Advances in the study of vascular related protective effect of garlic (Allium sativum) extract and compounds.

Garlic (Allium sativum) is a functional food containing multiple bioactive compounds that find widespread applications in culinary and medicinal practices. It consists of multiple chemical components, including allicin and alliin. This article offers a comprehensive review of the protective effects of garlic extracts and their active constituents on the vascular system. In vitro and in vivo experiments have shown that garlic extracts and their active ingredients possess various bioactive properties. These substances demonstrate beneficial effects on blood vessels by demonstrating anti-inflammatory and antioxidant activities, inhibiting lipid accumulation and migration, preventing lipid peroxidation, promoting angiogenesis, reducing platelet aggregation, enhancing endothelial function, and inhibiting endothelial cell apoptosis. In clinical studies, garlic and its extracts have demonstrated their efficacy in managing vascular system diseases, including atherosclerosis, diabetes, and high cholesterol levels. In summary, these studies highlight the potential therapeutic roles and underlying mechanisms of garlic and its constituents in managing conditions like diabetes, atherosclerosis, ischemic diseases, and other vascular disorders.

COVID-19 Biomarkers for Critically Ill Patients: A Compendium for the Physician.

BACKGROUND: SARS-CoV-2 clinical manifestation and progression are variable and unpredictable, hence the importance of considering biomarkers in clinical practice that can be useful for both diagnosis and prognostic evaluation. This review aims to summarize, for intensive care physicians, the most recent state of knowledge regarding known COVID-19 in critical patients. We searched PubMed® using the Boolean operators and identified all results on the PubMed® database of all studies regarding COVID-19 biomarkers. We selected studies regarding endothelium, cytokines, bacterial infection, coagulation, and cardiovascular biomarkers. METHODS: We divided the results into four essential paragraphs: "Cytokine storm", "Endothelium dysfunction and coagulation biomarkers in COVID-19", "Biomarker of sepsis", and Cardiovascular lung and new perspectives. RESULTS: The assessments of the severe COVID-19 prognosis should monitor, over time, IL-6, soluble Von Willebrand factor (VWF), P-selectin, sCD40L, thrombomodulin, VCAM-1, endothelin- Troponin, D-dimer, LDH, CRP, and procalcitonin. Metabolomic alterations and ACE2 receptors represent new perspectives. DISCUSSION AND CONCLUSIONS: Early identification of critically ill patients has been crucial in the first COVID-19 pandemic wave for the sustainability of the healthcare emergency system and clinical management. Only through the early identification of the most severe patients can they be provided with the most appropriate treatments.

The epithelial sodium channel in inflammation and blood pressure modulation.

A major regulator of blood pressure and volume homeostasis in the kidney is the epithelial sodium channel (ENaC). ENaC is composed of alpha(α)/beta(ß)/gamma(γ) or delta(δ)/beta(ß)/gamma(γ) subunits. The δ subunit is functional in the guinea pig, but not in routinely used experimental rodent models including rat or mouse, and thus remains the least understood of the four subunits. While the δ subunit is poorly expressed in the human kidney, we recently found that its gene variants are associated with blood pressure and kidney function. The δ subunit is expressed in the human vasculature where it may influence vascular function. Moreover, we recently found that the δ subunit is also expressed human antigen presenting cells (APCs). Our studies indicate that extracellular Na+ enters APCs via ENaC leading to inflammation and salt-induced hypertension. In this review, we highlight recent findings on the role of extra-renal ENaC in inflammation, vascular dysfunction, and blood pressure modulation. Targeting extra-renal ENaC may provide new drug therapies for salt-induced hypertension.

SOX17 is a Critical Factor in Maintaining Endothelial Function in Pulmonary Hypertension by an Exosome-Mediated Autocrine Manner.

