Degradation of Glycocalyx and Multiple Manifestations of Endothelial Dysfunction Coincide in the Early Phase of Endothelial Dysfunction Before Atherosclerotic Plaque Development in Apolipoprotein E/Low‐Density Lipoprotein Receptor‐Deficient Mice

Abstract

Background The impairment of endothelium‐dependent vasodilation, increased endothelial permeability, and glycocalyx degradation are all important pathophysiological components of endothelial dysfunction. However, it is still not clear whether in atherosclerosis, glycocalyx injury precedes other features of endothelial dysfunction or these events coincide. Methods and Results Herein, we demonstrate that in 4‐ to 8‐week‐old apolipoprotein E/low‐density lipoprotein receptor‐deficient mice, at the stage before development of atherosclerotic plaques, impaired acetylcholine‐induced vasodilation, reduced NO production in aorta, and increased endothelial permeability were all observed; however, flow‐mediated dilation in the femoral artery was fully preserved. In 4‐week‐old mice, glycocalyx coverage was reduced and endothelial stiffness was increased, whereas glycocalyx length was significantly decreased at 8 weeks of age. Early changes in endothelial function were also featured by increased plasma concentration of biomarkers of glycocalyx disruption (endocan), biomarkers of endothelial inflammation (soluble vascular cell adhesion molecule 1), increased vascular permeability (angiopoietin 2), and alterations in hemostasis (tissue plasminogen activator and plasminogen activator inhibitor 1). In 28‐week‐old mice, at the stage of advanced atherosclerotic plaque development, impaired NO production and nearly all other features of endothelial dysfunction were changed to a similar extent, compared with the preatherosclerotic plaque phase. The exceptions were the occurrence of acetylcholine‐induced vasoconstriction in the aorta and brachiocephalic artery, impaired flow‐mediated vasodilation in the femoral artery, and further reduction of glycocalyx length and coverage with a concomitant further increase in endothelial permeability. Conclusions In conclusion, even at the early stage before the development of atherosclerotic plaques, endothelial dysfunction is a complex multifactorial response that has not been previously appreciated.

Distinct Chemical Changes in Abdominal but Not in Thoracic Aorta upon Atherosclerosis Studied Using Fiber Optic Raman Spectroscopy

“…It is known that atherosclerosis develops faster in the abdominal aorta compared to the thoracic one [ 50 ], which is consistent with the biochemical studies on endothelial function in this model indicating more pronounced endothelial dysfunction in the abdominal aorta in Apoe -/- /Ldlr -/- mice [ 51 ]. To answer the question of how these changes in the aorta wall correlate with alterations in the perivascular adipose tissue, PVAT from the thoracic and abdominal fragments was extracted and investigated.…”

“…In order to exclude additional factors that could disturb the results, and because the male mice model is more stable, we used only males. The Apoe -/- /Ldlr -/- murine model developed initially by Ishibashi and coworkers [ 57 ] represents a validated model of murine atherosclerosis as shown in numerous previous studies from our group using various methodologies [ 51 , 58 , 59 , 60 ] including also Raman and IR spectroscopy [ 32 , 61 , 62 ].…”

The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases

“…Recent work with 4- to 8-week-old apolipoprotein E/low-density lipoprotein receptor deficient mice, at the stage before development of atherosclerotic plaques, displayed increased endothelial stiffness, reduced GCX coverage and thickness, reduced NO production in the aorta, impaired acetylcholine-induced vasodilation, and increased endothelial permeability. 9 These observations are consistent with independent studies reviewed in the sections on mechanotransduction and sepsis.…”

Protective effect of sonic hedgehog against oxidized low‑density lipoprotein‑induced endothelial apoptosis: Involvement of NF‑κB and Bcl‑2 signaling

“…The vascular endothelium, which is located between the blood and tissues, plays a major role in maintaining body homeostasis. Upon exposure to proatherogenic factors, such as oxidized low-density lipoprotein (ox-LdL), endothelial cells (Ecs) undergo a series of changes, including increased permeability, induced inflammation and apoptosis, ultimately disrupting the balance of Ec homeostasis and initiating of atherosclerosis (2,3). Apoptosis, a mode of programmed cell death, is a direct consequence of impaired endothelial function.…”