title: Semaphorin-PlexinD1 signaling limits angiogenic potential via the VEGF decoy receptor sFlt1.
abstract: Sprouting angiogenesis expands the embryonic vasculature enabling survival and homeostasis. Yet how the angiogenic capacity to form sprouts is allocated among endothelial cells (ECs) to guarantee the reproducible anatomy of stereotypical vascular beds remains unclear. Here we show that Sema-PlxnD1 signaling, previously implicated in sprout guidance, represses angiogenic potential to ensure the proper abundance and stereotypical distribution of the trunk's segmental arteries (SeAs). We find that Sema-PlxnD1 signaling exerts this effect by antagonizing the proangiogenic activity of vascular endothelial growth factor (VEGF). Specifically, Sema-PlxnD1 signaling ensures the proper endothelial abundance of soluble flt1 (sflt1), an alternatively spliced form of the VEGF receptor Flt1 encoding a potent secreted decoy. Hence, Sema-PlxnD1 signaling regulates distinct but related aspects of angiogenesis: the spatial allocation of angiogenic capacity within a primary vessel and sprout guidance.
authors.affiliation: Department of Cell Biology, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zygmunt
authors.forename: Carl Michael
authors.initials: CM
authors.lastname: Gay
authors.forename: Jordan
authors.initials: J
authors.lastname: Blondelle
authors.forename: Manvendra K
authors.initials: MK
authors.lastname: Singh
authors.forename: Kathleen McCrone
authors.initials: KM
authors.lastname: Flaherty
authors.forename: Paula Casey
authors.initials: PC
authors.lastname: Means
authors.forename: Lukas
authors.initials: L
authors.lastname: Herwig
authors.forename: Alice
authors.initials: A
authors.lastname: Krudewig
authors.forename: Heinz-Georg
authors.initials: HG
authors.lastname: Belting
authors.forename: Markus
authors.initials: M
authors.lastname: Affolter
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
authors.forename: Jesús
authors.initials: J
authors.lastname: Torres-Vázquez
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000033:anatomy & histology / Q000196:embryology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D017690:Cell Transplantation / Q000502:physiology; D004625:Embryo, Nonmammalian; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004727:Endothelium / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000172:deficiency / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D020533:Angiogenesis Inhibitors; D007211:Indoles; D008164:Luminescent Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D011758:Pyrroles; D011810:Quinoxalines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D039961:Semaphorins; D045162:Thiazolidinediones; D029961:Zebrafish Proteins; C488979:plxnd1 protein, zebrafish; C116890:Semaxinib; D040281:Vascular Endothelial Growth Factor Receptor-1