Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function.
Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function.
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DOI：
10.1016/j.mbplus.2022.100121
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发表时间：
2022-12
影响因子：
--
通讯作者：
Richter, Jillian R
中科院分区：
文献类型：
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作者：
Pretorius, Danielle;Richter, Robert P;Anand, Tanya;Cardenas, Jessica C;Richter, Jillian R
根尖表面硫酸肝素蛋白聚糖（HSPG）具有独特的内皮功能。炎症和剪切应力紊乱会改变HSPG的合成和磺化。减少HSPG表达影响调节内皮细胞稳态的机制。内皮糖萼HSPG硫酸化的变化是巨大的，并且依赖于环境。靶向内皮HSPG生物合成和磺化是很有前途的治疗策略。附着在血管内皮细胞顶端表面的糖萼是一个丰富的蛋白聚糖、糖胺聚糖和糖蛋白网络，在血管稳态中起着重要作用。鉴于其分子复杂性和与细胞内外环境相互作用的能力，硫酸肝素蛋白聚糖在糖萼调节内皮通透性、机械信号传导和同源细胞表面受体的配体识别方面发挥着独特的作用。近年来，人们越来越关注硫酸肝素蛋白聚糖在内皮细胞糖萼中的酶解脱落及其对血管功能的影响。然而，对硫酸肝素蛋白聚糖的其他分子修饰是可能的，并且可能具有同等或互补的临床意义。在这篇叙述性综述中，我们将重点关注驱动硫酸肝素蛋白聚糖表达的非蛋白水解变化和内皮糖萼内硫酸肝素侧链磺化变化的假定机制。然后，我们讨论了内皮糖萼的这些特定变化如何影响内皮细胞功能，并强调了针对或潜在逆转这些病理变化的治疗策略。
Apical surface heparan sulfate proteoglycans (HSPG) have unique endothelial roles. Inflammation and shear stress derangement can alter HSPG synthesis and sulfation. Reduced HSPG expression impacts mechanisms that regulate endothelial cell homeostasis. Changes to endothelial glycocalyx HSPG sulfation are vast and contextually dependent. Targeting endothelial HSPG biosynthesis and sulfation are promising therapeutic strategies. 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.