Doubling-down on doppel's role in brain angiogenesis Free

A complex vascular network is crucial to support the development and homeostasis of the central nervous system (CNS). However, the mechanisms that regulate CNS-specific blood vessel morphogenesis remain largely unknown. Now, Joseph McCarty and colleagues characterise the function of the prion protein doppel, encoded by the Prnd gene, during angiogenesis in the brain and retina. The authors quantify the expression of Prnd mRNA and doppel protein to show that Prnd is expressed by developing neonatal endothelial cells. Expression decreases with age and is absent in quiescent endothelial cells of the adult CNS. Using a reverse-phase protein array to analyse brain endothelial cell lines, the authors demonstrate that doppel interacts with receptor tyrosine kinases, such as VEGFR2, to activate signalling involved in endothelial cell survival, migration and metabolism. In vivo, Prnd-deficient mice have impaired endothelial cell sprouting in the CNS and distended blood vessel morphologies, revealed through immunostaining and electron microscopy. Furthermore, PRND-null mice have defects in endothelial blood-brain barrier (BBB) integrity, with gaps between the blood vessels and surrounding parenchyma, and leakage across the BBB. Together, these results reveal important functions for PRND/doppel in promoting sprouting angiogenesis and endothelial barrier integrity in the CNS.