Sex differences and risk factors for bleeding in Alagille syndrome

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Authors

HANKEOVÁ Simona NOEMI Van Hul LAZNOVSKY Jakub VERBOVEN Elisabeth MANGOLD Katrin HENSENS Naomi ADORI Csaba VERHOEF Elvira ZIKMUND Tomas DAWIT Feven KAVKOVA Michaela SALPLACHTA Jakub SJÖQVIST Marika JOHANSSON Bengt R HASSAN Mohamed G FREDRIKSSON Linda BAUMGÄRTEL Karsten BRYJA Vítězslav LENDAHL Urban JHEON Andrew ALTEN Florian FAHNEHJELM Kristina Teär FISCHLER Björn KAISER Jozef ANDERSSON Emma R

Year of publication 2022
Type Article in Periodical
Magazine / Source EMBO Molecular Medicine
MU Faculty or unit

Faculty of Science

Citation
Web https://www.embopress.org/doi/full/10.15252/emmm.202215809
Doi http://dx.doi.org/10.15252/emmm.202215809
Keywords Alagille syndrome; Bleeding; Jagged1; Notch; Vasculature
Description 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 Jag1(Ndr/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 Jag1(Ndr/Ndr) mice, using retina as a model. Jag1(Ndr/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, Jag1(Ndr/Ndr) mice represent a new model for vascular compromise in ALGS.
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