Vascular Permeability Index

Wall permeability disorders are observed in the exchange vessels of the great and small circulatory circles. The causes of abnormalities are intra- and extravascular factors caused by many diseases. Acute violation of vascular permeability in the small circle of circulation is manifested by pulmonary oedema.

Intravascular permeability disorders include:

- Hypertension of any genesis. Increase in intravascular pressure causes sweating (seepage of blood plasma through the vessel walls). The most dangerous is hypertension in the small circulation circle, which is manifested by cardiac asthma and pulmonary oedema. Examples of sweating in the large circulation circle are diapedesis haemorrhagic stroke, diapedesis haemorrhages in the retina, etc., which can be manifested by cardiac asthma and pulmonary oedema.

- Increase in intravascular osmotic pressure, 80% determined by albumin. In starvation, exhaustion, prolonged severe illnesses, when the amount of albumin in plasma critically drops, it passes from the vascular bed to the tissues, causing oedema.

- Inflammatory and immune reactions of the body, as a result of which the blood is saturated with biologically active amines (serotonin, histamine). They briefly increase the permeability of the vascular endothelium and trigger mechanisms that damage the vascular wall, causing its increased permeability for a long time.

Extravascular permeability disorders include, first of all, all types of local tissue inflammation, due to which tissue basophils release biologically active substances and enzymes. They increase vascular permeability and inhibit fluid resorption.

Often intra- and extravascular factors are combined, which occurs in generalised inflammation. This is how acute respiratory distress syndrome (ARDS or shock lung) manifests itself, which complicates pneumonias by increasing the permeability of the aerohematic barrier and causing pulmonary oedema. Therefore, monitoring of vascular permeability abnormalities plays a leading role in the early detection of dangerous complications. However, due to the labour-intensive analysis and lack of necessary equipment, such a study is performed only in specialised pulmonological centres.

For detailed information, please read the following articles:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462517/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998843/

Vascular Permeability in Diseases

Vascular permeability, in various circumstances, can be modified. Hypothyroidism endothelium-dependent dilation is impaired but expression of mRNA for nitric oxide synthase is unchanged in muscles isolated from rats with thyroid dysfunction [22]. The elevated plasma level of homocysteine is associated with various vascular complications. Homocysteine limiting inhibition of metalloproteinases causes changes of the matrix of blood brain barrier and, consequently, the permeability [23,24].

1.    Pulmonary Edema

Hemostasis of lung fluid is dependent upon endothelial cell barrier function. Increased flux of fluid and/or plasma-rich protein across endothelium of pulmonary capillaries results in pulmonary edema. Alteration of endothelial cell junctions VE-cadherin, associated with α, β catenin, and p120-catenin, leads to high permeability of pulmonary capillaries [25]. Pulmonary edema can be provoked by pathogens and inflammatory cells, mostly leukocytes and inflammatory mediators. Alternatively, left heart failure, high altitude, and high pulmonary pressure can be responsible of stress failure [26]. The mechanism resulting in the breakdown of the endothelial barrier function can be induced by pressure increase and endothelial cell activation. Lung vascular permeability can be increased by extracellular matrix alteration, for example, by in vitro modification of collagen crosslinking [27].

A newly described component, Piezo 1, a transmembrane molecule, can modulate the signaling pathways modifying membrane tension. It can modify vascular pressure and disturb endothelial adherens junctions. Piezo 1 is a potential target for pharmacological agents in the prevention of pulmonary edema [28].

Urokinase plasminogen activator (UPA) concentration is augmented in acute pulmonary lung injury. Mice deficient in UPA are protected against pulmonary edema induced by endotoxin; however, the mechanism involving UPA for the regulation of vascular tone and permeability in the lung is still not known [29].

2.    Cerebral Edema

Various brain diseases, traumatic brain injury, and stroke can be associated to cerebral edema. It can be life-threatening, if not treated adequately and in a timely manner.

