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 Blood, 23 July 2009, Vol. 114, No. 4, pp. 915-924.
Prepublished online as a Blood First Edition Paper on April 27, 2009; DOI 10.1182/blood-2008-10-186239.

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VASCULAR BIOLOGY

Peripheral mural cell recruitment requires cell-autonomous heparan sulfate

Denise Stenzel1, Emma Nye2, Maya Nisancioglu3, Ralf H. Adams4, Yu Yamaguchi5, and Holger Gerhardt1

1 Vascular Biology Laboratory, and 2 Experimental Mouse Pathology Laboratory, London Research Institute–Cancer Research UK, London, United Kingdom; 3 Laboratory of Vascular Biology, Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; 4 Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, Muenster, Germany; and 5 Sanford Children's Health Research Center, Burnham Institute for Medical Research, La Jolla, CA

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-β (PDGFR-β) 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-β and transforming growth factor-β (TGF-β)–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-β and TGF-β 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-β activation in trans.


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