Regulation Of Vascular Tone Research Articles

Efficiency of chewing load deficiency correction in clinical dental practice

Weakening of the chewing act, typical for modern humans due to consumption of soft food, causes a deficit of chewing load and has a negative effect on the dental system. To combat hypodynamia of the masticatory apparatus with the aim of preventing destructive processes in its structures, a gnathotraining system was developed, including electrical stimulation of the masticatory muscles themselves in physiological parameters, which develops the effect of “imaginary chewing”, and gnathotraining using chewing gum. In addition, functional training of the masticatory apparatus using chewing exercises was proposed. Considering that chewing gum practically does not compensate for the deficit of chewing load observed in modern society, the staff of the Kazan State Medical University and the Kazan National Research Technological University developed the “Denta Fit” dental trainer and a dental training system. It has been established that dental and jaw training stimulates secretion of saliva, its mineralizing potential, functional resistance of tooth enamel, allows achieving a good level of oral hygiene, reduces the rate of increase in the intensity of dental caries, as well as the severity of muscular-articular disorders of the temporomandibular joints, enhances neuromuscular activity of the masticatory muscles and regional blood flow. In children with permanent bite, dental and jaw training maintains the hydrogen index (pH) of oral fluid at a neutral level and provides, in combination with a toothbrush, optimal hygienic dental care, contributes to the formation of a correct dental occlusion. Thus, the effects of increased neuromuscular activity of the masticatory muscles, as well as regional vascular tone, arising during dental and jaw training, indirectly indicate that the dental and jaw system receives adequate mechanical loads necessary for the normal functioning of all its links. The results of the conducted studies indicate the effectiveness and feasibility of using dental training to improve dental status, which serves as a new approach to the prevention and treatment of dental diseases.

Biochemistry of Redox-Active Sulphur Compounds in Mammalian Cells and Approaches to Detecting Them

The discovery of new classes of regulatory molecules in human and animal metabolism always leads to a large-scale study of their properties in the context of biochemistry, physiology, and pharmacology. About 20 years ago, hydrogen sulfide (H2S) and its derivatives – active sulfur forms (ASFs): persulfides, polysulfides, nitrosothiols, sulfenic acids, etc. – became one of such classes of molecules. The participation of ASFs in a variety of physiological and pathological processes, such as regulation of vascular tone, inflammation, long-term potentialization in the central nervous system, etc., has been shown. Changes in ASF levels or patterns of modification of their targets are associated with a wide range of pathologies: cardiovascular, oncologic, neurodegenerative, and others. For a part of these processes, mechanisms have been studied that involve direct modification of regulatory (NF-κB, Keap1) or effector (GAFD, eNOS, TRPA1) proteins through reactions of cysteine residues and metal-containing centers with APS. The presence of different regulated enzymatic systems producing APS and numerous molecular targets allows us to consider H2S and its derivatives as an important class of small regulatory molecules. H2S is counted among the so-called “gas transmitters”, along with nitric oxide(II) and carbon monoxide. Over the last 20 years, a huge amount of data on the biochemistry of these compounds and approaches to their study has been accumulated.

