Increased responsiveness of hypoxic endothelial cells to FGF2 is mediated by HIF-1alpha-dependent regulation of enzymes involved in synthesis of heparan sulfate FGF2-binding sites
Authors: Nicholas W Shworak
Michael Simons
Jian Li
Journal: Journal of Cell Science (2002)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: fibroblast growth factor; heparan sulfate; endothelial cells; hypoxia; FGF2 binding
Affiliations: Division of Cardiology, Department of Medicine, the Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.

Abstract:  Binding of basic fibroblast growth factor (FGF2) to its high affinity receptors requires the presence of specific heparan sulfate (HS) moieties on the cell surface that act as coreceptors. To determine the contribution of cell-surface HS to modulation of FGF2-dependent cell growth, we studied the changes in the cell mass and FGF2 binding of endothelial cell HS under normoxic and hypoxic conditions in vitro. Both large vein and cardiac microvascular endothelial cells cultured under hypoxic conditions demonstrated an increase in the ratio of cell-surface HS to chondroitin sulfate (CS), as well as an increase in the number of low affinity (HS-associated) binding sites for FGF2 with no change in the apparent K(d). This increase in the number of HS-FGF2 binding sites, in the absence of a significant change in FGF receptor expression, resulted in enhanced responsiveness of hypoxic, compared with normoxic, endothelial cells to FGF2 stimulation. Gene expression studies demonstrated increased expression of the key regulatory enzyme responsible for HS chain synthesis, 1,4 GlcNAc transferase (GlcNAcT-I), as well as increased expression of 2-O sulfotransferase (HS2ST), the enzyme responsible for sulfation of IdoA, a crucial part of the HS-FGF2 binding site. Transduction of cells with an adenovirus encoding a HIF-1alpha expression construct resulted in a similar increase in GlcNAcT-I and HS2ST expression. We conclude that hypoxia increases endothelial cell responsiveness to FGF2 by promoting preferential synthesis of HS rather than CS chains and increasing the number of FGF2-binding sites on HS chains. Both of these events are mediated by a HIF-1alpha-dependent increase in expression of the enzymes GlnNAcT-I and HS2ST. This shift in cell-surface HS composition results in enhanced cell sensitivity to FGF2-induced growth stimulation. 

Retracted: No

PubPeer comments:
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 Data re-used in a paper the next year to represent different things. https: imgur.com o6zhK4a For reference the other paper is: https: pubpeer.com publications E95EA3498B83BEBA897E0684839284#2 , 
 #1 This is clearly a mess. Disappointing that the corresponding author is unwilling to address this, given his stature in his field. u201dHe has published over 270 research papers and reviews and has been elected to a number of honorary societies including Association of American Physicians, American Society of Clinical Investigations and Association of University Cardiologists. He also a Fellow of the American Heart Association, American College of Cardiology and the American Society of Physiology.u201d *** False color  , 
 14 October 2022 Expression of Concern. https: journals.biologists.com jcs article 135 20 jcs260635 277380 Expression-of-Concern-Increased-responsiveness-of There are issues in Fig. 2 in J. Cell Sci.(2002)115, 1951-1959 (doi:10.1242 jcs.115.9.1951). Bands are duplicated three times in western blots in Fig. 2, despite these blots representing different conditions. The authors no longer have the original data but state that the results have since been verified and the conclusions of the paper are not affected. Without the original data, it is difficult to determine how the issues arose, so the journal is publishing this note to alert readers to our concerns. ,