Sex differences and risk factors for bleeding in Alagille syndrome
Abstract Spontaneous bleeds are a leading cause of death in the pediatric JAG1‐related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in bleeding events in patients, whether Jag1Ndr/Ndr mice display bleeds or vascular defects, and whether discovered vascular patho...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2022-11-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202215809 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849761805063159808 |
|---|---|
| author | Simona Hankeova Noemi Van Hul Jakub Laznovsky Elisabeth Verboven Katrin Mangold Naomi Hensens Csaba Adori Elvira Verhoef Tomas Zikmund Feven Dawit Michaela Kavkova Jakub Salplachta Marika Sjöqvist Bengt R Johansson Mohamed G Hassan Linda Fredriksson Karsten Baumgärtel Vitezslav Bryja Urban Lendahl Andrew Jheon Florian Alten Kristina Teär Fahnehjelm Björn Fischler Jozef Kaiser Emma R Andersson |
| author_facet | Simona Hankeova Noemi Van Hul Jakub Laznovsky Elisabeth Verboven Katrin Mangold Naomi Hensens Csaba Adori Elvira Verhoef Tomas Zikmund Feven Dawit Michaela Kavkova Jakub Salplachta Marika Sjöqvist Bengt R Johansson Mohamed G Hassan Linda Fredriksson Karsten Baumgärtel Vitezslav Bryja Urban Lendahl Andrew Jheon Florian Alten Kristina Teär Fahnehjelm Björn Fischler Jozef Kaiser Emma R Andersson |
| author_sort | Simona Hankeova |
| collection | DOAJ |
| description | Abstract Spontaneous bleeds are a leading cause of death in the pediatric JAG1‐related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in bleeding events in patients, whether Jag1Ndr/Ndr mice display bleeds or vascular defects, and whether discovered vascular pathology can be confirmed in patients non‐invasively. We performed a systematic review of patients with ALGS and vascular events following PRISMA guidelines, in the context of patient sex, and found significantly more girls than boys reported with spontaneous intracranial hemorrhage. We investigated vascular development, homeostasis, and bleeding in Jag1Ndr/Ndr mice, using retina as a model. Jag1Ndr/Ndr mice displayed sporadic brain bleeds, a thin skull, tortuous blood vessels, sparse arterial smooth muscle cell coverage in multiple organs, which could be aggravated by hypertension, and sex‐specific venous defects. Importantly, we demonstrated that retinographs from patients display similar characteristics with significantly increased vascular tortuosity. In conclusion, there are clinically important sex differences in vascular disease in ALGS, and retinography allows non‐invasive vascular analysis in patients. Finally, Jag1Ndr/Ndr mice represent a new model for vascular compromise in ALGS. |
| format | Article |
| id | doaj-art-06eb0c1933c14c07a0211bd34884636e |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-06eb0c1933c14c07a0211bd34884636e2025-08-20T03:05:54ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-11-01141212310.15252/emmm.202215809Sex differences and risk factors for bleeding in Alagille syndromeSimona Hankeova0Noemi Van Hul1Jakub Laznovsky2Elisabeth Verboven3Katrin Mangold4Naomi Hensens5Csaba Adori6Elvira Verhoef7Tomas Zikmund8Feven Dawit9Michaela Kavkova10Jakub Salplachta11Marika Sjöqvist12Bengt R Johansson13Mohamed G Hassan14Linda Fredriksson15Karsten Baumgärtel16Vitezslav Bryja17Urban Lendahl18Andrew Jheon19Florian Alten20Kristina Teär Fahnehjelm21Björn Fischler22Jozef Kaiser23Emma R Andersson24Department of Cell and Molecular Biology, Karolinska InstitutetDepartment of Cell and Molecular Biology, Karolinska InstitutetCEITEC – Central European Institute of Technology, Brno University of TechnologyDepartment of Cell and Molecular Biology, Karolinska InstitutetDepartment of Cell and Molecular Biology, Karolinska InstitutetDepartment of Cell and Molecular Biology, Karolinska InstitutetDepartment of Neuroscience, Karolinska InstitutetDepartment of Cell and Molecular Biology, Karolinska InstitutetCEITEC – Central European Institute of Technology, Brno University of TechnologyDepartment of Pediatrics, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University HospitalCEITEC – Central European Institute of Technology, Brno University of TechnologyCEITEC – Central European Institute of Technology, Brno University of TechnologyDepartment of Cell and Molecular Biology, Karolinska InstitutetEM Unit, Institute of Biomedicine, University of GothenburgUniversity of San FranciscoDepartment of Medical Biochemistry and Biophysics, Karolinska InstitutetTravere TherapeuticsDepartment of Experimental Biology, Masaryk UniversityDepartment of Cell and Molecular Biology, Karolinska InstitutetUniversity of San FranciscoDepartment of Ophthalmology, University of Muenster