8532 Circulating Neprilysin in Pregnancy

Abstract Disclosure: A. Kulovic-Sissawo: None. E. Weiss: None. E. Jantscher-Krenn: None. U. Hiden: None. Background: In the complex nature of pregnancy, the female organism undergoes pivotal vascular and metabolic changes orchestrated by a tightly regulated interplay of bioactive regulatory molecules. The neutral endopeptidase, neprilysin, exists both in a membrane-bound and a soluble form (sNEP), of with the latter present in the circulatory system. Neprilysin degrades an exciting range of bioactive peptides involved in glycemic control (insulin B chain, GLP-1) and vascular tone regulation (angiotensin I and II, bradykinin, ANP, BNP), and both of them are altered in pregnancy. Objective: Due to the substrate-specificity of neprilysin and its multifaceted role we hypothesize that neprilysin may be involved in metabolic and vascular adaptions during pregnancy. However, the link between sNEP and maternal metabolism in pregnancy has not yet been investigated. Methodology: Serum sNEP concentration (n=102), longitudinally collected from metabolically healthy women (trial number NTC05496712), was measured at three visits throughout gestation (gestational age: 12.5±0.7; 20±0.8; 33±1.6 weeks) and post-partum (2±1.2 days after delivery) using commercially available sandwich ELISA. In addition, sNEP levels in pregnancy were compared to a cohort of non-pregnant women within reproductive age (n=50). Clinical and anthropometric measurements were determined and the association of sNEP and metabolic characteristics elucidated. Results: Circulating sNEP levels were non-normally distributed (median ± IQR: 2334±232624 pg/ml, n=82, gestational age 12.5±0.7 weeks) and showed high biological variability, with individual levels remaining constant over gestation. After delivery, however, sNEP concentration decreased (median± IQR: 1968±171060 pg/ml n=82, p=0.0001). sNEP showed a positive correlation with systolic blood pressure (Spearman, n=56, r=0.321, p=0.02) at early stages of pregnancy and non-fasting GLP-1 (Spearman, n=98, r=0.309, p=0.002) throughout gestation, but not with blood glucose, insulin resistance or BMI. In the non-pregnant state sNEP concentration (median±IQR: 4322±392152 pg/ml, n=38) positively correlated with body fat percentage (Pearson, n=38, r=0.405, p=0.01), fasting glucose (Pearson, n=43, r=0.301, p=0.05) and body mass index (Spearman, n=38, r=0.369, p=0.02) but did not correlate with systolic blood pressure (Pearson, n=36, r=-0.120, p=0.48). Conclusion: For the first time, the link between sNEP, metabolism and blood pressure during uncomplicated pregnancy was investigated. The decrease in post-partum circulating sNEP as compared to levels throughout pregnancy suggests a particular way of sNEP regulation and release during gestation. Our data indicate that in both, pregnant and non-pregnant state, sNEP may be involved in metabolic and cardiovascular regulation, with circulating sNEP levels showing massive individual differences. Presentation: 6/3/2024

"Evaluation of the effects of pioglitazone on perivascular adipose tissue function, properties and structure in a rat model of type-2 diabetes."

Perivascular adipose tissue (PVAT) plays an important role in many physiological and pathological processes, such as regulation of vascular tone. The aim of this study is to evaluate the effects of pioglitazone on functional, structural, and biochemical properties of PVAT in an experimental model of type-2 diabetes (T2DM). T2DM was induced by high-fat-diet/low-dose-streptozotocin (HFD/STZ) in rats, and pioglitazone (20mg/kg/p.o.) was administered for 6 weeks. Changes in biochemical parameters, PVAT-mass, vascular-reactivity in thoracic-aorta as well as PVAT adipocytokine and PPARG-expression levels, and histopathology were evaluated. Pioglitazone administration improved blood glucose and lipid profiles in T2DM. Pioglitazone did not change the anticontractile effect of PVAT on aortic contractile reactivity and besides, had no influence on endothelium-dependent and -independent relaxation responses. Pioglitazone administration increased PVAT-mass and TNF-α levels while adiponectin, leptin, and IL-6 levels were unchanged. Also, a prominent increase was observed in PPARG-expression in T2DM-Pio group. Moreover, pioglitazone decreased liver steatosis, aortic wall thickening and myocardial damage whereas increased adipocyte size and adiposity in PVAT. Overall, pioglitazone treatment changed the mass and in part the inflammatory profile of PVAT but did not modify vasoreactivity in T2DM. This study provides novel findings in relationship with the adipogenic effect of pioglitazone and PVAT function.

Regulation of Skeletal Muscle Resistance Arteriolar Tone: Temporal Variability in Vascular Responses

Introduction: A full understanding of the integration of the mechanisms of vascular tone regulation requires an interrogation of the temporal behavior of arterioles across vasoactive challenges. Building on previous work, the purpose of the present study was to start to interrogate the temporal nature of arteriolar tone regulation with physiological stimuli. Methods: We determined the response rate of ex vivo proximal and in situ distal resistance arterioles when challenged by one-, two-, and three-parameter combinations of five major physiological stimuli (norepinephrine, intravascular pressure, oxygen, adenosine [metabolism], and intralumenal flow). Predictive machine learning models determined which factors were most influential in controlling the rate of arteriolar responses. Results: Results indicate that vascular response rate is dependent on the intensity of the stimulus used and can be severely hindered by altered environments, caused by application of secondary or tertiary stimuli. Advanced analytics suggest that adrenergic influences were dominant in predicting proximal arteriolar response rate compared to metabolic influences in distal arterioles. Conclusion: These data suggest that the vascular response rate to physiologic stimuli can be strongly influenced by the local environment. Translating how these effects impact vascular networks is imperative for understanding how the microcirculation appropriately perfuses tissue across conditions.

