A PLASTICITY WINDOW FOR BLOOD-VESSEL REMODELING IS DEFINED BY PERICYTE COVERAGE OF THE PREFORMED ENDOTHELIAL NETWORK AND IS REGULATED BY PDGF-B AND VEGF

Little is known about how the initial endothelial plexus is remodelled into a mature and functioning vascular network, Studying postnatal re modelling of the retina vasculature, we show that a critical step in v ascular maturation, namely pericyte recruitment, proceeds by outmigrat ion of cells positive for alpha-smooth muscle actin from arterioles an d that coverage of primary and smaller branches lags many days behind formation of the endothelial plexus, The transient existence of a peri cyte-free endothelial plexus coincides temporally and spatially with t he process of hyperoxia-induced vascular pruning, which is a mechanism for fine tuning of vascular density according to available oxygen. Ac quisition of a pericyte coating marks the end of this plasticity windo w. To substantiate that association with pericytes stabilizes the vasc ulature, endothelial-pericyte associations were disrupted by intraocul ar injection of PDGF-BB. Ectopic PDGF-BB caused the detachment of PDGF -beta receptor-positive pericytes from newly coated vessels, presumabl y through interference with endogenous cues, but had no effect on matu re vessels, Disruption of endothelial-pericyte associations resulted i n excessive regression of vascular loops and abnormal remodelling, Con versely, intraocular injection of VEGF accelerated pericyte coverage o f the preformed endothelial plexus, thereby revealing a novel function of this pleiotropic angiogenic growth factor. These findings also pro vide a cellular basis for clinical observations that vascular regressi on in premature neonates subjected to oxygen therapy [i.e. in retinopa thy of prematurity] drops precipitously upon maturation of retina vess els and a mechanistic explanation to our previous findings that VEGF c an rescue immature vessels from hyperoxia-induced regression.