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(Circulation. 2009;120:1883-1892.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Glycome and Transcriptome Regulation of Vasculogenesis

Rania Harfouche, PhD^*; Dirk M. Hentschel, MD^*; Stephanie Piecewicz, BS^*; Sudipta Basu, PhD; Cristin Print, MBChB, PhD; David Eavarone, BS; Tanyel Kiziltepe, PhD; Ram Sasisekharan, PhD; Shiladitya Sengupta, PhD

From the Department of Medicine (R.H., D.M.H., S.P., S.B., S.S.), Brigham and Women’s Hospital, Boston, Mass; Department of Molecular Medicine and Pathology (C.P.), University of Auckland, Auckland, New Zealand; Department of Biological Engineering (D.E., T.K., R.S.), Massachusetts Institute of Technology, Cambridge, Mass; and Harvard-MIT Division of Health Sciences and Technology (R.H., S.P., S.B., D.E., T.K., R.S., S.S.), Cambridge, Mass.

Correspondence to Dirk M. Hentschel and Shiladitya Sengupta, Room 317, 65 Landsdowne St, Cambridge, MA 02139. E-mail shiladit{at}mit.edu or dhentschel@partners.org

Received November 24, 2008; accepted August 25, 2009.

Background— Therapeutic vasculogenesis is an emerging concept that can potentially be harnessed for the management of ischemic pathologies. The present study elucidates the potential coregulation of vasculogenesis by the heparan sulfate glycosaminoglycan–rich cell-surface glycome and the transcriptome.

Methods and Results— Differentiation of embryonic stem cells into endothelial cells in an in vitro embryoid body is paralleled by an amplification of heparan sulfate glycosaminoglycan sulfation, which correlates with the levels of the enzyme N-deacetylase/N-sulfotransferase 1 (NDST1). Small hairpin RNA–mediated knockdown of NDST1 or modification of heparan sulfate glycosaminoglycans in embryonic stem cells with heparinases or sodium chlorate inhibited differentiation of embryonic stem cells into endothelial cells. This was translated to an in vivo zebrafish embryo model, in which the genetic knockdown of NDST1 resulted in impaired vascularization characterized by a concentration-dependent decrease in intersegmental vessel lumen and a large tail-vessel configuration, which could be rescued by use of exogenous sulfated heparan sulfate glycosaminoglycans. To explore the cross talk between the glycome and the transcriptome during vasculogenesis, we identified by microarray and then validated wild-type and NDST1 knockdown–associated gene-expression patterns in zebrafish embryos. Temporal analysis at 3 developmental stages critical for vasculogenesis revealed a cascade of pathways that may mediate glycocalyx regulation of vasculogenesis. These pathways were intimately connected to cell signaling, cell survival, and cell fate determination. Specifically, we demonstrated that forkhead box O3A/5 proteins and insulin-like growth factor were key downstream signals in this process.

Conclusions— The present study for the first time implicates interplay between the glycome and the transcriptome during vasculogenesis, revealing the possibility of harnessing specific cellular glyco-microenvironments for therapeutic vascularization.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 120: 1843-1844. [Extract] [Full Text]