Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function

Danielle Pretorius; Robert P Richter; Tanya Anand; Jessica C Cardenas; Jillian R Richter

doi:10.1016/j.mbplus.2022.100121

Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function

Matrix Biol Plus. 2022 Sep 7:16:100121. doi: 10.1016/j.mbplus.2022.100121. eCollection 2022 Dec.

Authors

Danielle Pretorius¹, Robert P Richter^{2

3}, Tanya Anand⁴, Jessica C Cardenas^{5

6}, Jillian R Richter^{1

3}

Affiliations

¹ Division of Trauma & Acute Care Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States.
² Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, United States.
³ Center for Injury Science, University of Alabama at Birmingham, Birmingham, AL, United States.
⁴ Division of Trauma, Critical Care, Burn & Emergency Surgery, Department of Surgery, University of Arizona, Tucson, AZ, United States.
⁵ Division of Acute Care Surgery, Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States.
⁶ Center for Translational Injury Research, University of Texas Health Science Center at Houston, Houston, TX, United States.

Abstract

The glycocalyx attached to the apical surface of vascular endothelial cells is a rich network of proteoglycans, glycosaminoglycans, and glycoproteins with instrumental roles in vascular homeostasis. Given their molecular complexity and ability to interact with the intra- and extracellular environment, heparan sulfate proteoglycans uniquely contribute to the glycocalyx's role in regulating endothelial permeability, mechanosignaling, and ligand recognition by cognate cell surface receptors. Much attention has recently been devoted to the enzymatic shedding of heparan sulfate proteoglycans from the endothelial glycocalyx and its impact on vascular function. However, other molecular modifications to heparan sulfate proteoglycans are possible and may have equal or complementary clinical significance. In this narrative review, we focus on putative mechanisms driving non-proteolytic changes in heparan sulfate proteoglycan expression and alterations in the sulfation of heparan sulfate side chains within the endothelial glycocalyx. We then discuss how these specific changes to the endothelial glycocalyx impact endothelial cell function and highlight therapeutic strategies to target or potentially reverse these pathologic changes.

Keywords: ACE2, Angiotensin-converting enzyme 2; CLP, cecal ligation and puncture; COVID-19, Coronavirus disease 2019; EXT, Exostosin; EXTL, Exostosin-like glycosyltransferase; FFP, Fresh frozen plasma; FGF, Fibroblast growth factor; FGFR1, Fibroblast growth factor receptor 1; GAG, Glycosaminoglycan; GPC, Glypican; Gal, Galactose; GlcA, Glucuronic acid; GlcNAc, N-actetyl glucosamine; Glycocalyx; HLMVEC, Human lung microvascular endothelial cell; HS, Heparan sulfate; HS2ST, Heparan sulfate 2-O-sulfotransferase; HS3ST, Heparan sulfate 3-O-sulfotransferase; HS6ST, Heparan sulfate 6-O-sulfotransferase; HSPG, Heparan sulfate proteoglycan; HUVEC, Human umbilical vein endothelial cell; Heparan sulfate proteoglycan; LPS, lipopolysaccharide; NDST, N-deacetylase/N-sulfotransferase; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; SDC, Syndecan; Sulf, Endosulfatase; Sulfation; Synthesis; TNFα, Tumor necrosis factor alpha; UA, Hexuronic acid; VEGF, Vascular endothelial growth factor; Vascular endothelium; XYLT, Xylosyltransferase; Xyl, Xylose; eGCX, Endothelial glycocalyx; eNOS, Endothelial nitric oxide synthase.

Publication types

Review

Abstract

Publication types

Grants and funding