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• W2800693044 abstract "HomeHypertensionVol. 71, No. 6Sodium Handling by the Blood Vessel Wall Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBSodium Handling by the Blood Vessel WallCritical for Hypertension Development Eliane F.E. Wenstedt, Rik H.G. Olde Engberink and Liffert Vogt Eliane F.E. WenstedtEliane F.E. Wenstedt From the Division of Nephrology, Department of Internal Medicine, Amsterdam Cardiovascular Sciences, Academic Medical Center, University of Amsterdam, The Netherlands. Search for more papers by this author , Rik H.G. Olde EngberinkRik H.G. Olde Engberink From the Division of Nephrology, Department of Internal Medicine, Amsterdam Cardiovascular Sciences, Academic Medical Center, University of Amsterdam, The Netherlands. Search for more papers by this author and Liffert VogtLiffert Vogt Search for more papers by this author Originally published16 Apr 2018https://doi.org/10.1161/HYPERTENSIONAHA.118.10211Hypertension. 2018;71:990–996Extensive research has focused on the association between high-sodium intake and hypertension. New ideas about sodium homeostasis decisively influence the existing ideas about this association. Classically, according to the 2-compartment model, sodium particularly accumulates in the extracellular space, where it equally divides between the intravascular and the interstitial compartment. This is followed by commensurate water retention to maintain normal osmolality. The consequent increase in extracellular volume was considered to be the main causative factor for hypertension. However, consecutive studies revealed that increases in sodium load were neither accompanied by the expected increases in total body water or body weight nor could be accounted for by the excreted amounts of sodium in the urine.1–3 In other words, sodium was missing. Accordingly, the existence of nonosmotic sodium buffers was suggested.3 In this review, we will speculate on the implications of this missing sodium with regard to blood pressure regulation by discussing the journey that sodium undertakes from the circulation and state that sodium handling by the blood vessel wall seems crucial in the development and prevention of hypertension.Concept of Nonosmotic Sodium StorageTwo meticulously performed balance studies in 2000 and 2002 were the first to point out that something was amiss in the common view about sodium homeostasis. In 2000, Heer et al2 revealed that, in contrast to the common thought, an increase in body sodium induced by high-sodium diet was not paralleled by an increase in total body water. Subsequently, Titze et al3 executed a long-term study of 135 days in healthy volunteers who were confined to spaceflight stimulating conditions. Sodium and other electrolyte intake were carefully monitored. Toward the end of the study, sodium gain exceeded weight gain, which introduced the possibility of a nonosmotic sodium storage compartment. A few years later, this hypothesis was confirmed, as rats demonstrated to accumulate sodium in their skin and calculations revealed that the majority of this sodium was osmotically inactive.4 A recent study estimated the potential capacity for nonosmotic sodium storage by measuring sodium and water balance after hypertonic sodium loading in healthy individuals.1 Four hours after infusion, the observed plasma sodium levels were lower than expected according to the Adrogue-Madias and Nguyen-Kurtz formulas, 2 well-known and widely used formulas that are based on the classical 2-compartment model. In the urine, only half of the expected amount of sodium was retrieved. This suggests that sodium was not excreted but osmotically inactivated and remained in the body, again supporting the existence of a significant nonosmotic sodium buffer.Sodium and the Blood Vessel WallWhen transiting from blood to skin, sodium first encounters the vascular endothelium, preceded by a delicate layer that is located on the luminal side of this endothelium: the endothelial surface layer (ESL) or endothelial glycocalyx. The ESL ranges from 0.5 μm in capillaries to 4.5 μm in larger arteries and mostly comprises glycosaminoglycans, which are polymers of disaccharide unit repeats.5 Attached to core proteins, glycosaminoglycans form complexes called proteoglycans. On the basis of their types of disaccharide units, different types of glycosaminoglycans involve heparan sulfate, dermatan sulfate, chondroitin sulfate, keratan sulfate, and hyaluronic acid. The most prevalent glycosaminoglycan in the ESL is heparan sulfate.5,6 The ESL was first visualized in 1966 by Luft,7 and in the decades that followed, it became apparent that this layer wields a varied range of functions, such as providing a lubrication layer for red blood