Examining the Human Blood Vessels
The human circulatory system consists of blood vessels that transport blood throughout the body. There are three major types of blood vessels:
- Arteries (Arteries carry the blood away from the heart)
- Veins (Veins carry blood from the capillaries back toward the heart)
- Capillaries (Capillaries allow the exchange of water and chemicals between the blood and the tissues)
Figure 1: Comparison of Arteries, Capillaries and Veins
The tunicae (a membranous sheath enveloping or lining an organ) of blood vessels, specifically the arteries and veins, contain three layers:
- Inner layer (the tunica intima)
- This is the thinnest layer of squamous endothelial cells glued by a polysaccharide intercellular matrix
- Middle layer (the tunica media)
- This is the thickest layer in the arteries of circularly arranged elastic fiber and connective tissue. It is prominent in vascular smooth muscle.
- Outer layer (the tunica adventitia)
- This is the thickest layer in the veins made of entirely connective tissue composed of collagen. The collagen serves to anchor the blood vessel to nearby organs, giving it stability. Nerves are contained in the tunica adventitia.
The Capillaries consist of a layer of endothelium and connective tissue.
Figure 2: Structure of the Artery Wall
Introduction to the Glycocalyx in General
The glycocalyx is a glycoprotein-polysaccharide coating that surrounds the cell membranes of some epithelia and other cells. The epithelia is a form of tissue that lines the cavities and surfaces of blood vessels and organs throughout the body.
The glycocalyx surrounding the cell membrane consist of a fuzzy-like coat and provide backbone molecules for support. The polysaccharide portion of the glycocalyx molecule assists the molecule in: 1
- cell-cell recognition
- intercellular adhesion
The body utilizes the glycocalyx as a mechanism to distinguish between its own healthy cells and transplanted tissues, diseased cells, or invading organisms.
The major role of the glycocalyx is in the regulation of the endothelial vascular tissue through the endothelial glycocalyx. 2
Introduction to the Endothelial Glycocalyx
The endothelial glycocalyx is a very thin (approximately 1 μm magnitude or .001 millimeters or 0.00003937007874 inches) 3 hydrated gel-like layer on the luminal surface of the vascular endothelium. The thickness of the glycocalyx increases with vascular diameter, at least in the arterial system, ranging from 2 to 3 μm in small arteries 4 to 4.5 μm in carotid arteries. 5
It is commonly referred to as the endothelial glycocalyx layer (EGL) or endothelial surface layer (ESL). 6 7 The glycocalyx is located on the apical surface of vascular endothelial cells which line the lumen.
The endothelial glycocalyx was already visualized some 40 years ago by JH Luft using electron microscopy. 8 The importance and validity of the endothelial glycocalyx as a vital factor in vascular physiology and pathology has increased over the years. 9 10
Figure 3: High-powered electron microscope photograph of the endothelial glycocalyx (Source)
The name “glycocalyx” means “sweet husk” or “sugar coat”, referring to its high polysaccharide content. The term was initially applied to the polysaccharide matrix coating epithelial cells which is a delicate gel lining inside our arteries.
The glycocalyx is a gel-like coating that acts as a shield for the endothelium and forms the interface between the vessel wall and moving blood. The glycocalyx is held in place to the arterial wall by protein hair-like fibers. The composition of the glycocalyx is not static as there is a balance between biosynthesis and shedding of glycocalyx components.
The glycocalyx is composed of a negatively charged network of proteoglycans, glycoproteins, and glycolipids. 11 Located between the blood stream and the endothelium, the endothelial glycocalyx is an important determinant of vascular permeability. 12 It is able to limit access of certain molecules to the endothelial cell membrane. A dynamic equilibrium exists between the glycocalyx and the flowing blood, continuously affecting composition and thickness of the glycocalyx. In fact, the shear stress applied from blood flow patterns provide the stimulus for the synthesis of the glycosaminoglycans present in the glycocalyx. As would be expected, the more turbulent blood flow patterns around vessel bifurcations and curvatures result in an inherently thinner glycocalyx, which explains the vulnerability of these areas to clot formation.
