RT Journal Article
SR Electronic
T1 Bleeding in patients and mice with Alagille syndrome: sex differences and risk factors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.13.439679
DO 10.1101/2021.04.13.439679
A1 Simona Hankeova
A1 Noemi Van Hul
A1 Jakub Laznovsky
A1 Naomi Hensen
A1 Elvira Verhoef
A1 Tomas Zikmund
A1 Feven Dawit
A1 Michaela Kavkova
A1 Jakub Salplachta
A1 Liting Li
A1 Marika Sjöqvist
A1 Bengt R. Johansson
A1 Mohamed Hassan
A1 Vitezslav Bryja
A1 Urban Lendahl
A1 Andrew Jheon
A1 Jian She Wang
A1 Florian Alten
A1 Kristina Teär Fahnehjelm
A1 Björn Fischler
A1 Jozef Kaiser
A1 Emma R. Andersson
YR 2021
UL http://biorxiv.org/content/early/2021/04/14/2021.04.13.439679.abstract
AB Alagille syndrome (ALGS) is generally thought of as a pediatric cholestatic liver disease, but spontaneous bleeds are a major cause of death. Here, we investigated bleeding in patients and a mouse model for ALGS (Jag1Ndr/Ndr mice) and asked whether phenotypes identified in mice could be detected in patients non-invasively. Jag1Ndr/Ndr mice spontaneously bled, exhibiting a thin skull and vascular defects. Vascular abnormalities included artery-vein crossings, tortuous vessels, and capillary breakdown. Furthermore, Jag1Ndr/Ndr arteries had sparse vascular smooth muscle cell coverage, which was further aggravated by hypertension. Retinographs from patients with ALGS, biliary atresia, or CADASIL confirmed tortuous blood vessels and artery-vein crossings in ALGS. We also identified sex-specific differences: fewer major vessels in female Jag1Ndr/Ndr mice, and four-fold more female than male patients with intracranial hemorrhage. In conclusion, dysfunctional Jag1 disrupted vascular growth and homeostasis, with sex-specific differences. The mouse model for Alagille syndrome demonstrated multiple bleeding risk factors and vascular defects that can be identified in patients non-invasively.Competing Interest StatementThe authors have declared no competing interest.Aartery/arterioleALGSAlagille syndromeAngIIAngiotensin IIASMAalpha smooth muscle cell actinAVarteriovenousBAbiliary atresiaBPblood pressurecCasp3cleaved Caspase 3CADASILcerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathyCD31PECAM-1ColIVCollagen IVCTRLcontrolDdeepDCPdeep capillary plexusDll4Delta-like 4EBEvans blueECendothelial cellErgETS-related geneggramGIgastrointestinalGFAPGlial fibrillary acidic proteinIintermediateHgmercuryICintracranialICPintermediate capillary plexusJag1Jagged1mmmillimeternnumber of biological replicatesNdrNodderNFneurofilamentnsnot significantODoptical densityPpostnatal dayPASpulmonary artery stenosisPH3phospho-histone 3SsuperficialSCPsuperficial capillary plexusTATthrombin-antithrombinVvein/venuleVSMCvascular smooth muscle cellmCTmicro computed tomographymmmicrometer