TRPV4 Channel in Neurological Disease: from Molecular Mechanisms to Therapeutic Potential.

Transient Receptor Potential Vanilloid 4 (TRPV4) is a non-selective cation channel with pivotal roles in various physiological processes, including osmosensitivity, mechanosensation, neuronal development, vascular tone regulation, and bone homeostasis in human bodies. Recent studies have made significant progress in understanding the structure and functional role of TRPV4, shedding light on its involvement in pathological processes, particularly in the realm of neurological diseases. Here, we aim to provide a comprehensive exploration of the multifaceted contributions of TRPV4 to neurological diseases, spanning its intricate molecular mechanisms to its potential as a target for therapeutic interventions. We delve into the structural and functional attributes of TRPV4, scrutinize its expression profile, and elucidate the possible mechanisms through which it participates in the pathogenesis of neurological disorders. Furthermore, we discussed recent years' progress in therapeutic strategies aimed at harnessing TRPV4 for the treatment of these diseases. These insights will provide a basis for understanding and designing modality-specific pharmacological agents to treat TRPV4-associated disorders.

The role of microenvironmental factors in the pre-ovulatory oocyte in the pathogenesis of “poor” ovarian response to in vitro fertilization (IVF) programs

Background. The “poor” response to ovarian stimulation during IVF (in vitro fertilization) cycles depends on various factors, including the biochemical composition of the follicle microenvironment. Recent studies have focused on the relationship between vascular tone regulators, angiogenic factors, oxidative stress, and the quality of oocytes. Despite this, there is still no consensus on the exact effect of these factors on folliculogenesis or their role in “poor” responses.Objective. To evaluate the content of biochemical factors and regulators of vascular tone and angiogenesis in follicular fluid in patients with a “poor” ovarian response to stimulation in IVF programs, compared to similar indicators in women with a normal ovarian response.Materials and methods. An open prospective cohort study was conducted, including 56 patients who were part of the IVF program. The criterion for separating the cohort of women was their response to controlled ovarian stimulation during the IVF cycle. Women with a “poor” response (n=32) were placed in the main group, while those with a normal response (n=24) were in the comparison group. Follicular fluid samples from women with a “poor” response were divided into two subgroups based on the presence or absence of an oocyte-cumulus complex in the follicle. The biochemical and soluble regulatory factors in follicular fluid were analyzed in both groups after controlled ovarian stimulation was completed. Statistical analysis of the data was done using methods from variation statistics. A critical level of significance for the differences was set at p ≤0.05.Result. The levels of urea, glucose, high-density lipoprotein, and total antioxidant status (TAOS) in follicular fluid (FF) from patients with a “poor” ovarian response were statistically significantly higher compared to those in the control group. The levels of bilirubin, low-density lipoprotein, and uric acid were also significantly lower in VF from patients in the main group compared to the control group, p<0.05. The indices of vascular endothelial growth factor (VEGF-A) and vascular endothelial growth receptor-2 (VEGFR-2) in FF from women with a “poor” response were significantly lower than those from patients with a normal response, while the levels of endogenous nitric oxide were significantly higher in the former group compared to the latter, p<0.05.Conclusion. The absence of an oocyte-cumulus complex in the pre-ovulatory follicle, which is associated with a “poor” response of the ovary to stimulation, is likely due to a disruption in vascularization processes. This is supported by a decrease in the levels of pro- and anti-angiogenic factors, such as VEGF-A and VEGFR-2.

