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Purpose <p>Atherosclerotic cardiovascular disease originates from endothelial dysfunction, characterized by a shift toward a pro-inflammatory state and increased production of reactive oxygen species (ROS). This dysfunction occurs under adverse mechanical conditions, such as blood flow oscillation, multi-directionality, recirculation, shear stress gradients, and low or stagnation flows. This study investigates how degradation of heparan sulfate (HS), a major component of the endothelial glycocalyx, drives the transition of endothelial cells from a functional, anti-inflammatory, and antioxidant phenotype under streamlined flow conditions to a dysfunctional, pro-inflammatory, and pro-oxidant phenotype when flow is stagnant. Pro-inflammatory and pro-oxidant endothelial behavior precedes atherosclerosis development.</p> Methods <p>Human aortic endothelial cells were exposed to uniform shear stress (14 dynes/cm<sup>2</sup>) to model healthy endothelium. Unhealthy conditions were simulated via static conditions (0 dynes/cm<sup>2</sup>) or enzymatic HS degradation using heparinase III. Endothelial cell phenotype was assessed using fluorescent labeling, confocal microscopy, Western blotting, and RNA sequencing.</p> Results <p>Endothelial cells conditioned by 14 dynes/cm<sup>2</sup> shear stress without heparinase III exhibited low expression of pro-inflammatory genes (HIF1A, VCAM1, and IL1B), minimal ROS production, and up-regulation of Kruppel-like transcription factors. Under the same flow conditions, HS degradation via heparinase III induced an inflammatory phenotype, resembling responses observed at 0 dynes/cm<sup>2</sup> shear stress, while ROS levels remained largely unaffected.</p> Conclusions <p>The endothelial glycocalyx is a protective, dynamic, and complex structure, with HS as a key component. This study demonstrates that intact HS mitigates endothelial dysfunction by suppressing inflammation linked to flow-dependent atherosclerosis, but not ROS production. Future research will focus on translating these findings into HS-targeted therapies for atherosclerotic cardiovascular disease.</p>

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Multimodal Profiling Reveals Distinct Endothelial Activation Pathways Regulated by Flow and Heparan Sulfate

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月1日

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  • Ian C. Harding,
  • Nicholas R. O’Hare,
  • Ira M. Herman,
  • Eno E. Ebong

摘要

Purpose

Atherosclerotic cardiovascular disease originates from endothelial dysfunction, characterized by a shift toward a pro-inflammatory state and increased production of reactive oxygen species (ROS). This dysfunction occurs under adverse mechanical conditions, such as blood flow oscillation, multi-directionality, recirculation, shear stress gradients, and low or stagnation flows. This study investigates how degradation of heparan sulfate (HS), a major component of the endothelial glycocalyx, drives the transition of endothelial cells from a functional, anti-inflammatory, and antioxidant phenotype under streamlined flow conditions to a dysfunctional, pro-inflammatory, and pro-oxidant phenotype when flow is stagnant. Pro-inflammatory and pro-oxidant endothelial behavior precedes atherosclerosis development.

Methods

Human aortic endothelial cells were exposed to uniform shear stress (14 dynes/cm2) to model healthy endothelium. Unhealthy conditions were simulated via static conditions (0 dynes/cm2) or enzymatic HS degradation using heparinase III. Endothelial cell phenotype was assessed using fluorescent labeling, confocal microscopy, Western blotting, and RNA sequencing.

Results

Endothelial cells conditioned by 14 dynes/cm2 shear stress without heparinase III exhibited low expression of pro-inflammatory genes (HIF1A, VCAM1, and IL1B), minimal ROS production, and up-regulation of Kruppel-like transcription factors. Under the same flow conditions, HS degradation via heparinase III induced an inflammatory phenotype, resembling responses observed at 0 dynes/cm2 shear stress, while ROS levels remained largely unaffected.

Conclusions

The endothelial glycocalyx is a protective, dynamic, and complex structure, with HS as a key component. This study demonstrates that intact HS mitigates endothelial dysfunction by suppressing inflammation linked to flow-dependent atherosclerosis, but not ROS production. Future research will focus on translating these findings into HS-targeted therapies for atherosclerotic cardiovascular disease.