title: Peripheral mural cell recruitment requires cell-autonomous heparan sulfate.
abstract: Blood vessel maturation and stability require recruitment of mural cells (MCs) to the nascent vessel. Loss or detachment of MCs causes vascular dysfunction in diseases. N-sulfation of heparan sulfate (HS) is required for platelet-derived growth factor B (PDGF-B) retention and platelet-derived growth factor receptor-beta (PDGFR-beta) signaling during MC recruitment. To analyze the specific role of MC-derived HS in this process, we inactivated HS synthesis in MCs. MC-specific loss of HS causes embryonic lethality associated with vascular patterning defects, edema, and hemorrhages during late gestation. MC recruitment in the skin is impaired, correlating with defective PDGFR-beta and transforming growth factor-beta (TGF-beta)-SMAD signaling. Accumulation of rounded cells positive for MC markers close to the vessels indicates defective polarization and migration of local MC progenitors. In contrast, MC recruitment and signaling in the central nervous system (CNS) are unaffected by MC HS loss. Our results suggest that HS is selectively required in a cell-autonomous manner, acting in cis with PDGFR-beta and TGF-beta receptors during induction/polarization and migration of local progenitor cells to the nascent vessel. Once MCs are in contact with the vessel, as during CNS vascularization, endothelial HS appears sufficient to facilitate PDGFR-beta activation in trans.
authors.affiliation: Vascular Biology Laboratory, London Research Institute-Cancer Research UK, 44 Lincoln's Inn Fields, London, United Kingdom.
authors.forename: Denise
authors.initials: D
authors.lastname: Stenzel
authors.forename: Emma
authors.initials: E
authors.lastname: Nye
authors.forename: Maya
authors.initials: M
authors.lastname: Nisancioglu
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D001808:Blood Vessels / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002490:Central Nervous System / Q000196:embryology / Q000378:metabolism; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D017353:Gene Deletion; D006497:Heparan Sulfate / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000099058:Exostosin 1
chemical_list: D006497:Heparan Sulfate; D017351:N-Acetylglucosaminyltransferases; D020797:Receptor, Platelet-Derived Growth Factor beta; D000099058:Exostosin 1