1Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
2Department of Experimental Biology, Masaryk University, Brno, Czech Republic.
3CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic.
4University of Applied Sciences Utrecht, Utrecht, The Netherlands.
5Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
6Department of Pediatrics, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University Hospital, Huddinge, Sweden.
7EM Unit, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
8University of San Francisco, San Francisco, CA, USA.
9Department of Orthodontics, Faculty of Dentistry, Assiut University, Assiut, Egypt.
10Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
11Travere Therapeutics, San Diego, CA, USA.
12Department of Ophthalmology, University of Muenster Medical Center, Münster, Germany.
13Department of Pediatric Ophthalmology, Strabismus, Electrophysiology and Ocular Oncology, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
14Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
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.