Pulmonary Hypertension: Diagnosis and Management

Pulmonary hypertension (PH) affects 1% of people worldwide. Changes in the pulmonary vasculature, obstructive lesions in the pulmonary arteries, and an increase in pulmonary artery pressure are the hallmarks of PH, a progressive and deadly cardiovascular illness. These modifications result in a rise in right ventricular afterload, which frequently causes unfavorable right ventricular remodeling, right ventricular dysfunction and, in the end, mortality. One of the more severe and well-researched types of PH is pulmonary arterial hypertension (PAH), which is treatable with medication. The mechanisms involved in the regulation of pulmonary vascular tone and proliferation are the focus of PAH as well as some other forms of PH. The main characteristics of PAH (group 1) are discussed in this article, along with new and existing treatment options for the condition.

A Skeletal Muscle-Mediated Anticontractile Response on Vascular Tone: Unraveling the Lactate-AMPK-NOS1 Pathway in Femoral Arteries.

The regulation of vascular tone by perivascular tissues is a complex interplay of various paracrine factors. Here, we investigate the anti-contractile effect of skeletal muscle surrounding the femoral and carotid arteries and its underlying mechanisms. Using male and female Wistar rats, we demonstrated that serotonin, phenylephrine, and U-46619 induced a concentration-dependent vasoconstrictor response in femoral artery rings. Interestingly, this response was diminished in the presence of surrounding femoral skeletal muscle, irrespective of sex. No anti-contractile effect was observed when the carotid artery was exposed to its surrounding skeletal muscle. The observed effect in the femoral artery persisted even in the absence of endothelium and when the muscle was detached from the artery. Furthermore, the skeletal muscle surrounding the femoral artery was able to promote an anti-contractile effect in three other vascular beds (basilar, mesenteric, and carotid arteries). Using inhibitors of lactate dehydrogenase and the 1/4 monocarboxylate transporter, we confirmed the involvement of lactate, as both inhibitors were able to abolish the anti-contractile effect. However, lactate did not directly promote vasodilation; rather, it exerted its effect by activating 5' AMP-activated protein kinase (AMPK) and neuronal nitric oxide synthase (NOS1) in the skeletal muscle. Accordingly, Nω-propyl L-arginine, a specific inhibitor of NOS1, prevented the anti-contractile effect, as well as lactate-induced phosphorylation of NOS1 at the stimulatory serine site (1417) in primary skeletal muscle cells. Phosphorylation of NOS1 was reduced in the presence of Bay-3827, a selective AMPK inhibitor. In conclusion, femoral artery-associated skeletal muscle is a potent paracrine and endocrine organ that influences vascular tone in both sexes. Mechanistically, the anti-contractile effect involves muscle fiber type and/or its anatomical location but not the type of artery or its related vascular endothelium. Finally, the femoral artery anti-contractile effect is mediated by the lactate-AMPK-phospho-NOS1Ser1417-NO signaling axis.

Changes in nitric oxide inhibitors and mortality in critically ill patients: a cohort study

BackgroundOptimal balance between macro- and microcirculation in critically ill patients is crucial for ensuring optimal organ perfusion. Nitric oxide (NO) is a regulator of vascular hemostasis and tone. The availability of NO is controlled by asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the availability of the NO substrates arginine and homoarginine. We investigated the changes in plasma concentrations of ADMA, SDMA, arginine, and homoarginine days 1–5 of intensive care unit (ICU) admission and the association between the change in concentration days 1–3 and 30-day all-cause mortality.MethodsSingle-center cohort study of adult critically ill patients from the ICU at Copenhagen University Hospital – North Zealand. ADMA, SDMA, arginine, and homoarginine (NO-biomarkers) were measured on days 1–5. Initially, we determined the changes in NO-biomarkers days 1–5 with linear mixed models, and subsequently how the changes in NO-biomarkers days 1–3 were associated with 30-day all-cause mortality. Post-hoc we analyzed the association between plasma concentration at admission and 30-day all-cause mortality.ResultsIn total 567 out of 577 patients had plasma samples from days 1–5. Plasma concentrations of ADMA and arginine increased from days 1–5. SDMA concentrations increased from days 1–2, followed by a decrease from days 2–5. Concentrations of homoarginine did not change from days 1–3 but slightly increased from days 3–5. In total 512 patients were alive 3 days after ICU admission. Among these patients, a daily twofold increase in ADMA concentration from days 1–3 was associated with decreased mortality in multivariate analysis (HR 0.45; 95% CI 0.21–0.98; p = 0.046). An increase in SDMA, arginine, or homoarginine was not associated with mortality. Post-hoc we found that a twofold increase in ADMA or SDMA concentrations at admission was associated with mortality (HR 1.78; 95% CI 1.24–2.57; p = 0.0025, and HR 1.41; 95% CI 1.05–1.90; p = 0.024, respectively).ConclusionsIncreasing ADMA concentrations on days 1–3 are inversely associated with mortality, however not with the same strength as high ADMA or SDMA concentrations at admission. We suggest that admission concentrations are the focus of future research on ADMA and SDMA as predictors of mortality or potential therapeutical targets in ICU patients.

