VEGFR1; Flt-1) levels were reduced in\n              <jats:italic>Acvrl1<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              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.\n              <jats:italic>Acvrl1<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              embryonic stem cell lines recapitulated the vascular anomalies in\n              <jats:italic>Acvrl1<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              (HHT2) mice. Genetic insertion of either the membrane or soluble form of VEGFR1 into the ROSA26 locus of\n              <jats:italic>Acvrl1<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              embryonic stem cell lines prevented the vascular anomalies, suggesting that high VEGFR2 activity in\n              <jats:italic>Acvrl1<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              endothelial cells induces HHT2 vascular anomalies. To confirm our hypothesis,\n              <jats:italic>Acvrl1<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              mice were infected by\n              <jats:italic>Mycoplasma pulmonis<\/jats:italic>\n              to induce sustained airway inflammation. Infected\n              <jats:italic>Acvrl1<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              tracheas showed excessive angiogenesis with the formation of multiple telangiectases, vascular defects that were prevented by VEGFR2 blocking antibodies.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.117.033062","type":"journal-article","created":{"date-parts":[[2018,12,3]],"date-time":"2018-12-03T19:00:50Z","timestamp":1543863650000},"page":"2698-2712","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":39,"title":["Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2"],"prefix":"10.1161","volume":"138","author":[{"given":"J\u00e9r\u00e9my H.","family":"Thalgott","sequence":"first","affiliation":[{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, The Netherlands (J.H.T., G.G., H.C.d.B., T.J.R., K.R., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Dos-Santos-Luis","sequence":"additional","affiliation":[{"name":"CNRS UMR 7241, INSERM U1050, Coll\u00e8ge de France, Paris (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)."},{"name":"MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna E.","family":"Hosman","sequence":"additional","affiliation":[{"name":"St. Antonius Hospital, Nieuwegein, The Netherlands (A.E.H., S.K., R.J.S., F.D., J.J.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Martin","sequence":"additional","affiliation":[{"name":"CNRS UMR 7241, INSERM U1050, Coll\u00e8ge de France, Paris (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)."},{"name":"MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"No\u00ebl","family":"Lamand\u00e9","sequence":"additional","affiliation":[{"name":"CNRS UMR 7241, INSERM U1050, Coll\u00e8ge de France, Paris (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)."},{"name":"MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Bracquart","sequence":"additional","affiliation":[{"name":"CNRS UMR 7241, INSERM U1050, Coll\u00e8ge de France, Paris (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)."},{"name":"MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samly","family":"Srun","sequence":"additional","affiliation":[{"name":"CNRS UMR 7241, INSERM U1050, Coll\u00e8ge de France, Paris (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)."},{"name":"MEMOLIFE Laboratory of Excellence and PSL Research University, Paris, France (D.D.-S.-L., S.M., N.L., D.B., S.S., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Galaris","sequence":"additional","affiliation":[{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, The Netherlands (J.H.T., G.G., H.C.d.B., T.J.R., K.R., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hetty C.","family":"de Boer","sequence":"additional","affiliation":[{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, The Netherlands (J.H.T., G.G., H.C.d.B., T.J.R., K.R., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Tual-Chalot","sequence":"additional","affiliation":[{"name":"Institute of Genetic Medicine, Centre of Life, Newcastle University, United Kingdom (S.T.-C., H.M.A., )."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Kroon","sequence":"additional","affiliation":[{"name":"St. Antonius Hospital, Nieuwegein, The Netherlands (A.E.H., S.K., R.J.S., F.D., J.J.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen M.","family":"Arthur","sequence":"additional","affiliation":[{"name":"Institute of Genetic Medicine, Centre of Life, Newcastle University, United Kingdom (S.T.-C., H.M.A., )."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihai","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and cell Biology, Karolinska Institute, Stockholm, Sweden (Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Repke J.","family":"Snijder","sequence":"additional","affiliation":[{"name":"St. Antonius Hospital, Nieuwegein, The Netherlands (A.E.H., S.K., R.J.S., F.D., J.J.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans","family":"Disch","sequence":"additional","affiliation":[{"name":"St. Antonius Hospital, Nieuwegein, The Netherlands (A.E.H., S.K., R.J.S., F.D., J.J.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes J.","family":"Mager","sequence":"additional","affiliation":[{"name":"St. Antonius Hospital, Nieuwegein, The Netherlands (A.E.H., S.K., R.J.S., F.D., J.J.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ton J.","family":"Rabelink","sequence":"additional","affiliation":[{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, The Netherlands (J.H.T., G.G., H.C.d.B., T.J.R., K.R., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine L.","family":"Mummery","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Embryology, 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