Editing Glycocalyx (section)

==Disruption and disease==

Because the glycocalyx is so prominent throughout the cardiovascular system, disruption to this structure has detrimental effects that can cause disease. Certain stimuli that cause [[atheroma]] may lead to enhanced sensitivity of vasculature. Initial dysfunction of the glycocalyx can be caused by hyperglycemia or oxidized low-density lipoproteins ([[LDL]]s), which then causes [[atherothrombosis]]. In microvasculature, dysfunction of the glycocalyx leads to internal fluid imbalance, and potentially [[edema]]. In arterial vascular tissue, glycocalyx disruption causes inflammation and atherothrombosis.<ref>Drake-Holland, Angela & Mark Noble. "The Important New Drug Target in Cardiovascular Medicine – the Vascular Glycocalyx." Cardiovascular & Hematological Disorders-Drug Targets, 2009, 9, p. 118–123</ref>

Experiments have been performed to test precisely how the glycocalyx can be altered or damaged.  One particular study used an isolated perfused heart model designed to facilitate detection of the state of the vascular barrier portion, and sought to cause insult-induced shedding of the glycocalyx to ascertain the cause-and-effect relationship between glycocalyx shedding and vascular permeability.  [[Hypoxia (medical)|Hypoxic]] perfusion of the glycocalyx was thought to be sufficient to initiate a degradation mechanism of the endothelial barrier.  The study found that flow of oxygen throughout the blood vessels did not have to be completely absent ([[ischemic]] hypoxia), but that minimal{{Clarify|reason=vague|date=August 2016}} levels of oxygen were sufficient to cause the degradation.  Shedding of the glycocalyx can be triggered by inflammatory stimuli, such as [[tumor necrosis factor-alpha]].  Whatever the stimulus is, however, shedding of the glycocalyx leads to a drastic{{Clarify|reason=vague|date=August 2016}} increase in vascular permeability.  Vascular walls being permeable is disadvantageous, since that would enable passage of some macromolecules or other harmful antigens.<ref>Annecke, T., et al. "Shedding of the coronary endothelial glycocalyx: effects of hypoxia/reoxygenation vs ischaemia/reperfusion." British Journal of Anaesthesia, 2011. 107 (5): 679–86</ref>

Other sources of damage to the endothelial glycocalyx have been observed in several pathological conditions such as inflammation,<ref>{{Cite journal |last1=Henry |first1=Charmaine B. S. |last2=Duling |first2=Brian R. |date=2000-12-01 |title=TNF-α increases entry of macromolecules into luminal endothelial cell glycocalyx |journal=American Journal of Physiology. Heart and Circulatory Physiology |language=en |volume=279 |issue=6 |pages=H2815–H2823 |doi=10.1152/ajpheart.2000.279.6.H2815 |pmid=11087236 |s2cid=86646327 |issn=0363-6135|doi-access=free }}</ref> hyperglycemia,<ref>{{Cite journal |last1=Zuurbier |first1=Coert J. |last2=Demirci |first2=Cihan |last3=Koeman |first3=Anneke |last4=Vink |first4=Hans |last5=Ince |first5=Can |date=October 2005 |title=Short-term hyperglycemia increases endothelial glycocalyx permeability and acutely decreases lineal density of capillaries with flowing red blood cells |url=https://www.physiology.org/doi/10.1152/japplphysiol.00436.2005 |journal=Journal of Applied Physiology |language=en |volume=99 |issue=4 |pages=1471–1476 |doi=10.1152/japplphysiol.00436.2005 |pmid=16024521 |issn=8750-7587|url-access=subscription }}</ref> ischemia-reperfusion,<ref>{{Cite journal |last1=Mulivor |first1=A. W. |last2=Lipowsky |first2=H. H. |date=May 2004 |title=Inflammation- and ischemia-induced shedding of venular glycocalyx |url=https://www.physiology.org/doi/10.1152/ajpheart.00832.2003 |journal=American Journal of Physiology. Heart and Circulatory Physiology |language=en |volume=286 |issue=5 |pages=H1672–H1680 |doi=10.1152/ajpheart.00832.2003 |pmid=14704229 |issn=0363-6135}}</ref>  viral infections<ref>{{Cite journal |last1=Becker |first1=Bernhard F. |last2=Jacob |first2=Matthias |last3=Leipert |first3=Stephanie |last4=Salmon |first4=Andrew H. J. |last5=Chappell |first5=Daniel |date=September 2015 |title=Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases: Endothelial glycocalyx - emerging clinical impact |journal=British Journal of Clinical Pharmacology |language=en |volume=80 |issue=3 |pages=389–402 |doi=10.1111/bcp.12629 |pmc=4574825 |pmid=25778676}}</ref> and sepsis.<ref>{{Cite journal |last1=Steppan |first1=Jochen |last2=Hofer |first2=Stefan |last3=Funke |first3=Benjamin |last4=Brenner |first4=Thorsten |last5=Henrich |first5=Michael |last6=Martin |first6=Eike |last7=Weitz |first7=Jürgen |last8=Hofmann |first8=Ursula |last9=Weigand |first9=Markus A. |date=January 2011 |title=Sepsis and major abdominal surgery lead to flaking of the endothelial glycocalix |url=https://pubmed.ncbi.nlm.nih.gov/19560161 |journal=The Journal of Surgical Research |volume=165 |issue=1 |pages=136–141 |doi=10.1016/j.jss.2009.04.034 |issn=1095-8673 |pmid=19560161}}</ref>

