Role And Mechanism Of Receptor Tyrosine Kinase TIE1 In Retinal Vascular Development

Objective:Vascular growth is a multi-step process involving endothelial cell migration,proliferation,establishment of intercellular junctions,recruitment of mural cells and further remodeling into a mature vascular network.Angiogenesis is regulated by a variety of signaling pathways.Among them,the receptor tyrosine kinases TIE1 and TIE2 are important factors that regulate the maturation and maintenance of blood vessels.At present,the role and mechanism of TIE receptors in postnatal blood vascular development are still incompletely understood.In this study,we aim to study the roles of TIE1 in retinal angiogenesis,and the synergistic effect of TIE1 and TIE2 in the process of retinal vascularization.Methods:We have employed conditional knockout mouse models targeting Tie1 and Tek,and the transgenic mouse line expressing CreERT2 recombinase in vascular endothelial cells.The effects of deletion of Tiel and Tek on retinal angiogenesis is analyzed at the neonatal stages.Results:Here we show that the deletion of Tiel significantly inhibits the development of the retinal vascular network,including the decrease in the number of retinal veins,increased angiogenesis at the venous side and delayed growth of arteries.The simultaneous deletion of Tie1 and Tek leads to a greater suppression of retinal angiogenesis,suggesting that TIE 1 and TIE2 have a synergistic effect in the vascular development.Mechanistically,Tie1 deletion significantly inhibits endothelial cell migration during retinal vascularization,and the expression of venous markers including Tek,AP J and EphB4 are significantly down-regulated.Tie1 knockout in mice or Tie1 knockdown by siRNA in HUVECs(human umbilical vein endothelial cells)significantly reduce COUP-TFⅡ protein level.It is worth pointing out that it is unclear whether the decrease of COUP-TFⅡ protein is directly due to TIE1 insufficiency or indirectly resulting from the decrease of TIE2.The mechanism underlying TIE1 function in vein development remains to be studiedConclusion:Experiments in vitro and in vivo showed that Tie1 deletion disrupts retinal vein development with a significant decrease of the key venous transcription factor COUP-TFⅡ as well as other venous markers.Evidence from the doubly knockout studies indicate that TIE1 and TIE2 play a synergistic role in the formation and remodeling of the retinal vascular network.