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

Abstract

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.

GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis

“…CHT, however, does not correspond to the developing liver in mammals. Endothelial Notch signaling also contributes to LSEC differentiation and seems to be essential for the development and maintenance of a proper hepatic vascular architecture and its function (37). Functionally, sinusoidal dilatation and enhanced angiogenesis as seen in endothelial Notch signaling-deficient LSECs may promote hepatic metastasis (38).…”

Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice

“…Inducible disruption of Notch1 or RBP‐J using Mx‐Cre resulted in abnormal sinusoidal remodeling, intussusceptive angiogenesis, and hepatic angiosarcomas . To discriminate roles of Notch signaling in hepatocytes and LSECs, Cuervo et al specifically disrupted RBP‐J or Notch1 in LSECs, which resulted in altered sinusoidal structure and disturbed microcirculation . It was observed that loss of function of Notch signaling leads to LSEC capillarization .…”

“…It was observed that loss of function of Notch signaling leads to LSEC capillarization . However, because LSECs are vulnerable to environmental insults such as shear stress, the capillarization phenotype of LSECs in these loss‐of‐function models could be a consequence of tortuous sinusoids . In the current study, we utilized a gain‐of‐function model of Notch signaling.…”

“…In quiescence, Notch2 is highly expressed by LSECs, whereas Jagged1, delta‐like ligand (Dll)1, and Dll4 are expressed at low level . Previous studies have shown that deficiencies in Notch1 or RBP‐J in adult mice disrupted sinusoidal and hepatocyte homeostasis . However, the overall consequence of Notch activation in LSECs has not been assessed.…”

Inactivating mutations in Drosha mediate vascular abnormalities similar to hereditary hemorrhagic telangiectasia

“…The casting assay was performed as previously described (45, 46). Mice were anesthetized with 2% isoflurane and oxygen at 2 ml/min.…”