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

Abstract

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.

Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity

“…Genome-wide loss-of-function screens in HAP1 haploid or myeloid cells identified ADAM10 as a necessary factor in Hla-mediated cell death, and overexpression of ADAM10 lead to increased Hla binding and toxicity [114–116]. Because ADAM10 is necessary for embryonic development and maintenance of the epithelium, in vivo studies are limited to the use of conditional or inducible ADAM10 knockout lines [117, 118]. Nevertheless, these studies have provided valuable insights which are discussed in detail below.…”

What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies

“…The biological link between TSPAN15 and VTE is still obscure. Of note, TSPAN15 has been shown to partner with ADAM10 to modulate the N‐cadherin adhesion molecule and to control vascular development (Alabi et al , ) as well as to act as a negative regulator of the Notch signalling pathway (Matthews et al , ), a key pathway controling angiogenesis (Benedito & Hellström, ). In addition, TSPAN15 contributes to the cleavage of platelets amyloid precursor protein (Matthews et al , ) whose regulation is proposed as a new player in the pathophysiology of VTE (Canobbio et al , ).…”

The developmental biology of genetic Notch disorders

“…Notch1 homozygous knockout mice are also embryonic lethal prior to E11 (Conlon et al, 1995;Swiatek et al, 1994), and this is recapitulated in processing-deficient Notch1 embryos (Huppert et al, 2000) and in Rbpj −/− embryos (Oka et al, 1995), indicating that canonical Notch1 signaling is required for vascular development and embryonic survival. However, endothelial deletion of Notch1 using a Tie2-Cre specifically expressed in endothelial cells is far less severe and 50% of these mice survive for at least 8 weeks, albeit with vascular anomalies (Alabi et al, 2016). This is in stark contrast to an earlier study in which the use of another Tie2-Cre strain (Limbourg et al, 2005) suggested that loss of endothelial Notch1 was the sole cause of embryonic death seen in null mice; however, it was subsequently noted that the Tie2 promoter used in this strain is also active in the female germ line (de Lange et al, 2008).…”