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: Bing Zhang, Wenyuan Xiao, Hong Qiu, Fuming Zhang, Heather A Moniz, Alexander Jaworski, Eduard Condac, Gerardo Gutierrez-Sanchez, Christian Heiss, Robin D Clugston, Parastoo Azadi, John J Greer, Carl Bergmann, Kelley W Moremen, Dean Li, Robert J Linhardt, Jeffrey D Esko, Lianchun Wang
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 1 Pg. 209-21 (Jan 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 24355925 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Proteins
• Nerve Tissue Proteins
• Receptors, Cell Surface
• Receptors, Immunologic
• Robo4 protein, mouse
• Slit3 protein, mouse
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Heparitin Sulfate
• Sulfotransferases
• heparitin sulfotransferase

Topics

• Animals
• Apoptosis
• Cell Hypoxia
• Cell Movement
• Cell Proliferation
• Cell Survival
• Diaphragm (abnormalities, blood supply, enzymology)
• Endothelial Cells (enzymology)
• Female
• Genetic Association Studies
• Heparitin Sulfate (deficiency)
• Hernia, Diaphragmatic (enzymology, genetics)
• Hernias, Diaphragmatic, Congenital
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Knockout
• Neovascularization, Physiologic
• Nerve Tissue Proteins (genetics, metabolism)
• Penetrance
• Receptors, Cell Surface
• Receptors, Immunologic (genetics, metabolism)
• Signal Transduction
• Sulfotransferases (deficiency, genetics)
• Tendons (abnormalities, pathology)
• Vascular Endothelial Growth Factor A (metabolism)