Endothelial dysfunction is considered a predominant driver for pulmonary vascular remodeling in pulmonary hypertension (PH). SOX17, a key regulator of vascular homoeostasis, has been found to harbor mutations in PH patients, which are associated with PH susceptibility. Here, this study explores whether SOX17 mediates the autocrine activity of pulmonary artery ECs to maintain endothelial function and vascular homeostasis in PH and its underlying mechanism. It is found that SOX17 expression is downregulated in the endothelium of remodeled pulmonary arteries in IPH patients and SU5416/hypoxia (Su/hypo)-induced PH mice as well as dysfunctional HPAECs. Endothelial knockdown of SOX17 accelerates the progression of Su/hypo-induced PH in mice. SOX17 overexpression in the pulmonary endothelium of mice attenuates Su/hypo-induced PH. SOX17-associated exosomes block the proliferation, apoptosis, and inflammation of HPAECs, preventing pulmonary arterial remodeling and Su/hypo-induced PH. Mechanistic analyses demonstrates that overexpressing SOX17 promotes the exosome-mediated release of miR-224-5p and miR-361-3p, which are internalized by injured HPAECs in an autocrine manner, ultimately repressing the upregulation of NR4A3 and PCSK9 genes and improving endothelial function. These results suggest that SOX17 is a key gene in maintaining endothelial function and vascular homeostasis in PH through regulating exosomal miRNAs in an autocrine manner.

Morphological and Functional Remodeling of Vascular Endothelium in Cardiovascular Diseases.

The vascular endothelium plays a vital role during embryogenesis and aging and is a cell monolayer that lines the blood vessels. The immune system recognizes the endothelium as its own. Therefore, an abnormality of the endothelium exposes the tissues to the immune system and provokes inflammation and vascular diseases such as atherosclerosis. Its secretory role allows it to release vasoconstrictors and vasorelaxants as well as cardio-modulatory factors that maintain the proper functioning of the circulatory system. The sealing of the monolayer provided by adhesion molecules plays an important role in cardiovascular physiology and pathology.

Hantaan virus-induced elevation of plasma osteoprotegerin and its clinical implications in hemorrhagic fever with renal syndrome.

OBJECTIVES: The bleeding tendency is a hallmark of hemorrhagic fever with renal syndrome (HFRS) after Hantaan virus (HTNV) infection. Growing reports indicate the importance of osteoprotegerin (OPG) in vascular homeostasis, implying OPG might be involved in the pathogenesis of coagulopathy in patients with HFRS. METHODS: Acute and convalescence plasmas of 32 patients with HFRS were collected. Enzyme-linked immunosorbent assays (ELISA) were used to detect plasma OPG levels and other parameters. The human umbilical vein endothelial cells were stimulated with HTNV and/or tumor necrosis factor-α (TNF-α) to explore the source of OPG. RESULTS: Plasma OPG levels of patients with HFRS were elevated and correlated positively with the severity of HFRS and negatively with platelet counts. Abundant OPG was released from endothelial cells in response to TNF-α stimuli, along with HTNV infection, which was in accordance with the findings of positive correlations between plasma OPG and TNF-α or c-reactive protein. Importantly, plasma OPG levels correlated positively with activated partial thromboplastin time and the content of d-dimer. CONCLUSION: These findings suggested that increased plasma OPG levels induced by HTNV might be an important factor for the severity of HFRS, and was likely involved in endothelium dysfunction and hemorrhagic disorder of HFRS, which might contribute to the pathogenesis of hemorrhage in HFRS.

Diabetes-Induced Cardiac Autonomic Neuropathy: Impact on Heart Function and Prognosis.

Cardiovascular autonomic neuropathy (CAN) is a severe complication of the advance stage of diabetes. More than 50% of diabetic patients diagnosed with peripheral neuropathy will have CAN, with clinical manifestations including tachycardia, severe orthostatic hypotension, syncope, and physical exercise intolerance. Since the prevalence of diabetes is increasing, a concomitant increase in CAN is expected and will reduce quality of life and increase mortality. Autonomic dysfunction is associated with reduced baroreflex sensitivity and impairment of sympathetic and parasympathetic modulation. Various autonomic function tests are used to diagnose CAN, a condition without adequate treatment. It is important to consider the control of glucose level and blood pressure as key factors for preventing CAN progression. However, altered biomarkers of inflammatory and endothelial function, increased purinergic receptor expression, and exacerbated oxidative stress lead to possible targets for the treatment of CAN. The present review describes the molecular alterations seen in CAN, diagnosis, and possible alternative treatments.

