title: Modulation of microvascular signaling by heparan sulfate matrix: studies in syndecan-4 transgenic mice.
abstract: The onset of tissue ischemia is associated with significant changes in the expression of heparan sulfate- (HS) carrying core proteins that, in turn, lead to alterations in composition of the extracellular HS matrix. Since HS can bind numerous growth factors and cytokines, such changes in the HS matrix content can have profound effects on the ability of these factors to interact with their target cells. To investigate the role of increased HS matrix content on microvascular function, we used alpha-myosin heavy chain (MHC) promoter to overexpress a HS-carrying core protein, syndecan-4, in cardiac myocytes in mice. Mice expressing the transgene (alpha MHC-S4) demonstrated a significant increase in nitric oxide (NO) release in the coronary effluent in response to fibroblast growth factor 2 (FGF2, 1 microg/mL) administration despite similar expression levels of NO synthase genes II and III (iNOS and eNOS, respectively). In vitro studies of coronary microvessels derived from alpha MHC-S4 mice demonstrated increased relaxation response to FGF2 compared to control mice. At the same time, vasodilator response to adenosine diphosphate (ADP) was significantly impaired in alpha MHC-S4 mice-derived microvessels. Addition of exogenous HS to microvessels derived from control mice enhanced FGF2-induced vasodilation while inhibiting ADP-induced vasomotion. The vasomotor activity of the endothelial receptor-independent agent (A23187) and the endothelium-independent agent (sodium nitroprusside) was not affected by heparan sulfate. These results demonstrate that alterations in HS production have a profound and heterogeneous effect on endothelial receptor-dependent vasodilators and point to a novel role of the HS matrix in regulation of microvascular homeostasis.
authors.affiliation: Angiogenesis Research Center and Section of Cardiology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Chohreh
authors.initials: C
authors.lastname: Partovian
authors.forename: Jianyi
authors.initials: J
authors.lastname: Li
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hampton
authors.forename: Caroline
authors.initials: C
authors.lastname: Metais
authors.forename: Eugene
authors.initials: E
authors.lastname: Tkachenko
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.forename: Chohren
authors.initials: C
authors.lastname: Parovian
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D009206:Myocardium / Q000378:metabolism; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011485:Protein Binding; D011509:Proteoglycans / Q000235:genetics*; D012313:RNA / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D053671:Syndecan-4; D014018:Tissue Distribution; D014664:Vasodilation
chemical_list: D000244:Adenosine Diphosphate; D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate; D008562:Membrane Glycoproteins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011509:Proteoglycans; D012313:RNA; D053671:Syndecan-4; C508306:Sdc4 protein, mouse; C508307:Sdc4 protein, rat; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat