Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice

Nielsen, Corinne M.; Cuervo, Henar; Ding, Vivianne W.; Kong, Yupeng; Huang, Eric J.; Wang, Rong A.

doi:10.1242/dev.108951

Cited by 47 publications

(68 citation statements)

References 60 publications

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“…Our results show a down‐regulation of ephrin‐B2 in the endothelium of Rbpj iΔEC mice, which is in agreement with previous work . Ephrin‐B2 is regulated by Notch and selectively expressed in arteries .…”

Section: Discussionsupporting

confidence: 93%

“…In the absence of observed liver fibrosis on histology, these results are suggestive of presinusoidal portal hypertension (which is encountered commonly in nodular regenerative hyperplasia) in Rbpj iΔEC mice. However, we cannot rule out that hemodynamic changes resulting from other abnormalities in Rbpj iΔEC mice contribute to the nodular phenotype, and the elevated portal pressure observed in these mice.…”

Section: Resultsmentioning

confidence: 92%

“…Observations in other vascular beds, such as the developing retina, support a role for endothelial Notch in regulating vessel diameter. Increased diameter of venule branches was observed in Rbpj iΔEC mice . Additionally, endothelial Notch was reported to regulate vessel diameter in the yolk sac …”

Section: Discussionmentioning

confidence: 96%

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Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice

et al. 2016

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Liver vasculature is crucial for adequate hepatic functions. Global deletion of Notch signaling in mice results in liver vascular pathologies. However, whether Notch in endothelium is essential for hepatic vascular structure and function remains unknown. To uncover the function of endothelial Notch in the liver, we deleted Rbpj, a transcription factor mediating all canonical Notch signaling, or Notch1, specifically from the endothelium of postnatal mice. We investigated the hepatic vascular defects in these mutants. The liver was severely affected within two weeks following endothelial deletion of Rbpj from birth. Two-week old mutant mice had enlarged vessels on the liver surface, abnormal vascular architecture, and dilated sinusoids. Vascular casting and fluorosphere passage experiments indicated the presence of porto-systemic shunts. These mutant mice presented severely necrotic liver parenchyma and significantly larger hypoxic areas, likely resulting from vascular shunts. We also found elevated levels of VEGF receptor 3 together with reduced levels of ephrin-B2, suggesting a possible contribution of these factors to the generation of hepatic vascular abnormalities. Deletion of Rbpj from the adult endothelium also led to dilated sinusoids, vascular shunts, and necrosis albeit milder than that in mice with deletion from birth. Similar to deletion of Rbpj, loss of endothelial Notch1 from birth led to similar hepatic vascular malformations within two weeks. Conclusions Endothelial Notch signaling is essential for the development and maintenance of proper hepatic vascular architecture and function. Our findings may help understand the molecular pathogenesis of hepatic vascular malformation and the safety of therapeutics inhibiting Notch.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 92%

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Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice

et al. 2016

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“…Inactivation of the Notch ligand Dll4 in endothelial cells for 10 weeks postnatally led to abnormal subcapsular liver vessels and dilated sinusoids 45 . Meanwhile, knockdown of endothelial RBPJ starting from birth resulted in abnormally large vessels near the heart surface in 2-week old mutant mice 46 . Finally, inactivation of RBPJ in endothelial cells at 2 weeks resulted in defects in the femoral and tibial growth plates and in metaphyseal vessels 47 .…”

Section: Discussionmentioning

confidence: 99%

ADAM10-Dependent Signaling Through Notch1 and Notch4 Controls Development of Organ-Specific Vascular Beds

Alabi

Glomski

Haxaire

et al. 2016

Circulation Research

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Rationale Endothelial Notch signaling is critical for early vascular development and survival. Yet, previously described mice lacking endothelial ADAM10 (a disintegrin and metalloproteinase 10), a key regulator of Notch signaling, survived into adulthood with organ-specific vascular defects. These findings raised questions about whether these vascular defects were related to Notch signaling or other functions of ADAM10. Objective Determine whether compensatory or redundant functions of ADAM17 in Notch signaling can explain the survival of Adam10ΔEC mice, explore the contribution of different Tie2-Cre transgenes to the differences in survival, and establish whether the Adam10ΔEC vascular phenotypes can be recapitulated by inactivation of Notch receptors in endothelial cells. Methods and Results Mice lacking ADAM10 and ADAM17 in endothelial cells (Adam10/Adam17ΔEC), which survived postnatally with organ-specific vascular defects, resembled Adam10ΔEC mice. In contrast, Adam10ΔEC mice generated with the Tie2Cre transgene previously used to inactivate endothelial Notch (Adam10ΔECFlv) died by E10.5. qPCR analysis demonstrated that Cre-mediated recombination occurs earlier in Adam10ΔECFlv mice than in the previously described Adam10ΔEC mice. Finally, mice lacking endothelial Notch1 (Notch1ΔEC) share some organ-specific vascular defects with Adam10ΔEC mice, whereas Notch4−/− mice lacking endothelial Notch1 (Notch1ΔEC/Notch4−/−) had defects in all vascular beds affected in Adam10ΔEC mice. Conclusions Our results argue against a major role for ADAM17 in endothelial Notch signaling and clarify the difference in phenotypes of previously described mice lacking ADAM10 or Notch in endothelial cells. Most notably, these findings uncover new roles for Notch signaling in the development of organ-specific vascular beds.

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“…30 Endothelial deletion of Rbpj at birth results in tortuous vessels, AV shunting, vessel aggregates, hemorrhage and signs of neurological deficits by P14 in the brain. AV shunts show decreased Efnb2 and increased Ephb4 expression, suggesting acquisition of venous identity.…”

Section: Bench To Bedside: Mutations In the Notch Pathway Lead To Halmentioning

confidence: 99%

Mouse Models of Cerebral Arteriovenous Malformation

Nielsen

Huang

Murphy

et al. 2016

Stroke

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Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice

Cited by 47 publications

References 60 publications

Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice

Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice

ADAM10-Dependent Signaling Through Notch1 and Notch4 Controls Development of Organ-Specific Vascular Beds

Mouse Models of Cerebral Arteriovenous Malformation

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