cell motion, preventing leukocyte adhesion, and scavenging free oxygen radicals.5,6ESL and Endothelial Cells Under Normal ConditionsA relatively new notion is that the ESL may also play a considerable role in sodium and water homeostasis.8,9 Located at the luminal side of the blood vessel wall, the ESL is the first barrier that sodium ions encounter when transiting through the blood stream. Apart from its location, its constituents make the ESL a particularly suitable candidate for a role in sodium homeostasis, as the negatively charged glycosaminoglycans enable binding of positive ions.5,6 In vitro experiments demonstrated that under flow, cations like sodium, potassium, and magnesium bind to ESL glycosaminoglycans.10,11 The ESL could, therefore, function as an intravascular sodium buffer.8 Extrapolation of data from in vitro experiments shows that the systemic ESL may be able to buffer up to 35 mmol of sodium.12 This is most likely an underestimation because the ESL is far less well developed in vitro than in vivo.13By acting as an intravascular sodium buffer, the ESL provides a first barrier that prevents sodium from transiting from blood to skin. The second barrier for sodium is the endothelium. After a sodium load, the majority of sodium diffuses to the interstitium via the paracellular route. In addition, sodium can enter the endothelial cell through endothelial sodium channels. These sodium channels have been predominantly described in the epithelium of the kidneys (epithelial sodium channels) but were also shown to be present in the plasma membrane of the vascular endothelium.14 Besides a sodium barrier, the ESL is also an important obstacle for inflammatory cells. An intact ESL prevents leukocytes from binding to cell adhesion molecules such as P-selectin, ICAM-1 (intercellular adhesion molecule 1), and VCAM-1 (vascular cell adhesion molecule 1), thereby minimizing leukocyte–endothelium interaction.5,15Another important function of the ESL and the vascular endothelium comprises production of nitric oxide (NO), which is an important vasodilatory agent. The ESL functions as a necessary mechanotransducer that converts a biomechanical signal—shear stress—into a biochemical signal—the production of NO by the vascular endothelium.5 The enzyme that is primarily responsible for the generation of NO in the vascular endothelium is endothelial nitric oxide synthase (eNOS).16ESL and Endothelial Cells Under High Sodium ConditionsAlthough both the ESL and the vascular endothelium play an important role in sodium homeostasis, excess of sodium seems to affect their function. The effect of sodium overload on the ESL was first investigated in 2011.17 With atomic force microscopy, ESL stiffness and height were measured in vitro, and it was demonstrated that 5-day high sodium exposure of endothelial cells (culture medium with 150 mmol/L sodium) caused both the ESL and endothelial cells to stiffen.18 In addition, it was demonstrated that high sodium decreased ESL heparan sulfates by 68%, which may considerably reduce the buffering capacity for sodium.17These alterations not only affect the buffer capacity of the ESL but also impair the barrier function that both the ESL and the vascular endothelium normally wield.17,19 A damaged ESL facilitates sodium entry into endothelial cells17 probably via increased access to or increased activity of endothelial sodium channels.19 This may not only cause endothelial dysfunction but may also ease sodium transport to the interstitium. The reduced barrier function may also apply to inflammatory cells. Leukocyte adhesion to the endothelium is increased under high sodium conditions, mediated by reactive oxygen species and eNOS.20 In addition, both damage15 and stiffness21 of the ESL increase leukocyte adhesion in a VCAM-1–dependent and ICAM-1–dependent manner.17,19,22 The described observations derive from in vitro studies and animal studies. In humans, the effect of sodium on the ESL is hard to investigate. Yet, a recent study that determined vascular permeability through measurement of the transcapillary escape rate of 125I-labeled albumin demonstrated that an acute intravenous hypertonic sodium load (2.4% NaCl) increased vascular permeability.23Another consequence of the sodium-induced increased stiffness of the endothelium and ESL concerns a reduction of the effects of shear stress. When the effect of shear stress is decreased, endothelial NO production is reduced, and blood vessel wall tonus and concurrently blood pressure can be altered.12,24 Indeed, in different rat models, high-sodium diet for 3 weeks reduced eNOS and increased blood pressure.25 Of note, the sodium-mediated reduction of eNOS and NO might not only be caused by the disturbance of the shear stress conversion but