Figure 4: Schematic representation of the endothelial glycocalyx, showing its main components. Left: The endothelial glycocalyx can be observed in vivo as a red blood cell exclusion zone, located on the luminal side of the vascular endothelium. It consists of membrane-bound and soluble molecules. Right: Components of the endothelial glycocalyx. Bound to the endothelial membrane are proteoglycans, with long unbranched glycosaminoglycan side-chains (GAG-chain) and glycoproteins, with short branched carbohydrate side-chains. (Source: The endothelial glycocalyx: composition, functions, and visualization, flugers Arch. 2007 Jun; 454(3): 345–359., Published online 2007 Jan 26. doi: 10.1007/s00424-007-0212-8)
- heparin sulfate
- chondroitin sulfate
- hyaluronic acid
Figure 5: Structure of glycocalyx: the backbone molecules, glycoproteins and proteoglycans; GAG chains linked to core proteins; soluble molecules derived from plasma or endothelium bound to proteoglycans; intertwined HA molecules; sheltered adhesive molecules. (Source: Modulation of Endothelial Glycocalyx Structure under Inflammatory Conditions, Mediators of Inflammation, Volume 2014 (2014), Article ID 694312, 17 pages)
The molecular components of the endothelial glycocalyx are characterized by a polyanionic charge which helps repel circulating platelets. The exact composition varies greatly according to the local microenvironment.
At any given time, it also contains constituents of the routine molecular traffic which passes through it or lodges within it, such as:
- Plasma proteins
- Enzymes and enzyme inhibitors
- Growth factors
- Amino acids
- The glycocalyx is comprised of 95% water.
The endothelial glycocalyx also consists of a wide range of enzymes and proteins that regulate leukocyte and thrombocyte adherence, since its principal role in the vasculature is to maintain plasma and vessel wall homeostasis.
These enzymes and proteins include:
- Extracellular superoxide dismutase (SOD3)
- Angiotensin converting enzyme
- Lipoprotein lipase
- Growth factors
Biological Function of the Endothelial Glycocalyx
The endothelial glycocalyx plays a major role in the regulation of endothelial vascular tissue and thus has a variety of biological functions.
- Vascular permeability
- Impenetrable layer
- Glycocalyx serves as a slippery layer to prevent things such as oxidized LDL cholesterol and white blood cells from sticking to the endothelial cells. Once endothelial cells are exposed, then cholesterol plaque may develop.
- Exclusion zone
- Acts as the exclusion zone between blood cells and the endothelium.
- Physical barrier
- Provides a physical barrier against inadvertent adhesion of platelets and leukocytes to the vascular wall. 17
- Modulates red blood cell volume
- Modulation of red blood cell volume in capillaries 18
- Barrier against leakage of certain molecules
- Acts as a barrier against leakage of fluid, proteins and lipids across the vascular wall.
- Dynamic interaction
- Interacts dynamically with blood constituents.
- Natural coagulant regulator
- Regulates coagulation under normal physiological condition 19
- Modulation of adhesion
- Modulates adhesion of inflammatory cells and platelets to the endothelial surface.
- Sensor and mechanotransducer
- Functions as a sensor and mechanotransducer of the fluid shear forces to which the endothelium is exposed.
- Protective enzymes
- Retains protective enzymes (eg. superoxide dismutase).
- Protection of cell membrane
- Cushions the plasma (cell) membrane and protects it from chemical injury.
- Inflammation regulation
- Glycocalyx coating on endothelial walls in blood vessels prevents leukocytes from rolling/binding in healthy states. 20
- Filtration of interstitial fluid
- Affects the filtration of interstitial fluid from capillaries into the interstitial space. 21
- Binding site
- Serves as a significant binding site for antithrombin III (ATIII), tissue factor pathway inhibitor, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and lipoprotein lipase. 22
Damage to the Endothelial Glycocalyx
The glycocalyx is fragile and subject to damage. Damage to the glycocalyx is the result of either:
- Thinning of the glycocalyx layer, and/or
- Shedding of the glycocalyx layer
The major common factors that contribute to the damage and disruption of the glycocalyx are:
- Lack of moderate exercise.
- Note that excessive or strenuous exercise or over training can also damage the glycocalyx.
- Poor diet
- Single high sugar meal
- Frequent and repeated meals consisting of sugars eventually wears the glycocalyx down into a thinner, less healthy layer. High blood sugar is the most damaging cause of the glycocalyx
Despite the factors that contribute to a damaged glycocalyx, it has the ability to restore itself and is self-repairing. A study found that the glycocalyx’s ability to restore itself can take up to 6 to 8 hours under normal and healthy circumstances. The problem is that before it has time to repair itself, it my be assaulted repeatedly through smoking, poor diet or a high sugar meal.
