title: A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF.
abstract: Little is known about how the initial endothelial plexus is remodelled into a mature and functioning vascular network. Studying postnatal remodelling of the retina vasculature, we show that a critical step in vascular maturation, namely pericyte recruitment, proceeds by outmigration of cells positive for (alpha)-smooth muscle actin from arterioles and that coverage of primary and smaller branches lags many days behind formation of the endothelial plexus. The transient existence of a pericyte-free endothelial plexus coincides temporally and spatially with the process of hyperoxia-induced vascular pruning, which is a mechanism for fine tuning of vascular density according to available oxygen. Acquisition of a pericyte coating marks the end of this plasticity window. To substantiate that association with pericytes stabilizes the vasculature, endothelial-pericyte associations were disrupted by intraocular injection of PDGF-BB. Ectopic PDGF-BB caused the detachment of PDGF-beta receptor-positive pericytes from newly coated vessels, presumably through interference with endogenous cues, but had no effect on mature vessels. Disruption of endothelial-pericyte associations resulted in excessive regression of vascular loops and abnormal remodelling. Conversely, intraocular injection of VEGF accelerated pericyte coverage of the preformed endothelial plexus, thereby revealing a novel function of this pleiotropic angiogenic growth factor. These findings also provide a cellular basis for clinical observations that vascular regression in premature neonates subjected to oxygen therapy [i.e. in retinopathy of prematurity] drops precipitously upon maturation of retina vessels and a mechanistic explanation to our previous findings that VEGF can rescue immature vessels from hyperoxia-induced regression.
authors.affiliation: Department of Molecular Biology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: L E
authors.initials: LE
authors.lastname: Benjamin
authors.forename: I
authors.initials: I
authors.lastname: Hemo
authors.forename: E
authors.initials: E
authors.lastname: Keshet
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D000831:Animals, Newborn; D001160:Arterioles / Q000166:cytology; D000077214:Becaplermin; D002465:Cell Movement; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000254:growth & development*; D006801:Humans; D018496:Hyperoxia; D007231:Infant, Newborn; D037102:Lectins / Q000032:analysis; D008222:Lymphokines / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D037121:Plant Lectins; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000032:analysis; D012171:Retinal Vessels / Q000254:growth & development*; D012178:Retinopathy of Prematurity / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D000199:Actins; D016228:Endothelial Growth Factors; C045475:Griffonia simplicifolia lectins; D037102:Lectins; D008222:Lymphokines; D037121:Plant Lectins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000077214:Becaplermin; D017479:Receptors, Platelet-Derived Growth Factor