may also be related to the endothelial sodium channels, as these channels are shown to decrease eNOS and NO production.26ESL and Blood PressureConsidering the potential role of the ESL in osmotic inactivation of sodium, prevention of endothelial dysfunction, and NO-mediated vasodilation, ESL status may affect volume and blood pressure regulation. Interestingly, ESL damage is observed in many patients who are at high risk for salt-sensitive hypertension, such as diabetic,27–29 hypertensive,30 and chronic kidney disease patients.31 In this respect, restoration of the ESL may affect blood pressure regulation. Indeed, sulodexide, an oral drug consisting of a highly purified mixture of glycosaminoglycans, has shown to restore ESL thickness and decrease vascular permeability in both animal and human subjects.27,32 A meta-analysis also demonstrated that sulodexide significantly reduced blood pressure in human subjects.33 This systolic/diastolic blood pressure decrease of 10/5 mm Hg was similar to blood pressure reductions one can expect when using regular antihypertensive drugs.34 A post hoc analysis showed that the blood pressure–lowering effect was associated with the degree of albuminuria, which is known to reflect systemic ESL volume.28,35 These data advocate that the ESL has a clinically significant role in blood pressure regulation that can be influenced by oral medication.In short, the function of the ESL and the vascular endothelium with regard to sodium and blood pressure regulation seems to be 3-fold by (1) providing a sodium buffer that is directly in contact with the blood (2) accomplishing NO production for vasodilation, and (3) establishing a barrier that prevents sodium and inflammatory cells from reaching the skin (Figure 1). Although the negative consequences in case of impairment of the first 2 functions are clear, the (patho)physiological consequences of more sodium and inflammatory cells traveling to the skin are much less understood.Download figureDownload PowerPointFigure 1. In the case of an intact endothelial surface layer (ESL), the sodium is buffered in the ESL, and the ESL and the endothelium form a barrier against sodium migration to the underlying tissue. If the ESL is impaired, its sodium buffering capacity is decreased, its barrier function is decreased, and endothelial nitric oxide synthase (eNOS) production is decreased. Besides paracellular transport, transcellular transport of sodium is increased by increased access to or activity of endothelial sodium channels (EnNaCs). In addition, an impaired ESL increases leukocyte–endothelium adhesion in a VCAM-1 (vascular cell adhesion molecule 1)–dependent and ICAM-1 (intercellular adhesion molecule 1)–dependent manner. GAG indicates glycosaminoglycan.Sodium and the SkinIn 1978, sodium was found to be stored within the skin of white rats.36 This finding was generally overlooked, until the above-described balance studies revealed that a substantial amount of ingested sodium could not be accounted for, and the possibility of sodium buffers in the body gained attention again.2,3 Just like the ESL, the skin is abundant in negatively charged glycosaminoglycans, which can bind and neutralize sodium, storing it in a nonosmotic manner.36–38 High-sodium diet increases the sodium content of the skin, as has been demonstrated in both animal4,36,37 and human39 studies. Concomitant with this sodium increase, skin glycosaminoglycan content and XYLT-1 (xylosyltransferase 1) expression increase, the last being the enzyme initiating glycosaminoglycan synthesis (Table).4,37,42 In addition, many other enzymes involved in skin glycosaminoglycan synthesis are upregulated in response to high sodium.37 The increase of skin glycosaminoglycans is, therefore, most likely the driving force allowing for skin sodium accumulation during high sodium conditions. Low-sodium diet decreases skin sodium content, suggesting the possibility of mobilization of the nonosmotically stored sodium.43 In humans, high skin sodium content has been associated with a variety of pathological conditions. 