Thinning of the glycocalyx layer
The thinning of the glycocalyx layer is caused by the following pathological processes:
- Hyperglycemia (a condition in which an excessive amount of glucose circulates in the blood plasma. Diabetes mellitus and metabolic syndrome (insulin resistance))
- Individuals with hyperglycemia and diabetes are known to have less endothelial glycocalyx.
- Hyperlipidemia (involves abnormally elevated levels of any or all lipids and/or lipoproteins in the blood)
- The glycocalyx can also be reduced in thickness when subjected to oxidized LDL cholesterol. 23
The pathological processes are known to cause atheroma formation, which is an accumulation of degenerative material in the tunica intima (inner layer) of artery walls. 24
Shedding of the glycocalyx layer
The second major cause of glycocalyx damage derives from enzymatic or shear-induced shedding.
Figure 6: Example of a healthy glycocalyx and a shedding glycocalyx (Source: Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy, Br. J. Anaesth. (2012) doi: 10.1093/bja/aer515)
Shedding of the glycocalyx layer can be caused by:
- Inflammatory mediators (when systemic inflammation is present and at raised levels)
- Ischaemia-reperfusion injury (which halts the endothelial synthesis of glycosaminoglycans) 30
- Hypervolemia (medical condition where there is too much fluid in the blood) 31
- Major vascular surgery 32
- Major abdominal surgery (significant flaking of the endothelial glycocalix occurred in patients with sepsis, and to a lesser extent in patients after major abdominal surgery) 33
- Sepsis (Sepsis is a whole-body inflammatory response to an infection) 34
Whatever the stimulus, shedding of the glycocalyx leads to a drastic increase in vascular permeability. 35 When the glycocalyx is damaged, the vasculoprotective properties of the blood vessels are lost. 36
Adverse Biological Effects of Glycocalyx Damage and Disruption
The modulation of glycocalyx structure is seen under systemic inflammatory conditions and the possible consequences for pathogenesis of selected diseases and medical conditions. The damage to the endothelial glycocalyx is due primarily to many inflammation-based pathological states.
Figure 7: The glycocalyx in a healthy physiological state versus a state of Ischemia or Inflammation
Many studies have demonstrated that the degree of glycocalyx shedding depends on the extent of the systemic inflammatory state. There exists a correlation between the severity of a disease and the level of glycocalyx components in the blood. 37 38 39
Figure 8: Overview of alternated glycocalyx functions as a result of its shedding which could lead to pathological states connected with various diseases. Matrix metalloproteinases (MMPs), reactive oxygen and nitrogen species (ROSs/RNSs), and tumor necrosis factor α (TNF-α). (Source: Modulation of Endothelial Glycocalyx Structure under Inflammatory Conditions, Mediators of Inflammation, Volume 2014 (2014), Article ID 694312, 17 pages)
Damaged and impaired endothelial glycocalyx is also demonstrated in the patients with:
- Coronary heart disease 40
- Renal diseases 41
- Lacunar stroke (a small vessel disease) 42
- Severe trauma 43
- Hypoglycemia/Diabetes 44
- Ischemia/reperfusion 45
- Atherosclerosis 46
- Local hypercoagulability 47
- Global autoheparinisation (especially during trauma) 48
- Impaired microcirculatory oxygen distribution 49
- Loss of vascular responsiveness 50
- Increased platelet aggregation 51
- Increased leucocyte-endothelium interaction 52
- Pulmonary Edema and Acute Lung Injury (Pulmonary endothelial dysfunction plays a major role in lung injury via alterations in barrier permeability, thus promoting pulmonary edema formation; the adjoining glycocalyx has recently emerged as a major endothelial element involved in the regulation of vascular integrity and fluid homeostasis. A glycocalyx mechanotransduction-mediated lung injury model predicts that activation of pressure- or flow-induced signals during pulmonary resection may lead to augmentation in endothelial cell hydraulic conductivity, i.e., capillary permeability, involved in the formation of pulmonary edema). 53
General Maintenance of the Glycocalyx
Maintaining the integrity of the glycocalyx demands the practice of a healthy lifestyle. In order to accomplish this, the daily positive habits should be practiced:
- Obtain a proper nights sleep
- Reduce daily stress or stressors
- Engage in moderate exercise daily or at least 6 times per week
- Eat real natural foods with no consumption of processed foods
In addition, the following negative habits should be avoided:
- High sugar diet. When dietary sugars are consumed, the glycocalyx is damaged and destroyed wherein the body then begins to re-build the glycocalyx.