Osmotic agents, such as mannitol and hypertonic saline, are widely used to treat patients with cerebral edema. Cerebral edema may be divided into cytotoxic, ionic, and vasogenic edema.

The edema is related to the change of the brain blood barrier (BBB) permeability. Endothelial cells of the brain capillaries, in association with pericytes, astrocytes, and perivascular microglia, are essential for homeostasis in BBB. As observed in other organs or tissues VEGF is an important regulator of vascular permeability. VEGF R2 has a crucial role in VEGF function on permeability. VEGF and VEGF R2 expression was increased with augmentation of BBB permeability. The disruption of the tight junctions between endothelial cells leads to BBB breakdown.

Treatment by anti-VEGF antibodies can reduce edema. Hypoxia-inducible factor-1 (HIF-1) can affect VEGF expression. Tight junction components zonula occludens-1 (ZO-1) and Claudin-5 could be regulated and, consequently, modify BBB permeability. Hypertonic saline has been reported to reduce TNF-α and IL1-β and be beneficial for reducing inflammation and limiting the release of proinflammatory cytokines by astrocytes [30]

3.    Infectious Diseases

In sepsis, elevated levels of TNF-α may participate in glycocalyx damage. In addition, a disintegrin metalloproteinase 15, heparanase, and matrix metalloproteinase 2/9 (MMP2/9) have been implicated in the degradation of glycocalyx [7].

SARS-CoV-2 proteins alter the barrier properties mediated by cell-junction proteins; 18 of 26 proteins of SARS-CoV-2, including nsp2, nsp5-c145a, and nsp7, affect the protein network regulating vascular functionality. The modulation of barrier functions can be measured via trans-epithelial–endothelial electrical resistance (TEER), which identifies changes in impedance values, reflecting the permeability of the cell monolayer [31]. In patients infected with SARS-CoV-2, fragmented vascular endothelial glycocalyx is elevated and may be an indicator of vascular complications [32].

SARS-CoV-2, after binding to the angiotensin-converting enzyme receptor, stimulates the formation of inflammatory cytokine (interleukin-6) and initiates coagulation, which leads to vascular thrombosis.

Anaphylaxis is a life-threatening type I allergic reaction, observed after contact to chemicals, venoms, bacteria, and/or virus components. The immunological-like reaction involved T cells, Th2 cytokines, and the production of IgE by B lymphocytes. The degranulation of basophils, provoked by IgE binding, results in the release of histamine, heparin, chymase, carboxypeptidase, TNFα, leukotriens, and VEGF. Several of these mediators, such as histamine and VEGF, increase vascular permeability [33].

Histamine and platelet activating factor (PAF) can stimulate NO synthesis and induce blood vessel dilatation, as well as the dysfunction of the endothelial barrier, by opening adherens junctions [5].

4.    Cancer

Tumor metastasis is one of the main factors associated with high rates death in cancer patients. Cancer metastasis is favored by the enhancement of vascular permeability. Circulating tumor cells, moving in the microvasculature, tend to invade into stromal tissue at the location, where vascular permeability is enhanced. Interactions between tumor and endothelial cells are important steps mediated by different receptors or chemical structures. The extravasation of tumor cells is dependent upon vascular permeability [34]. At least two mechanisms are involved in trans-endothelial permeability, vesicle transport, and migration through endothelial cell junctions. A tripeptide derived from collagen (proline–glycine–proline) promotes VE-cadherin phosphorylation and enhanced vascular permeability. Tumor cells can bind to endothelial cells and induce EC necrosis via a TNF receptor family mechanism. Tumor cells can also release a large number of molecules that affect EC permeability [35].

Hyaluronic acid, heparan sulfate, and chondroitin sulfate, present in the glycocalyx, limit the access of circulating tumor cells to adhesion receptors, such as ICAM-1 or P selectin.

Serum amyloid A (SAA) is a family of reactants that can increase during the acute phase and serve as chemoattractant in proinflammatory phase (SAA3 and SAA1.1/2.1). SAA3, which is a major hepatic acute phase component in mice, is not produced in humans [36].