Respiratory tract infection: an unfamiliar risk factor in high-altitude pulmonary edema.

The dramatic changes in physiology at high altitude (HA) as a result of the characteristic hypobaric hypoxia condition can modify innate and adaptive defense mechanisms of the body. As a consequence, few sojourners visiting HA with mild or asymptomatic infection may have an enhanced susceptibility to high-altitude pulmonary edema (HAPE), an acute but severe altitude sickness. It develops upon rapid ascent to altitudes above 2500 m, in otherwise healthy individuals. Though HAPE has been studied extensively, an elaborate exploration of the HA disease burden and the potential risk factors associated with its manifestation are poorly described. The present review discusses respiratory tract infection (RTI) as an unfamiliar but important risk factor in enhancing HAPE susceptibility in sojourners for two primary reasons. First, the symptoms of RTI s resemble those of HAPE. Secondly, the imbalanced pathways contributing to vascular dysfunction in HAPE also participate in the pathogenesis of the infectious processes. These pathways have a crucial role in shaping host response against viral and bacterial infections and may further worsen the clinical outcomes at HA. Respiratory tract pathogenic agents, if screened in HAPE patients, can help in ascertaining their role in disease risk and also point toward their association with the disease severity. The microbial screenings and identifications of pathogens with diseases are the foundation for describing potential molecular mechanisms underlying host response to the microbial challenge. The prior knowledge of such infections may predict the manifestation of disease etiology and provide better therapeutic options.

Ultrasound evaluation of endothelial dysfunction in immunoglobulin-resistant children with acute Kawasaki disease.

INTRODUCTION: Given the evidence that brachial artery flow-mediated dilation (FMD) is declined in children later after the onset of Kawasaki disease (KD), we hypothesized that indicators that detect the situation of the endothelium are useful parameters that can accurately reflect subclinical dysfunction in resistant patients and assist in differentiating patients with KD at a higher risk of IVIG resistance, which may be valuable in better understanding how to protect patients from endothelial and thrombotic complications. METHODS: Fifty IVIG-resistant KD children, 120 IVIG-responsive KD children, 35 febrile children with acute upper respiratory infection, and 50 healthy controls were recruited, and indicators reflecting endothelial inflammation, including flow-mediated dilation (FMD), were measured. Receiver operating characteristic (ROC) curve analysis was utilized to determine the threshold values of these indicators of IVIG resistance. Multiple logistic regression analysis was performed to determine whether FMD was an independent predictor of IVIG-resistant patients. RESULTS: In comparison with the lab data, PCT, Na + , and FMD exhibited AUCs of 0.727, 0.653, and 0.698 (P < 0.05), respectively, in predicting IVIG resistance in KD through ROC analysis. PCT > 1.69 ng/ml, Na + < 133.2 mmol/l, and FMD < 5.79% were independent predictors of IVIG resistance in KD (OR 4.257, 3.516, 3.563, 95% CI 1.549 ~ 11.700, 1.277 ~ 9.680, 1.299 ~ 9.772, P < 0.05). CONCLUSION: More severe endothelial dysfunction, especially lower FMD, was present in IVIG-resistant patients than in IVIG-responsive patients. It is a helpful diagnostic tool that provides supportive criteria to detect KD patients at a higher risk of IVIG resistance when FMD < 5.79% in children. Key Points • IVIG-resistant KD patients have more severe endothelial dysfunction than IVIG-sensitive patients. • FMD < 5.79% may indicate an increased risk of IVIG resistance in children with Kawasaki disease.