Cardiometabolic Risk Factors Associated with Magnesium and Vitamin D Nutrients during Pregnancy-A Narrative Review.

This narrative review comprehensively explores the cardiometabolic implications of two vital nutrients, magnesium and vitamin D, during gestation. Magnesium, a key regulator of vascular tone, glucose metabolism, and insulin sensitivity, plays a crucial role in mitigating gestational hypertension and diabetes, a point this review underscores. Conversely, vitamin D, critical for immune response and calcium level maintenance, is linked to gestational diabetes and hypertensive disorders of pregnancy. The authors aim to enhance comprehension of the complex interaction between these nutrients and cardiometabolic function in pregnancy, knowledge that is pivotal for optimizing maternal-fetal outcomes. The mother's health during pregnancy significantly influences the long-term development of the fetus. Recognizing the impact of these nutrient deficiencies on the physiology of cardiometabolic cycles underscores the importance of adequate nutritional support during pregnancy. It also emphasizes the pressing need for future research and targeted interventions to alleviate the burden of pregnancy complications, highlighting the crucial role of healthcare professionals, researchers, and policy makers in obstetrics and gynecology in this endeavor.

Placental Protein 13: Vasomodulatory Effects on Human Uterine Arteries and Potential Implications for Preeclampsia.

Placental protein 13 (PP13) exhibits a plasma concentration that increases gradually during normal gestation, a process that is disrupted in preeclampsia, which is characterized by elevated vascular resistance, reduced utero-placental blood flow, and intrauterine growth restriction. This study investigated PP13's role in vascular tone regulation and its molecular mechanisms. Uterine and subcutaneous arteries, isolated from both pregnant and non-pregnant women, were precontracted with the thromboxane analogue U46619 and exposed to PP13 using pressurized myography. The molecular mechanisms were further investigated, using specific inhibitors for nitric oxide synthase (L-NAME+LNNA at 10-4 M) and guanylate cyclase (ODQ at 10-5 M). The results showed that PP13 induced vasodilation in uterine arteries, but not in subcutaneous arteries. Additionally, PP13 counteracted U46619-induced vasoconstriction, which is particularly pronounced in pregnancy. Further investigation revealed that PP13's mechanism of action is dependent on the activation of the nitric oxide-cGMP pathway. This study provides novel insights into the vasomodulatory effects of PP13 on human uterine arteries, underscoring its potential role in regulating utero-placental blood flow. These findings suggest that PP13 may be a promising candidate for improving utero-placental blood flow in conditions such as preeclampsia. Further research and clinical studies are warranted to validate PP13's efficacy and safety as a therapeutic agent for managing preeclampsia.

Nfluence of extracellular acidosis on the functional contribution of KATP and TASK-1 potassium channels to the regulation of vascular tone in early postnatal ontogenesis