23Na magnetic resonance imaging demonstrated high skin sodium content in patients with primary44 and secondary45 hypertension, hemodialysis patients,46 and patients with diabetes mellitus.47 The earlier mentioned hypothesis that an intact ESL prevents excessive sodium accumulation in the skin is supported by the notion that these patient groups not only have high skin sodium content but are also known to have an impaired ESL.27,28,30,31 An impaired ESL may also facilitate leakage of glycosaminoglycans into the interstitium, as indicated by the findings that hypertonic sodium infusion induces increased endothelial permeability and a lower amount of urinary glycosaminoglycans.23 Increased leakage of glycosaminoglycans to the skin together with increased skin glycosaminoglycan synthesis may, therefore, serve as the explanation for a sodium-induced increase in tissue glycosaminoglycan content and concomitant sodium accumulation when ESL perturbations are present (Figure 2).Table. Changes That a High-Sodium Load Causes in the Skin Compared With a Low-Sodium Load, as Demonstrated by Animal4,36–38,40 and Human39,41 StudiesEffects of High-Sodium LoadIncreased skin sodium accumulation4,36–39Increased skin glycosaminoglycan content36–38Increased inflammatory cell influx38,40Increased skin lymph vessel density38,40Decreased skin blood vessel density41Download figureDownload PowerPointFigure 2. Sodium from endothelial surface layer (ESL) to skin. A, Intact ESL. Sodium is buffered in the ESL, and the ESL provides a barrier for sodium and for macrophages. B, Disturbed ESL. The buffer function and the barrier function of the ESL are impaired. Both sodium and macrophages easier transfer to the skin. Increased skin sodium content induces increased glycosaminoglycan (GAG) content and growth of the lymph vessels. Adapted from Olde Engberink and Vogt48 with permission. Copyright © 2017, FocusVasculair. All rights reserved.Skin Sodium and the MicrocirculationCurrently, knowledge of the consequences of sodium accumulation in the skin is incomplete. Although skin sodium accumulation may seem beneficial on first sight, the association between skin sodium accumulation and conditions related to salt-sensitive hypertension implies that it may be harmful. The reduction in blood vessel density (rarefaction) that has repeatedly been associated with high-sodium intake might be linked to tissue sodium accumulation (Table).41,49–51 Rarefaction can play a role in hypertension through the increase of microcirculatory peripheral resistance.52 Besides anatomic changes, skin sodium accumulation might also induce functional changes. This is in line with increasing evidence that links an abnormal vasodilatory response to salt-sensitive hypertension, also called the vasodysfunction theory.53 In the blood, hypersalinity is known to induce endothelial dysfunction,18 and likewise, local hypersalinity of the tissue surrounding the blood vessel wall might also exert negative effects on the embedded vessels. In a recent study, salt-sensitive subjects had an increased total peripheral resistance after salt loading compared with salt-resistant subjects.54 Concurrently, although salt-sensitive subjects gained the expected amount of weight based on iso-osmolar water retention, salt-resistant subjects actually lost weight. These findings indicate that salt-resistant subjects were able to store sodium nonosmotically, whereas salt-sensitive subjects were not and may suggest that nonosmotic sodium storage in the skin is beneficial and prevents vascular dysfunction. However, given the fact that salt-sensitive patient groups have been associated with high skin sodium content in previous studies, baseline skin sodium content may have been higher in the salt-sensitive subjects and the nonosmotic sodium buffer capacity may have been saturated, making it impossible to osmotically inactivate the administered sodium. The sodium that seems to be so conveniently stored in the interstitial space of their skin and other tissues may directly influence the embedded (micro)vessels and alter their structure and function. This hypothesis is in line with data that showed increased vasoconstriction of skin vessels from rats fed with a high-salt diet,55 and data that showed that skin sodium content closely correlated to arteriolar glycosaminoglycan and sodium content, which might lead to vascular stiffening.42 Moreover, skin sodium content also seems to have a direct relationship with organ damage, as skin sodium content (as assessed by 23Na magnetic resonance imaging) and left ventricular hypertrophy were significantly correlated, independent of blood pressure, in chronic kidney disease patients.47 It is currently unknown whether phenomena like these and hypertension development result from high skin sodium content itself or whether high skin sodium content is merely a reflection of other, more influential alterations, like generalized vascular stiffening.In animal studies, high-sodium diet increased lymph capillaries in both amount and size (Table).38 The lymphangiogenesis is induced by the production of VEGF-C (vascular endothelial growth factor C) by macrophages, which is in turn caused by activation of TonEBP (tonicity-responsive enhancer binding protein) in macrophages in response to high osmolarity.38 Disruption of lymphangiogenesis by macrophage depletion or a VEGF-C receptor antibody increased the salt-sensitive blood pressure response,38 whereas the increase