Thrombin, heparanase, and matrix metalloproteinase (MMP), produced in inflammatory conditions, degrade the glycocalyx component, favoring tumor cell access to the EC surface. The production of the tissue factor, by EC and/or macrophages, leads to factor X activation, which induces fibrin formation. Fibrinogen is highly represented in lung cancer and has been considered a permeability factor [37].

5.    Diabetes Mellitus

In diabetes mellitus, classically divided into types 1 and 2, microvascular complications are responsible for abnormal permeability. The risk of cardiovascular complications is 2- to 4-fold higher in diabetic patients. Hyperglycemia is associated with a reduction of the glycocalyx via different interactions with the glycocalyx components. In addition, the shear stress-induced dilation is reduced by hyperglycemia, and several EC functions are directly altered by hyperglycemia, glycated proteins, or lipids [38].

The level of N epsilon-carboxymethyl lysine protein (CML) is increased in type 2 diabetic patients, and it also correlated with the augmented macrophage colony-stimulating factor (M-CSF) blood level [39]. A causal relationship may exist between these two parameters, since advanced glycation end products (AGE), formed either in vitro or patient AGE, enhanced M-CSF production by human umbilical vein endothelial cells (HUVEC). It has been previously established that, by binding AGE to receptor RAGE, this can produce an increased vascular permeability or the development of atherosclerotic lesion in animal models [40]. RAGE is expressed by endothelial cells, lymphocytes, and monocyte macrophages. RAGE ligands can bind to the different cell types and participate in inflammatory reactions [41].

The duo endothelial cell/monocyte functioned in harmony or opposite ways, depending on the organ and clinical situation, infectious diseases, inflammatory conditions, atherogenesis, and neoangiogenesis.

Hyperpermeability is a precocious abnormality of diabetic vasculopathy. Endothelial cells in culture, when incubated with AGE proteins or glycated red blood cells, demonstrated an increased permeability to macromolecular tracers 125I albumin and 3H inulin, compared with endothelial cells incubated with normal proteins or red blood cells (RBC) from normal subjects. Membrane proteins of erythrocytes can be glycated: spectrin, band 3 transmembrane protein, and band 4–1 [42]. The glycation results in reduced RBC deformability and an increased adherence to endothelium [43]. When incubated with RBC from diabetic patients, anti-AGE antibodies or soluble RAGE (sRAGE) inhibit the enhanced adhesion to endothelium (Figure 3). The accelerated clearance of diabetic rat RBC, when infused in normal rats, is prevented by the co-infusion of the anti-RAGE antibody. These results support the concept that the abnormal adhesion of RBC, taken from diabetics, is mediated by the AGE present on RBC, as well as the RAGE expressed at the endothelial cell surface. The reduction of endothelial cell barrier function was inhibited by anti-AGE specific antibodies. In diabetic rats infused with soluble RAGE, hyperpermeability was corrected in the intestines and skin and suppressed by 90% in the kidney. According to reported experiments, reactive oxygen species formation is a likely means by which oxidative stress can increase vascular permeability by rapid changes in endothelial cell shape via calcium mediated pathways [44]. Increased reactive oxygen species (ROS) damage EC function and affect EC permeability. The best-known pathway of ROS generation involved NADPH oxidase [45].

As we previously showed, neoangiogenesis is impaired in animal models of diabetes, and collateral vessel development is significantly limited in diabetic patients [46]. Several factors may contribute to neoangiogenesis in diabetes. Glycation of basic fibroblast growth factor, with the intracellular sugars, fructose, and glucose-6-phosphate, reduced its high affinity heparin-binding capacity and mitogenic activity.