The activity of many proteins and, as a result, of the mechanisms of vascular tone regulation depends on pH. A decrease of pH (uncompensated acidosis), usually causes relaxation of blood vessels, which has been studied in sufficient detail for an adult, matured organism. However, the effect of acidosis on the mechanisms of vascular tone regulation in the early postnatal period remains almost completely unexplored. The aim of this work was to study the effect of extracellular metabolic acidosis on the functional contribution of KATP and TASK-1 potassium channels to the regulation of vascular tone in early postnatal period. We modeled extracellular metabolic acidosis (pH 6.8, equimolar replacement of NaHCO3 with NaCl in solution) and studied isometric contractile responses of the saphenous artery in rats aged 3–4 months and rat pups aged 12–15 days. Arterial contraction to the α1-adrenergic agonist methoxamine at pH 6.8 was reduced compared to normal pH 7.4 in both 3–4-month-old and 12–15-day-old rats. The KATP channel blocker glibenclamide did not change the arterial responses to methoxamine, neither at pH 7.4 nor at pH 6.8 in any of the age groups. The TASK-1 channel blocker AVE1231 did not alter arterial contractile responses at any pH in 3–4-month-old rats. However, in 12–15-day-old rat pups, the increase in contractile responses to methoxamine under the influence of AVE1231 was less at pH 6.8 than at pH 7.4. Thus, the results of this work demonstrate that acidosis reduces the contractile activity of the arteries of 3–4-month-old animals and animals during early postnatal ontogenesis, while in the latter, the anticontractile role of TASK-1 channels decreases, and KATP channels do not affect the regulation of vascular tone, either under normal, or at acidic pH in any of the age groups.

Influence of nuclear factor κB and adenosine monophosphate-activated protein kinase on the vascular bed of the liver under the conditions of modeling chronic alcoholic hepatitis

Chronic alcohol use activates the transcription factor κB (NF-κB) in liver sinusoidal endothelial cells (LSECs), macrophages and other cells of the liver parenchyma, which controls the regulation of the expression of pro-inflammatory cytokines that activate signaling pathways of immune regulation of liver inflammation and vascular tone. AMP-activated protein kinase (AMPK) is an important immunometabolic regulatory factor in macrophages and, as a metabolic sensor, AMPK in vascular cells may be involved in the regulation of blood flow. The aim of the work was to find out the effect of modulators of the transcription factor κB and AMP-activated protein kinase on the morphometric parameters of the vascular bed of the liver of rats under the conditions of modeling chronic alcoholic hepatitis. Simulation of chronic alcoholic hepatitis leads to a violation of the exchange of metabolites between the central and interlobular veins, which creates prerequisites for the development of hypoxic damage to hepatocytes, as evidenced by a decrease in the diameters of lobular arterioles and venules. Administration of ammonium pyrrolidinedithiocarbamate and bacterial lipopolysaccharide, which affect NF-κB signaling under the conditions of modeling chronic alcoholic hepatitis, helps to restore the exchange of metabolites between the central and interlobular veins, which is evidenced by an increase in the lumens of lobular arterioles and venules. The introduction of phenformin and doxorubicin, which affect AMPK under the conditions of modeling chronic alcoholic hepatitis, prevents the development of hypoxic damage to hepatocytes, as evidenced by an increase in the diameters of lobular arteries and veins, and leads to intensification of interlobular blood circulation.

Astrocytic NMDA Receptors.

Astrocytic NMDA receptors (NMDARs) are heterotetramers, whose expression and properties are largely determined by their subunit composition. Astrocytic NMDARs are characterized by a low sensitivity to magnesium ions and low calcium conductivity. Their activation plays an important role in the regulation of various intracellular processes, such as gene expression and mitochondrial function. Astrocytic NMDARs are involved in calcium signaling in astrocytes and can act through the ionotropic and metabotropic pathways. Astrocytic NMDARs participate in the interactions of the neuroglia, thus affecting synaptic plasticity. They are also engaged in the astrocyte-vascular interactions and contribute to the regulation of vascular tone. Astrocytic NMDARs are involved in various pathologies, such as ischemia and hyperammonemia, and their blockade prevents negative changes in astrocytes during these diseases.

Evaluation of glomerular hemodynamic changes by sodium-glucose-transporter 2 inhibition in type 2 diabetic rats using in vivo imaging