in eNOS remained unaltered.40 This suggests that lymphatic growth itself (along with its associated increase in draining capacity) encompasses an essential response for blood pressure regulation, although other concomitant mechanisms cannot yet be excluded. In another study, a VEGF receptor blocker aggravated salt-sensitive hypertension without affecting skin lymphangiogenesis, also indicating that more factors can play a role with regard to VEGF-C and salt sensitivity.56 Human studies that confirm the VEGF-C–related findings in the skin are still lacking. However, clinical studies did confirm an association between serum VEGF-C levels, salt intake,57,58 skin sodium,46 and (salt-sensitive) hypertension.38,58Skin Sodium and the Immune SystemPerhaps one of the most intriguing and unresolved issues about sodium storage in the skin extends to the relationship between sodium and the immune system, which seems to be 2 directional. First of all, skin infection is characterized by increased skin sodium content, which decreases after antibiotic treatment.59 Because it was shown in several studies that high sodium levels activate the immune response, the advantage of increased sodium content during infections seems obvious.59–62 Less clear are the consequences of a sodium-triggered immune response in the absence of an infection. In rats, high-sodium diet increased skin CD68+ macrophage content (Table).38 Although the exact underlying mechanisms remain unidentified, high sodium environments seem to attract macrophages independent of the TonEBP system.63 Other hypertonic environments, induced by urea and mannitol, did not induce any effect. The increased skin macrophage content after high-sodium diet coincides with the enhanced endothelial monocyte adhesion that occurs during high-sodium exposure.64 Not only the amount but also the phenotype of macrophages is altered by sodium, as sodium induces a proinflammatory state of macrophages and reduces the anti-inflammatory properties.65,66 Modulations in cellular metabolism, among which a reduction in glycolysis and mitochondrial metabolic output, underlie these alterations.66 Although macrophages in the skin are responsible for VEGF-C production and lymphangiogenesis, which seems to be beneficial, it is currently unclear whether the inflammatory alterations negatively influence blood pressure. Besides macrophages, also heparan sulfate has been shown to be converted into a highly proinflammatory state by high-sodium diet.67 Considering the fact that hypertension is, at least in part, an inflammatory disease, it was recently suggested that the sodium-triggered inflammation in microenvironments like the skin contributes to the emerging of hypertension, thus diminishing the concept that the skin is a convenient storage compartment for sodium.68 The extent of the role of macrophages in salt-sensitive hypertension might be dependent on their phenotype and their location and should be further elucidated. Of note, the influence of sodium on the immune system is not restricted to macrophages but also encompasses alterations of T cells69–72 and dendritic cells.73 Detailed description falls beyond the scope of this review and has been excellently reviewed elsewhere.74ConclusionsIn conclusion, the ESL, the vascular endothelium, and the skin (along with its microcirculatory changes) are all involved in sodium homeostasis and blood pressure regulation, with a pivotal role of the blood vessel wall. The ESL and the vascular endothelium enable a sodium buffer, a sodium barrier to the skin, and the production of NO. When these layers are impaired, either genetically or acquired, sodium may more easily reach the skin and becomes nonosmotically stored through glycosaminoglycan binding. Although the skin seems like an ideal storage compartment at first sight, at present, there is not enough knowledge about the (possibly deleterious) microcirculatory and immunologic effects that sodium storage triggers there. These questions bear essential consequences in the light of sodium homeostasis and blood pressure regulation and need to be further investigated to be able to successfully target new antihypertensive treatment options.Sources of FundingL. Vogt is supported by the Dutch Kidney Foundation (Kolff grant No. KJPB 11.22) and The Netherlands Organization for Scientific Research (Clinical Fellowship grant No. 90700310).DisclosuresNone.FootnotesCorrespondence to Liffert Vogt, Section of Nephrology, Department of Internal Medicine, Amsterdam Cardiovascular Sciences, Academic Medical Center, Room F4-215, PO Box 22660, 1100 DD Amsterdam, The Netherlands. E-mail [email protected]References1. Olde Engberink RH, Rorije NM, van den Born BH, Vogt L. 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