Role for Notch4 in Vascular Malformation Pathobiology
Abstract
We have developed a novel mouse model that carries a conditional allele for Notch4 (N4ex1). In preliminary studies, we demonstrated that N4Ex1 developed many of the hallmarks of patients with Hereditary Hemorrhagic Telangiectasia, while lymphatic endothelial cell deletion of Notch4 (N4ex1:LEC) resulted in lymphatic defects in the dermis, liver, and lungs consistent with human lymphatic malformations(LM). Whole exome sequencing of LM patient cells identified 4 variants of uncertain significance in Notch4. We hypothesize that Notch4functions in vascular maturation and homeostasis, and that its disruption contributes to the development of vascular malformations. In year 1 studies, we demonstrate that N4ex1homozygous mice are embryonic lethal. N4ex1 and N4ex1:LEC males, but not females, mice develop hepatic liver lymphatic defects associated with increased stellate cell activation, collagen deposition, and immune cell inflammation. We also found microbleeds in heterozygous N4ex1 brains, and progressive dermal lymphatic defect in N4ex1:LEC mice. The latter was associated with reduced LEC proliferation and VECADHERIN expression. Analysis of LM tissues and cells showed that DLL4 expression is increased the LECs carrying common pathogenic Pik3ca variants. Finally, analysis of LEC Jag1/Notch4 signaling suggests that it regulates inflammation, immune cell recruitment/activation and cellular locomotion which is distinct from Dll4/Notch signaling in LECs. Consistent with this, we find that Jag1 is expressed in the lymph node LECs and that there are lymph node lymphatic defects in N4ex1:LEC mice.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2023
- Accession Number
- AD1203904
Entities
People
- Carrie J. Shawber
Organizations
- Columbia University