title: Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia.
abstract: Congenital diaphragmatic hernia (CDH) is a common birth malformation with a heterogeneous etiology. In this study, we report that ablation of the heparan sulfate biosynthetic enzyme NDST1 in murine endothelium (Ndst1ECKO mice) disrupted vascular development in the diaphragm, which led to hypoxia as well as subsequent diaphragm hypoplasia and CDH. Intriguingly, the phenotypes displayed in Ndst1ECKO mice resembled the developmental defects observed in slit homolog 3 (Slit3) knockout mice. Furthermore, introduction of a heterozygous mutation in roundabout homolog 4 (Robo4), the gene encoding the cognate receptor of SLIT3, aggravated the defect in vascular development in the diaphragm and CDH. NDST1 deficiency diminished SLIT3, but not ROBO4, binding to endothelial heparan sulfate and attenuated EC migration and in vivo neovascularization normally elicited by SLIT3-ROBO4 signaling. Together, these data suggest that heparan sulfate presentation of SLIT3 to ROBO4 facilitates initiation of this signaling cascade. Thus, our results demonstrate that loss of NDST1 causes defective diaphragm vascular development and CDH and that heparan sulfate facilitates angiogenic SLIT3-ROBO4 signaling during vascular development.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Xiao
authors.forename: Hong
authors.initials: H
authors.lastname: Qiu
authors.forename: Fuming
authors.initials: F
authors.lastname: Zhang
authors.forename: Heather A
authors.initials: HA
authors.lastname: Moniz
authors.forename: Alexander
authors.initials: A
authors.lastname: Jaworski
authors.forename: Eduard
authors.initials: E
authors.lastname: Condac
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gutierrez-Sanchez
authors.forename: Christian
authors.initials: C
authors.lastname: Heiss
authors.forename: Robin D
authors.initials: RD
authors.lastname: Clugston
authors.forename: Parastoo
authors.initials: P
authors.lastname: Azadi
authors.forename: John J
authors.initials: JJ
authors.lastname: Greer
authors.forename: Carl
authors.initials: C
authors.lastname: Bergmann
authors.forename: Kelley W
authors.initials: KW
authors.lastname: Moremen
authors.forename: Dean
authors.initials: D
authors.lastname: Li
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Linhardt
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.forename: Lianchun
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D003964:Diaphragm / Q000002:abnormalities / Q000098:blood supply / Q000201:enzymology; D042783:Endothelial Cells / Q000201:enzymology; D005260:Female; D056726:Genetic Association Studies; D006497:Heparan Sulfate / Q000172:deficiency*; D006548:Hernia, Diaphragmatic / Q000201:enzymology / Q000235:genetics; D065630:Hernias, Diaphragmatic, Congenital; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019683:Penetrance; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics*; D013710:Tendons / Q000002:abnormalities / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D006497:Heparan Sulfate; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D015238:Sulfotransferases; D042461:Vascular Endothelial Growth Factor A; C540792:Robo4 protein, mouse; C432251:Slit3 protein, mouse; C467480:vascular endothelial growth factor A, mouse; C021350:heparitin sulfotransferase