Defective cerebrovascular development in mice lacking TFPI is restored by activated protein C - PubMed
4 hours ago
- #cerebrovascular development
- #TFPI
- #activated protein C
- Mice lacking Tissue Factor Pathway Inhibitor (Tfpi-/-) experience embryonic lethality due to excess thrombin production and cerebrovascular defects known as glomeruloid bodies.
- Introduction of a hyperactivatable mouse protein C (hMPC) transgene into Tfpi+/- mice rescued Tfpi-/- embryos, allowing them to survive to adulthood.
- hMPC reduced glomeruloid body numbers by 36% but did not prevent fibrin deposition or blood-brain barrier disruption within these structures.
- hMPC decreased hypoxia and cellular death in Tfpi-/-/hMPC+ brains, suggesting cytoprotective effects contributed to the rescue.
- Glomeruloid bodies were completely resolved in Tfpi-/-/hMPC+ P10 pups, indicating a temporal effect of TFPI on cerebrovascular development.
- RNAseq analysis of E15.5 brain tissue showed increased angiogenesis in Tfpi-/- brains, with changes in genes like apelin, adrenomedulin, and UNC5b.
- The hMPC transgene reversed the increased expression of angiogenic genes in Tfpi-/- brains.
- TFPI is essential for inhibiting thrombin generation during embryonic angiogenesis, with its role not compensated by other anticoagulant proteins.
- The study highlights the importance of blood coagulation proteases and their regulation in diverse biological processes.