Medical CenterDepartment of Pediatric Ophthalmology, Strabismus, Electrophysiology and Ocular Oncology, St. Erik Eye Hospital, Karolinska InstitutetDepartment of Pediatrics, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University HospitalCEITEC – Central European Institute of Technology, Brno University of TechnologyDepartment of Cell and Molecular Biology, Karolinska InstitutetAbstract Spontaneous bleeds are a leading cause of death in the pediatric JAG1‐related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in bleeding events in patients, whether Jag1Ndr/Ndr mice display bleeds or vascular defects, and whether discovered vascular pathology can be confirmed in patients non‐invasively. We performed a systematic review of patients with ALGS and vascular events following PRISMA guidelines, in the context of patient sex, and found significantly more girls than boys reported with spontaneous intracranial hemorrhage. We investigated vascular development, homeostasis, and bleeding in Jag1Ndr/Ndr mice, using retina as a model. Jag1Ndr/Ndr mice displayed sporadic brain bleeds, a thin skull, tortuous blood vessels, sparse arterial smooth muscle cell coverage in multiple organs, which could be aggravated by hypertension, and sex‐specific venous defects. Importantly, we demonstrated that retinographs from patients display similar characteristics with significantly increased vascular tortuosity. In conclusion, there are clinically important sex differences in vascular disease in ALGS, and retinography allows non‐invasive vascular analysis in patients. Finally, Jag1Ndr/Ndr mice represent a new model for vascular compromise in ALGS.https://doi.org/10.15252/emmm.202215809Alagille syndromeBleedingJagged1NotchVasculature |
| spellingShingle | Simona Hankeova Noemi Van Hul Jakub Laznovsky Elisabeth Verboven Katrin Mangold Naomi Hensens Csaba Adori Elvira Verhoef Tomas Zikmund Feven Dawit Michaela Kavkova Jakub Salplachta Marika Sjöqvist Bengt R Johansson Mohamed G Hassan Linda Fredriksson Karsten Baumgärtel Vitezslav Bryja Urban Lendahl Andrew Jheon Florian Alten Kristina Teär Fahnehjelm Björn Fischler Jozef Kaiser Emma R Andersson Sex differences and risk factors for bleeding in Alagille syndrome EMBO Molecular Medicine Alagille syndrome Bleeding Jagged1 Notch Vasculature |
| title | Sex differences and risk factors for bleeding in Alagille syndrome |
| title_full | Sex differences and risk factors for bleeding in Alagille syndrome |
| title_fullStr | Sex differences and risk factors for bleeding in Alagille syndrome |
| title_full_unstemmed | Sex differences and risk factors for bleeding in Alagille syndrome |
| title_short | Sex differences and risk factors for bleeding in Alagille syndrome |
| title_sort | sex differences and risk factors for bleeding in alagille syndrome |
| topic | Alagille syndrome Bleeding Jagged1 Notch Vasculature |
| url | https://doi.org/10.15252/emmm.202215809 |
| work_keys_str_mv | AT simonahankeova sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT noemivanhul sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT jakublaznovsky sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT elisabethverboven sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT katrinmangold sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT naomihensens sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT csabaadori sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT elviraverhoef sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT tomaszikmund sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT fevendawit sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT michaelakavkova sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT jakubsalplachta sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT marikasjoqvist sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT bengtrjohansson sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT mohamedghassan sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT lindafredriksson sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT karstenbaumgartel sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT vitezslavbryja sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT urbanlendahl sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT andrewjheon sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT florianalten sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT kristinatearfahnehjelm sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT bjornfischler sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT jozefkaiser sexdifferencesandriskfactorsforbleedinginalagillesyndrome AT emmarandersson sexdifferencesandriskfactorsforbleedinginalagillesyndrome |