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ADAM10-Dependent Signaling Through Notch1 and Notch4 Controls Development of Organ-Specific Vascular Beds.
ADAM10-Dependent Signaling Through Notch1 and Notch4 Controls Development of Organ-Specific Vascular Beds.
- Source :
-
Circulation research [Circ Res] 2016 Aug 05; Vol. 119 (4), pp. 519-31. Date of Electronic Publication: 2016 Jun 27. - Publication Year :
- 2016
-
Abstract
- Rationale: Endothelial Notch signaling is critical for early vascular development and survival. Yet, previously described mice lacking endothelial a disintegrin and metalloproteinase 10 (ADAM10), 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.<br />Objective: The aims of the study are to 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.<br />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 (Adam10ΔEC(Flv)) died by E10.5. Quantitative polymerase chain reaction analysis demonstrated that Cre-mediated recombination occurs earlier in Adam10ΔEC(Flv) 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.<br />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.<br /> (© 2016 American Heart Association, Inc.)
- Subjects :
- ADAM10 Protein deficiency
Amyloid Precursor Protein Secretases deficiency
Animals
Endothelial Cells physiology
Female
Membrane Proteins deficiency
Mice
Mice, Knockout
Mice, Transgenic
Pregnancy
Proto-Oncogene Proteins deficiency
Receptor, Notch1 deficiency
Receptor, Notch4
Receptors, Notch deficiency
ADAM10 Protein physiology
Amyloid Precursor Protein Secretases physiology
Blood Circulation physiology
Membrane Proteins physiology
Proto-Oncogene Proteins physiology
Receptor, Notch1 physiology
Receptors, Notch physiology
Regional Blood Flow physiology
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 119
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 27354212
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.115.307738