The mechanisms responsible for glomerular hemodynamic regulation with sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney disease due to type 2 diabetes remain unclear. Therefore, we investigated changes in glomerular hemodynamic function using an animal model of type 2 diabetes, treated with an SGLT2 inhibitor alone or in combination with a renin-angiotensin-aldosterone system inhibitor using male Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Afferent and efferent arteriolar diameter and single-nephron glomerular filtration rate (SNGFR) were evaluated in ZDF rats measured at 0, 30, 60, 90, or 120 minutes after the administration of a SGLT2 inhibitor (luseogliflozin). Additionally, we assessed these changes under the administration of the adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine), along with coadministration of luseogliflozin and an angiotensin II receptor blocker (ARB), telmisartan. ZDF rats had significantly increased SNGFR, and afferent and efferent arteriolar diameters compared to ZL rats, indicating glomerular hyperfiltration. Administration of luseogliflozin significantly reduced afferent vasodilatation and glomerular hyperfiltration, with no impact on efferent arteriolar diameter. Urinary adenosine levels were increased significantly in the SGLT2 inhibitor group compared to the vehicle group. A1aR antagonism blocked the effect of luseogliflozin on kidney function. Co-administration of the SGLT2 inhibitor and ARB decreased the abnormal expansion of glomerular afferent arterioles, whereas the efferent arteriolar diameter was not affected. Thus, regulation of afferent arteriolar vascular tone via the A1aR pathway is associated with glomerular hyperfiltration in type 2 diabetic kidney disease.

Non-neuronal cell-derived acetylcholine, a key modulator of the vascular endothelial function in health and disease.

Vascular endothelial cells play an important role in regulating peripheral circulation by modulating arterial tone in the microvasculature. Elevated intracellular Ca2+ levels are required in endothelial cells to induce smooth muscle relaxation via endothelium-dependent mechanisms such as nitric oxide production, prostacyclin, and endothelial cell hyperpolarization. It is well established that exogenous administration of acetylcholine can increase intracellular Ca2+ concentrations, followed by endothelium-dependent vasodilation. Although endogenous acetylcholine's regulation of vascular tone remains debatable, recent studies have reported that endogenously derived acetylcholine, but not neuronal cell-derived acetylcholine, is a key modulator of endothelial cell function. In this minireview, we summarize the current knowledge of the non-neuronal cholinergic system (NNCS) in vascular function, particularly vascular endothelial cell function, which contributes to blood pressure regulation. We also discuss the possible pathophysiological impact of endothelial NNCS, which may induce the development of vascular diseases due to endothelial dysfunction, and the potential of endothelial NNCS as a novel therapeutic target for endothelial dysfunction in the early stages of metabolic syndrome, diabetes, and hypertension.

Ca2+-Dependent Cl- Channels in Vascular Tone Regulation during Aging.

Identifying alterations caused by aging could be an important tool for improving the diagnosis of cardiovascular diseases. Changes in vascular tone regulation involve various mechanisms, like NO synthase activity, activity of the sympathetic nervous system, production of prostaglandin, endothelium-dependent relaxing, and contracting factors, etc. Surprisingly, Ca2+-dependent Cl- channels (CaCCs) are involved in all alterations of the vascular tone regulation mentioned above. Furthermore, we discuss these mechanisms in the context of ontogenetic development and aging. The molecular and electrophysiological mechanisms of CaCCs activation on the cell membrane of the vascular smooth muscle cells (VSMC) and endothelium are explained, as well as the age-dependent changes that imply the activation or inhibition of CaCCs. In conclusion, due to the diverse intracellular concentration of chloride in VSMC and endothelial cells, the activation of CaCCs depends, in part, on intracellular Ca2+ concentration, and, in part, on voltage, leading to fine adjustments of vascular tone. The activation of CaCCs declines during ontogenetic development and aging. This decline in the activation of CaCCs involves a decrease in protein level, the impairment of Ca2+ influx, and probably other alterations in vascular tone regulation.

Purinergic regulation of pulmonary vascular tone.

