Semaphorin-PlexinD1 Signaling Limits Angiogenic Potential via the VEGF Decoy Receptor sFlt1

• Published in: Developmental cell Vol. 21; no. 2; pp. 301 - 314
• Main Authors: Zygmunt, Tomasz, Gay, Carl Michael, Blondelle, Jordan, Singh, Manvendra K., Flaherty, Kathleen McCrone, Means, Paula Casey, Herwig, Lukas, Krudewig, Alice, Belting, Heinz-Georg, Affolter, Markus, Epstein, Jonathan A., Torres-Vázquez, Jesús
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.08.2011
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Animals, Genetically Modified; Aorta - anatomy & histology; Aorta - embryology; Cell Movement - drug effects; Cell Movement - genetics; Cell Transplantation - physiology; Embryo, Nonmammalian; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - physiology; Endothelium - cytology; Endothelium - embryology; Endothelium - metabolism; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - genetics; In Vitro Techniques; Indoles - pharmacology; Luminescent Proteins - genetics; Molecular Sequence Data; Neovascularization, Physiologic - genetics; Neovascularization, Physiologic - physiology; Oligodeoxyribonucleotides, Antisense - pharmacology; Pyrroles - pharmacology; Quinoxalines - pharmacology; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, Notch - genetics; Receptors, Notch - metabolism; RNA, Messenger - metabolism; Semaphorins - genetics; Semaphorins - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Thiazolidinediones - pharmacology; Vascular Endothelial Growth Factor Receptor-1 - deficiency; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2011.06.033

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. ► Sema-PlxnD1 signaling promotes expression of the secreted VEGF decoy sflt1 ► Sema-PlxnD1 signaling allocates angiogenic capacity in the trunk's arterial tree ► Sema-PlxnD1 signaling limits angiogenic responses within sprouts ► Sema-PlxnD1 and Notch signaling play distinct roles in SeA angiogenesis