High‐salt diet increases hormonal sensitivity in skin pre‐capillary resistance vessels

Helle, Frank; Karlsen, Tine Veronika; Tenstad, Olav; Titze, Jens; Wiig, Helge

doi:10.1111/apha.12049

Cited by 31 publications

(26 citation statements)

References 22 publications

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“…It is unclear to us why skin Cl -content, and not Na + and water content, was so tightly associated with salt-sensitive blood pressure increases in our mice. Recently, evidence from our group suggests that skin Na + and Cl -storage in rats is associated with increased in vitro contractility of skin resistance vessels (19). We speculate that changes in interstitial Cl -ion concentration, or unidentified organic components secreted by the lymphatic capillary network or immune cells, may modify vascular resistance in the skin and increase blood pressure.…”

Section: Discussionmentioning

confidence: 74%

“…We are intrigued by the observation that tissue Cl -content was directly related to blood pressure in that regard. We are aware that these studies do not explain why peripheral vascular resistance in skin vessels is increased in saltconsuming animals (19). Although we believe that our findings regarding lymphatic capillary density and its importance to skin electrolyte clearance are relevant to this process, future research must pursue this issue further.…”

Section: Figurementioning

confidence: 79%

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Immune cells control skin lymphatic electrolyte homeostasis and blood pressure

et al. 2013

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The skin interstitium sequesters excess Na + and Cl -in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl -accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na + , Cl -, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function.

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Section: Discussionmentioning

confidence: 74%

Section: Figurementioning

confidence: 79%

Immune cells control skin lymphatic electrolyte homeostasis and blood pressure

et al. 2013

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“…124–133 It is possible that in some salt-sensitive subjects, the sodium or chloride components might not only fail to cause a normal decrease in vascular resistance, either or both ionic components of salt might provoke increases in vascular resistance. It is also possible that alterations in the amount of sodium and or chloride stored in skin or other tissues, 134, 135 including the vasculature or the brain, might play a role in abnormal vascular resistance responses to salt.…”

Section: The Role Of the Sympathetic Nervous System And Other Mechanimentioning

confidence: 99%

Vasodysfunction That Involves Renal Vasodysfunction, Not Abnormally Increased Renal Retention of Sodium, Accounts for the Initiation of Salt-Induced Hypertension

et al. 2016

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Prevailing theory holds that abnormally large increases in renal salt retention and cardiac output are early pathophysiologic events mediating initiation of most instances of salt-induced hypertension. This theory has come under increasing scrutiny because it is based on studies that lack measurements of sodium balance and cardiac output obtained during initiation of salt-loading in proper normal controls, i.e., salt-resistant subjects with normal blood pressure. Here we make the case for a “vasodysfunction” theory for initiation of salt-induced hypertension: In response to an increase in salt intake, a subnormal decrease in total peripheral resistance that involves a subnormal decrease in renal vascular resistance, in the absence of abnormally large increases in sodium retention and cardiac output, is the hemodynamic abnormality that usually mediates initiation of salt-induced increases in blood pressure (BP). It is the failure to normally decrease vascular resistance in response to salt loading that enables a normal increase of cardiac output to initiate the salt-induced increase in blood pressure. This theory is based on the results of properly controlled studies which consistently demonstrate that in salt-sensitive subjects, salt-loading initiates increased BP through a hemodynamic mechanism that: 1) does not usually involve early increases in sodium retention and cardiac output greater than those which occur with salt-loading in normal controls, and 2) usually involves an early failure to decrease vascular resistance to the same extent as that observed during salt-loading in normal controls. Multiple mechanisms including disturbances in nitric oxide and sympathetic nervous system activity likely underlie this subnormal vasodilatory response to salt that usually precedes and initiates salt-induced hypertension.

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“…Also unclear is why a reduction in MPS cell-driven lymphatic clearance leads to predominant Cl − accumulation in the skin, and why this electrolyte accumulation is associated with blood pressure increase. Preliminary work suggests that increased contractility of skin blood vessels could be linked to Na + storage in the skin [27]. …”

Section: Animal Studies: Electrolyte Metabolism and Immune Functionmentioning

confidence: 99%

Sodium balance is not just a renal affair

Titze

2014

Current Opinion in Nephrology and Hypertension

107

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Purpose of review The equilibration theory of extracellular body fluids is tightly linked to sodium (Na+) metabolism. Accepted is the notion that with changes in salt intake, renal sodium elimination will prevent any change in interstitial Na+ content and concentration. This review summarizes recent anomalous findings in salt and water homeostasis that are inconsistent with current assumptions. Recent findings Recent findings from chemical analysis studies of laboratory animals, as well as noninvasive quantitative Na+ MRI (Na-MRI) studies in patients, have shown that remarkable amounts of Na+ are stored in muscle and in skin without commensurate water retention. Furthermore, an ultra-long Na+ balance study in humans suggests the presence of endogenous clocks that generate weekly and monthly infradian rhythmicity of Na+ storage independent of salt intake. Animal experiments suggest that fluids in the skin interstitium are hypertonic compared with plasma and that interstitial osmotic stress induces local extrarenal immune cell and lymph–capillary driven mechanisms for electrolyte clearance and maintenance of the internal environment. Summary Recent quantitative evidence challenges current ideas on salt-and-water homeostasis and suggests that Na+ homeostasis cannot be maintained without additional hitherto unappreciated extrarenal regulatory mechanisms.

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High‐salt diet increases hormonal sensitivity in skin pre‐capillary resistance vessels

Cited by 31 publications

References 22 publications

Immune cells control skin lymphatic electrolyte homeostasis and blood pressure

Immune cells control skin lymphatic electrolyte homeostasis and blood pressure

Vasodysfunction That Involves Renal Vasodysfunction, Not Abnormally Increased Renal Retention of Sodium, Accounts for the Initiation of Salt-Induced Hypertension

Sodium balance is not just a renal affair

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