Purinergic signaling is a crucial determinant in the regulation of pulmonary vascular physiology and presents a promising avenue for addressing lung diseases. This intricate signaling system encompasses two primary receptor classes: P1 and P2 receptors. P1 receptors selectively bind adenosine, while P2 receptors exhibit an affinity for ATP, ADP, UTP, and UDP. Functionally, P1 receptors are associated with vasodilation, while P2 receptors mediate vasoconstriction, particularly in basally relaxed vessels, through modulation of intracellular Ca2+ levels. The P2X subtype receptors facilitate extracellular Ca2+ influx, while the P2Y subtype receptors are linked to endoplasmic reticulum Ca2+ release. Notably, the primary receptor responsible for ATP-induced vasoconstriction is P2X1, with α,β-meATP and UDP being identified as potent vasoconstrictor agonists. Interestingly, ATP has been shown to induce endothelium-dependent vasodilation in pre-constricted vessels, associated with nitric oxide (NO) release. In the context of P1 receptors, adenosine stimulation of pulmonary vessels has been unequivocally demonstrated to induce vasodilation, with a clear dependency on the A2B receptor, as evidenced in studies involving guinea pigs and rats. Importantly, evidence strongly suggests that this vasodilation occurs independently of endothelium-mediated mechanisms. Furthermore, studies have revealed variations in the expression of purinergic receptors across different vessel sizes, with reports indicating notably higher expression of P2Y1, P2Y2, and P2Y4 receptors in small pulmonary arteries. While the existing evidence in this area is still emerging, it underscores the urgent need for a comprehensive examination of the specific characteristics of purinergic signaling in the regulation of pulmonary vascular tone, particularly focusing on the disparities observed across different intrapulmonary vessel sizes. Consequently, this review aims to meticulously explore the current evidence regarding the role of purinergic signaling in pulmonary vascular tone regulation, with a specific emphasis on the variations observed in intrapulmonary vessel sizes. This endeavor is critical, as purinergic signaling holds substantial promise in the modulation of vascular tone and in the proactive prevention and treatment of pulmonary vascular diseases.

Passive Heat Stress, Like Exercise Training, Leads to Improved Vascular Function

Epidemiological data indicate that repeated heat stress improves cardiovascular health, making passive heat therapy (PHT) a potential alternative for those unable to exercise. Few studies to date have examined the potential exercise mimetic effects in humans, and it is unclear how adaptations compare in magnitude to exercise training. OBJECTIVE: To examine the effects of 6 weeks of localized, muscle-focused PHT on resistance artery vascular function, exercise hemodynamics and performance, molecular regulators of vascular tone, and skeletal muscle capillarization relative to the adaptations observed following high-intensity aerobic exercise training focused on the same muscles. HYPOTHESIS: 6 weeks of PHT, applied to the knee extensor muscles through pulsed shortwave diathermy (2 hr, 3 days/week), would improve both resistance artery function and exercise hemodynamics, as well as increase vascular tone regulators more than a sham treatment, but less than single-leg knee extension (KE) exercise training (EX; 40 min, 3 days/week). Methods: We randomized 34 sedentary but otherwise healthy, young adults (ages 18–36; n = 17 female, 17 male) to receive PHT, EX, or sham heating sessions (SHAM; 2 hr, 3 days/week) over 6 weeks. Vascular function was determined through the blood flow response during both a passive leg movement (PLM) assessment and a knee extension graded exercise test (GXTmax). Muscle biopsies were taken from the vastus lateralis at baseline and after 6 weeks of intervention. Results: Peak blood flow during PLM increased to the same extent in both the EX (~10.5% increase, P=0.009) and PHT groups (~8.5% increase, P=0.044). KE peak flow increased in EX (~19%, P=0.005), but did not change in PHT (P=0.523) and decreased in SHAM (~7%, P=0.020). Peak vascular conductance during KE increased by ~25% in EX (P=0.030) and PHT (P=0.012). KE peak power increased in EX by ~27% (P=0.001) but did not significantly change in PHT (P=0.175) and SHAM groups (P=0.111). EX, but not PHT or SHAM, increased muscle capillary-to-fiber ratio (P = 0.0003), capillary density (P = 0.0428), and the Capillary to Fiber Perimeter Exchange Index (P = 0.0089). Protein expression of endothelial nitric oxide synthase (eNOS) increased significantly in both EX (P=0.0028) and PHT (P=0.0095), but only EX resulted in increased angiogenesis. CONCLUSIONS: 6 weeks of localized PHT, when applied to young healthy individuals, improved resistance artery function at rest and during exercise to the same extent as exercise training. Moreover, our data suggest that these PHT-induced improvements can be primarily attributed to increased expression of the regulators of vascular tone and not neo-angiogenesis. In conclusion, passive heat therapy mimics many, but not all the vascular benefits of exercise training. Funding for this study was provided by the Department of Exercise Sciences at Brigham Young University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.