Some key components of the glycocalyx such as [[Syndecan|syndecans]], [[Heparan sulfate|heparan sulphate]], [[Chondroitin sulfate|chondroitin sulphate]] and [[Hyaluronic acid|hyaluronan]] can be shed of the endothelial layer by enzymes. [[Hyaluronidase]], hepararanse/heparinase, matrix and membrane-type [[Matrix metalloproteinase|matrix metalloproteases]], thrombin, plasmin and elastase are some examples of enzymes that can induce shedding of the glycocalyx and these sheddases can therefor contribute to degradation of the glycocalyx layer in several pathological conditions.<ref>{{Cite journal |last1=Becker |first1=Bernhard F. |last2=Jacob |first2=Matthias |last3=Leipert |first3=Stephanie |last4=Salmon |first4=Andrew H. J. |last5=Chappell |first5=Daniel |date=September 2015 |title=Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases |journal=British Journal of Clinical Pharmacology |volume=80 |issue=3 |pages=389–402 |doi=10.1111/bcp.12629 |issn=1365-2125 |pmc=4574825 |pmid=25778676}}</ref> Research shows that plasma hyaluronidase activity is decreased in experimental as well as in clinical septic shock and is therefore not considered to be a sheddase in sepsis.<ref>{{Cite journal |last1=van der Heijden |first1=Jaap |last2=Kolliopoulos |first2=Constantinos |last3=Skorup |first3=Paul |last4=Sallisalmi |first4=Marko |last5=Heldin |first5=Paraskevi |last6=Hultström |first6=Michael |last7=Tenhunen |first7=Jyrki |date=2021-10-11 |title=Plasma hyaluronan, hyaluronidase activity and endogenous hyaluronidase inhibition in sepsis: an experimental and clinical cohort study |journal=Intensive Care Medicine Experimental |volume=9 |issue=1 |pages=53 |doi=10.1186/s40635-021-00418-3 |issn=2197-425X |pmc=8502523 |pmid=34632531 |doi-access=free }}</ref> Concomitant, the endogenous plasma inhibition of hyaluronidase is increased and could serve as a protection against glycocalyx shedding.

Fluid shear stress is also a potential problem if the glycocalyx is degraded for any reason.  This type of frictional stress is caused by the movement of viscous fluid (i.e. blood) along the lumen boundary. Another similar experiment was carried out to determine what kinds of stimuli cause fluid shear stress. The initial measurement was taken with intravital microscopy, which showed a slow-moving plasma layer, the glycocalyx, of 1 μm thick.  Light dye damaged the glycocalyx minimally, but that small change increased capillary [[hematocrit]]. Thus, fluorescence light microscopy should not be used to study the glycocalyx because that particular method uses a dye. The glycocalyx can also be reduced in thickness when treated with oxidized LDL.<ref>Gouverneur, Mirella. Dissertation. "Fluid shear stress directly stimulates synthesis of the endothelial glycocalyx : perturbations by hyperglycemia." 2006.  University of Amsterdam. p. 115–153</ref> These stimuli, along with many other factors, can cause damage to the delicate glycocalyx.  These studies are evidence that the glycocalyx plays a crucial role in cardiovascular system health.