Glycated collagen induces premature endothelial cell senescence, as indicated by the appearance of senescence-associated β-galactosidase, increased cell size, and rate of apoptosis. This glycated collagen-induced senescence is associated with a decreased synthesis of NO. Premature senescence may contribute to diabetic vasculopathy. Enhanced inflammation of the vascular system is associated with an enhanced expression of cyclooxygenase-2 and PGE synthase-1 in human diabetic atherosclerotic plaques. AGE formation limits proteolysis of glycated proteins and, therefore, is deleterious for mechanical properties of the vessel wall.

We previously reported that, after 28 days, the ischemic/nonischemic leg angiographic ratio was decreased by 1.4-fold in diabetic animals, when compared with the control animals. In contrast, when diabetic mice were treated with aminoguanidine, the angiographic score was in the same range of the level observed in control animals. When the diabetic mice were treated by aminoguanidine, the AGE levels were decreased 4.2-fold, compared with untreated diabetic mice. When collagen is glycated, as it occurs during ageing, synthesis of NO is decreased. Blockade of AGE formation normalized impaired ischemia, which is probably mediated by restoration of matrix degradation processes [47].

Atherosclerosis and microangiopathy are observed in various pathologies, including diabetes mellitus. The potentiation of VCAM-1 expression may facilitate monocyte adhesion and extravasation. The statistically significant correlation between CML-protein blood level and M-CSF suggests that this mechanism may exist in diabetic patients. An inflammatory cascade of events may be initiated by AGE and involve chemotactic factors, leukocyte mediators [48], and prostaglandin modulation [46].

The relationships between CML, M-CSF, and VCAM-1 in diabetic patients with microangiopathy suggest that, beside the inflammatory reaction involved in the genesis of atherosclerotic lesions, endothelial activation can result, not only in vascular hyperpermeability, but also in the alteration of the microvasculature.

6.    Vascular Permeability in Kidney

One of the frequent complications in diabetes is diabetic nephropathy. Albuminuria is linked to glomerular dysfunction. Glomerulosclerosis, observed in diabetic animals, is associated with AGE deposition in mesangium and hyalinized and/or sclerotic lesions [49]. Levels of N epsilon-carboxymethyl lysine (CML) adducts are increased in soluble proteins and insoluble collagen in patients, with diabetes and renal impairment [50]. Endothelial cells are different, according to the organs. Hepatic sinusoidal endothelial cells and endothelium lining the glomerular tuft represent a permeable barrier with selective, different properties, which have major functions in homeostasis and organ failure in chronic and acute diseases [51].

RAGE overexpression enhanced glomerulosclerosis development in mice [52]. The pharmacological blockade of RAGE in db/db mice or genetic deletion of RAGE in mice with streptozotocin-induced hyperglycemia result in decreased albuminuria, mesangial expansion, and glomerulosis [53].

Methylglyoxal (MG)-derived hydroimidazolone MG-H1, N epsilon-carboxymethyl lysine, and glucosepane are quantitively important in AGE. The cellular proteolysis of AGE-modified proteins forms AGE-free adducts and glycated amino acids, which are cleared by the kidneys and excreted in urine. AGE-free adducts accumulate markedly in plasma, when the glomerular filtration rate declines. A key precursor of AGE is the dicarbonyl metabolite MG, which is metabolized by the glyoxalase 1 (Glo1) from the cytoplasmic glyoxalase system. An abnormal increase in MG dicarbonyl stress is a characteristic of chronic kidney disease (CKD) and driven by the down-regulation of renal Glo1, which increases flux of MG-H1 formation.

In renal failure, peritoneal dialysis causes chemical peritonitis because of the limited biocompatibility of peritoneal dialysis fluids, which contain high glucose concentrations (up to 45 g/L) and, thus, the glucose-derived products that are the precursors for AGE. Due to the fact that RAGE is expressed on endothelial and mesothelial cells, the receptor may bind AGE present in patients or formed during peritoneal dialysis [54]. The binding of AGE to RAGE produces a local inflammatory reaction, likely as a consequence of vascular cell adhesion molecule-1 overexpression, leukocyte adhesion, and cytokine release [55].