Managing chronic (systemic) inflammation is also important to avoiding damaged glycocalyx.
Beyond practicing the positive daily habits and avoiding the negative daily habits, there are subsequent therapeutic strategies that can be followed to assure that the integrity of the glycocalyx is maintained. These strategies are discussed in the next two sections.
Certain Experimental Strategies to Regenerate and Repair the Glycocalyx
There are only handful of studies examining the strategies to regenerate and repair the glycocalyx. Most of the agents suggested for the repair or regeneration of the glycocalyx is pharmaceutical based, and thus require the administration from a licensed physician, if at all possible.
The following experimental strategies to repair the glycocalyx have been researched are are contained in the scientific literature: 54
- Adenosine A2A receptor agonists 55
- Adenosine A2A receptors are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow.
- Nitric oxide 56
- Nitric oxide is a cardiovascular signaling molecule and a powerful vasodilator with a short half-life of a few seconds in the blood.
- TNF-α inhibitors 57
- A TNF-alpha inhibitor is a substance or drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF-alpha or its effects are inhibited by several natural compounds, including curcumin (a compound present in turmeric), and catechins (in green tea).
- Allopurinol 58
- Allopurinol is a medication used primarily to treat excess uric acid in the blood.
- Sulodexide, a mixture of glycocalyx GAG precursors consisting of heparin sulphate (80%) and dermatan sulphate (20%), can be included among compounds suggested as a possible treatment of dysfunctional glycocalyx. 59
- Albumin Plasma Proteins
- A suggested way to protect the glycocalyx is to maintain a sufficiently high concentration of plasma proteins 60
- The protective effect of the albumin supplementation on glycocalyx preservation in a model of transplantation-induced ischemia/reperfusion glycocalyx damage was presented by Jacob et al. 61
- N-acetyl cysteine (NAC)
- In human research, NAC prevented the hyperglycemia-induced reduction of glycocalyx. 62 It is important to note that in this study NAC was infused into the blood stream 15 minutes before and then continuously with glucose infusion at a very a large dose. Such a protocol is good for research but has a very limited application in a real life situation. In another words, oral supplementation of NAC is unlikely to achieve this effect in hyperglycemic individuals.
- Chondroitin sulphate and hyaluronic acid
- Infusion of a mixture of hyaluronan and chondroitin sulfate after enzyme treatment reconstituted the glycocalyx, although treatment with either molecule separately had no effect. 63
Other than N-acetyl cysteine, chondroitin sulphate and hyaluronic acid, which are easy to obtain from a health store or online, the other strategies, such as Sulodexide and Allopurinol, require a prescription and supervision from a health professional.
An Alternative (Natural) Approach to Regenerating and Repairing the Glycocalyx
Scientists have spent years researching ways to regenerate and repair the endothelial glycocalyx in a simple effective manner. The answer to repairing the endothelial glycocalyx may lie in the consumption of sulphated polysaccharides.
Seaweeds (algal) are known as sources of sulfated polysaccharides. Green algal polysaccharides, or sulphated polysaccharides have emerged as rich and important sources of bioactive natural compounds with a wide range of physiological and biological activities. 64 65 These physiological activities include:
Figure 9: Many sea vegetables contain sulphated polysaccharides
Researchers discovered that sulphated polysaccharides from marine algae had heparin-like anticoagulant activities. 66 67 The sulphated polysaccharides from marine green algae show higher anticoagulant activities than sulphated polysaccharides from red and brown seaweeds. 68
A highly investigated green seaweed that produce anticoagulant sulphated polysaccharides belong to the genus Monostroma. Researchers found that there were high anticoagulant activities derived from extracts from Monostroma nitidum seaweed, which contains a high amount of sulphated polysaccharides . In Monostroma nitidum, the active polysaccharide was purified by chromatography to yield an approximately six fold higher activity than standard heparin. 69
In addition to the high anticoagulant activity of Monostroma nitidum, researchers also found that it possessed excellent anti-inflammatory activities. The following inflammation markers were suppressed with Monostroma nitidum: 70
- inducible NO synthase (iNOS)
- tumor necrosis factor-α (TNF-α)
- interleukin-6 (IL-6)
- interleukin-8 (IL-8)
Figure 10: Monostroma nitidum
Rhamnan sulfate is a sulphated polysaccharide in which more than one type of monosaccharide are present. Rhamnose is the major monosaccharide found in rhamnan sulfate and hence gives the polysaccharide its name.
