Increased responsiveness of hypoxic endothelial cells to FGF2 is mediated by HIF-1α-dependent regulation of enzymes involved in synthesis of heparan sulfate FGF2-binding sites

• DOI: 10.1242/jcs.115.9.1951
• Publication Date: 2021-04-25T23:46:58Z
• Authors: Jian Li; Nicholas W. Shworak; Michael Simons
• Keywords: 0301 basic medicine; Binding Sites; Chondroitin Sulfates; Neovascularization, Physiologic; Hypoxia-Inducible Factor 1, alpha Subunit; Receptors, Fibroblast Growth Factor; Gene Expression Regulation, Enzymologic; Rats; 03 medical and health sciences; Animals, Newborn; Animals; Humans; Fibroblast Growth Factor 2; Endothelium, Vascular; Heparitin Sulfate; Hypoxia; Cell Division; Cells, Cultured; Glycosaminoglycans; Protein Binding; Signal Transduction; Transcription Factors

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