7.    Retinopathy

The ocular complications are a hallmark of diabetic complications. Several decades ago, the deleterious effects of AGE formation in pig crystallin was observed in the pathogenesis of diabetic cataract [56]. One of the earliest changes observed in retinal micro vessels is the selective loss of intramural pericytes, which is a process that may be linked to the effects of AGE. AGE may induce apoptosis and necrosis in experimental models [55]. Macular edema is frequently observed in diabetic retinopathy. In reaction to hypoxemia-induced microvascular damage, the retinal epithelial and endothelial cells increase the production of VEGF and promote neoangiogenesis, which is a process that antibodies to RAGE prevent. Pyridoxamine, an inhibitor of AGE formation and lipoxidation end products, protects against diabetes-induced retinal vascular lesions [57]. The thiamine monophosphate derivative, benfotiamine, inhibits hyperglycemia-dependent pathways and NF-κB activation and prevents experimental diabetic retinopathy [58]. Beraprost sodium, a PGI 2 analog, has been reported to protect retinal pericytes from AGE-induced cytotoxicity, through its anti-oxidative properties; it was also previously shown to decrease vascular hyperpermeability in diabetic rats [59].

In patients with diabetes, mellitus diabetic macular edema and proliferative diabetic retinopathy (PDR) are the most frequent reasons for loss of vision. Macular edema causes the disruption of the inner blood-retinal barrier. Anti-VEGF was used to treat patients [60]. Diabetic retinopathy involves morphological and functional changes in the retinal capillaries. Basement membrane thickening, loss of pericytes, increased permeability, and vascular dysfunction are the prominent features. Diabetic macular edema is more commonly found in type 2 diabetes than in patients with type 1 diabetes.

On another hand, AGE can exert deleterious effects by acting directly to induce the cross linking of long-lived proteins, in order to promote vascular stiffness and, by interacting with receptor for AGE (RAGE), induce intracellular signaling, which leads to enhanced oxidative stress and the production of pro-inflammatory cytokines. Increased AGE accumulation has been found in cataract lenses in patients when ageing. Glycation of vitreal collagen fibrils can provoke the destabilization of the gel structure vitreous liquefaction and posterior vitreous detachment.

In diabetic patients, an increase in skin concentration of pentosidine is associated with the development of proliferative retinopathy [61]. The same holds true for 2-(2-fuoryl)-4(5)-(2-furanyl)-1H-imidazole (FFI), N-(epsilon) (carboxymethyl)lysine, which increases in parallel with the increasing severity of retinopathy [62].

8.    Permeability and Atherogenesis

Current theory of atherogenesis opens a large role to lipids, stimulating M1 macrophage inflammatory response. Monocytes, recruited in the sub endothelium space, phagocyte lipids and produce inflammatory cytokines. Macrophages can stimulate angiogenesis, increase permeability, and augment inflammatory cell attraction.

In atherosclerotic plaque, defective endothelial junctions are associated with inflammation and a potentiation of VEGFA-VEGFR2 interactions [63]. Endothelium, with altered barrier function, facilitates LDL accumulation. The LDL passage is first limited by the glycocalyx then LDL transport through EC via transcytosis. The different types of dyslipidemia alter EC functions. Hyperlipidemic serum increases permeability of EC in culture. Atherosclerosis progression resulted from multiple interactions between macrophages, endothelial cells, smooth muscle cells, and matrix cells. Plaques that exhibited increased vascular permeability have a higher propension to thrombosis.

Ultrasmall superparamagnetic iron oxide particles (UPSIOs) deposit in areas with abnormal permeability. UPSIOs are macrophage markers, not only in atherotic plaque, but also in inflammatory milieu.

Smooth muscle cells exhibited adhesion molecules and expressed tissue factors, which may lead to atherothrombosis. Evans blue deposition, used as permeability index, demonstrated that impaired endothelial permeability is associated with CLIO-CyAm7 (iron oxide nanoparticles) deposition. Impaired endothelial barrier function facilitates macrophage accumulation in the atheroma intima [64].

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