title: Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice.
abstract: Arteriovenous malformations (AVMs) are tortuous vessels characterized by arteriovenous (AV) shunts, which displace capillaries and shunt blood directly from artery to vein. Notch signaling regulates embryonic AV specification by promoting arterial, as opposed to venous, endothelial cell (EC) fate. To understand the essential role of endothelial Notch signaling in postnatal AV organization, we used inducible Cre-loxP recombination to delete Rbpj, a mediator of canonical Notch signaling, from postnatal ECs in mice. Deletion of endothelial Rbpj from birth resulted in features of AVMs by P14, including abnormal AV shunting and tortuous vessels in the brain, intestine and heart. We further analyzed brain AVMs, as they pose particular health risks. Consistent with AVM pathology, we found cerebral hemorrhage, hypoxia and necrosis, and neurological deficits. AV shunts originated from capillaries (and possibly venules), with the earliest detectable morphological abnormalities in AV connections by P8. Prior to AV shunt formation, alterations in EC gene expression were detected, including decreased Efnb2 and increased Pai1, which encodes a downstream effector of TGFβ signaling. After AV shunts had formed, whole-mount immunostaining showed decreased Efnb2 and increased Ephb4 expression within AV shunts, suggesting that ECs were reprogrammed from arterial to venous identity. Deletion of Rbpj from adult ECs led to tortuosities in gastrointestinal, uterine and skin vascular beds, but had mild effects in the brain. Our results demonstrate a temporal requirement for Rbpj in postnatal ECs to maintain proper artery, capillary and vein organization and to prevent abnormal AV shunting and AVM pathogenesis.
authors.affiliation: Laboratory for Accelerated Vascular Research, Department of Surgery, University of California, San Francisco, CA 94143, USA.
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Nielsen
authors.affiliation: Laboratory for Accelerated Vascular Research, Department of Surgery, University of California, San Francisco, CA 94143, USA.
authors.forename: Henar
authors.initials: H
authors.lastname: Cuervo
authors.affiliation: Laboratory for Accelerated Vascular Research, Department of Surgery, University of California, San Francisco, CA 94143, USA.
authors.forename: Vivianne W
authors.initials: VW
authors.lastname: Ding
authors.affiliation: Laboratory for Accelerated Vascular Research, Department of Surgery, University of California, San Francisco, CA 94143, USA.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Department of Pathology, University of California, San Francisco, CA 94143, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.affiliation: Laboratory for Accelerated Vascular Research, Department of Surgery, University of California, San Francisco, CA 94143, USA rong.wang@ucsfmedctr.org.
authors.forename: Rong A
authors.initials: RA
authors.lastname: Wang
mesh_terms: D000818:Animals; D001165:Arteriovenous Malformations / Q000235:genetics* / Q000473:pathology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D007091:Image Processing, Computer-Assisted; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008856:Microscopy, Fluorescence; D060888:Real-Time Polymerase Chain Reaction; D036224:Receptor, EphB4 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; C086681:Ephb4 protein, mouse; D036224:Receptor, EphB4
keywords: Arteriovenous; Cerebrovascular; Endothelial cell; Mouse; Notch; Rbpj