Monostroma nitidum is rich in rhamnan sulfate, a negatively charged polysaccharide, and has been shown to exhibit the following health benefits:
- anticoagulant 71
- antithrombotic 72
- antiviral 73
- antitumor 74
- immunomodulator 75
- lowers total and LDL cholesterol in borderline or mild hypercholesterolemia human subjects 76
- reduces blood glucose level compared to the control animals 77
Figure 11: Rhamnan sulphate from Monostroma nitidum
A study from 2015 investigated the use of Rhamnan sulphate obtained from Monostroma nitidum and its effect on endothelial cells and vascular smooth muscle cells. 78 The results show that Rhamnan sulphate has the potential to be used in the treatment of cardiovascular diseases.
Rhamnan sulfate has a remarkably similar chemical structure to heparan sulfate. Heparan sulphate is found abundantly in the endothelial glycocalyx. Because of this similarity, Rhamnan sulphate may act by repairing and regenerating the glycocalyx.
A 2013 study corroborated the ability of Rhamnan sulphate to repair the glycocalyx. The researchers reported that rhamnan sulfate enhances the endothelial glycocalyx and decreases the LDL permeability of human coronary artery endothelial cells in vitro. 79 This again is due to the fact that Rhamnan sulfate has a similar chemical structure to heparan sulfate.
Arterosil® is a product marketed by Calroy Health Sciences, and is the only dietary supplement that helps maintain optimal endothelial function through regeneration of the vascular endothelial glycocalyx.
Calroy Health Science focuses on developing original science-based solutions to major health challenges through a scientific research program led by Chief Scientific Officer Dr. Chen Chen. Dr. Chen Chen is a widely respected scientist and entrepreneur. With a PhD in nutritional science, he has conducted pioneering research in the field of food and nutrition for over 30 years. While championing healthy lipids, Dr. Chen has conducted extensive studies on functional carbohydrates and participated in the research and development of some of the most innovative products on the market, such as Arterosil®.
The primary active ingredient of Arterosil® is rhamnan sulfate, derived from Monostroma nitidum. The beneficial effects of Arterosil® on endothelial glycocalyx and its mediated endothelial functions are backed up by many years of research. In fact, an randomized double blind clinical study was conducted to evaluate the effectiveness of ArterosilHP® on endothelial function.
The study consisted of 20 healthy human subjects that were placed on ArterosilHP® for 4 weeks. At the beginning and the end of the study, the subjects were challenged with a high fat/high sugar meal in the morning and then followed up for 8 hours at the clinic.
The endothelial glycocalyx thickness was estimated by the measurement of sublingual capillary blood flow as described by Nieuwdorp et al. 80 Endothelial function is evaluated by reactive hyperemia index (RHI).
At the beginning of the study, the subjects experienced a compromised glycocalyx at 1.5 hours after consumption of the high fat/high sugar meal. With 4 weeks of ArterosilHP® supplementation, the same subjects showed a significantly improved glycocalyx at 1.5 hours after the high fat high sugar meal. In both visits, the glycocalyx recovered back close to normal 8 hours after the meal.
Similar trend was also observed with RHI in the subjects (see Figure 12 below). Before ArterosilHP® supplementation (blue baseline), subjects experienced a dramatic drop of RHI 1.5 hours following the high fat/high sugar meal. After 4 weeks on ArterosilHP® supplementation (red ArterosilHP®), the drop of RHI for the same subjects 1.5 hours after the high fat/high sugar meal was significantly reduced. Again RHI showed significant recovery after 8 hours in both visits.
Figure 12: Reactive hyperemia index (RHI) study results
These results clearly demonstrate that ArterosilHP® supplementation ameliorates the damage of endothelial glycocalyx and the loss of endothelial function caused by a high fat/high sugar meal in the healthy human subjects.
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