Pathophysiology of Cardiovascular Diseases: New Insights into Molecular Mechanisms of Atherosclerosis, Arterial Hypertension, and Coronary Artery Disease.

Cardiovascular diseases (CVDs) are disorders associated with the heart and circulatory system. Atherosclerosis is its major underlying cause. CVDs are chronic and can remain hidden for a long time. Moreover, CVDs are the leading cause of global morbidity and mortality, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of CVDs, focusing on coronary artery disease along with atherosclerosis as its major cause and arterial hypertension. We discuss the endothelium dysfunction, inflammatory factors, and oxidation associated with atherosclerosis. Mechanisms such as dysfunction of the endothelium and inflammation, which have been identified as critical pathways for development of coronary artery disease, have become easier to diagnose in recent years. Relatively recently, evidence has been found indicating that interactions of the molecular and cellular elements such as matrix metalloproteinases, elements of the immune system, and oxidative stress are involved in the pathophysiology of arterial hypertension. Many studies have revealed several important inflammatory and genetic risk factors associated with CVDs. However, further investigation is crucial to improve our knowledge of CVDs progression and, more importantly, accelerate basic research to improve our understanding of the mechanism of pathophysiology.

Treatment with ß-blocker nebivolol ameliorates oxidative stress and endothelial dysfunction in tenofovir-induced nephrotoxicity in rats.

Background: Tenofovir disoproxil fumarate (TDF), a widely prescribed component in antiretroviral regimens, has been associated with nephrotoxicity. Nebivolol is a third generation selective ß-1 adrenergic receptor blocker and may protect renal structure and function through the suppression of oxidative stress and enhancement of nitric oxide (NO) synthesis. We aimed to investigate whether nebivolol could be an effective therapeutic strategy to mitigate tenofovir-induced nephrotoxicity. Methods: We allocated Wistar rats to four groups: control (C), received a standard diet for 30 days; NBV, received a standard diet for 30 days added with nebivolol (100 mg/kg food) in the last 15 days; TDF, received a standard diet added with tenofovir (300 mg/kg food) for 30 days; and TDF+NBV, received a standard diet added with tenofovir for 30 days and nebivolol in the last 15 days. Results: Long-term exposure to tenofovir led to impaired renal function, induced hypertension, endothelial dysfunction and oxidative stress. Nebivolol treatment partially recovered glomerular filtration rate, improved renal injury, normalized blood pressure and attenuated renal vasoconstriction. Administration of nebivolol contributed to reductions in asymmetric dimethylarginine (ADMA) levels as well as increases in endothelial nitric oxide sintase (eNOS) accompanied by renin-angiotensin-aldosterone system downregulation and decreases in macrophage and T-cells infiltrate. Furthermore, nebivolol was responsible for the maintenance of the adequate balance of thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels and it was associated with reductions in NADPH oxidase (NOX) subunits. Conclusion: Nebivolol holds multifaceted actions that promote an advantageous option to slow the progression of kidney injury in tenofovir-induced nephrotoxicity.

Promising Strategies for Preserving Adult Endothelium Health and Reversing Its Dysfunction: From Liquid Biopsy to New Omics Technologies and Noninvasive Circulating Biomarkers.

The endothelium has multiple functions, ranging from maintaining vascular homeostasis and providing nutrition and oxygen to tissues to evocating inflammation under adverse conditions and determining endothelial barrier disruption, resulting in dysfunction. Endothelial dysfunction represents a common condition associated with the pathogenesis of all diseases of the cardiovascular system, as well as of diseases of all of the other systems of the human body, including sepsis, acute respiratory distress syndrome, and COVID-19 respiratory distress. Such evidence is leading to the identification of potential biomarkers and therapeutic targets for preserving, reverting, or restoring endothelium integrity and functionality by promptly treating its dysfunction. Here, some strategies for achieving these goals are explored, despite the diverse challenges that exist, necessitating significant bench work associated with an increased number of clinical studies.

Ellagic Acid prevents vascular dysfunction in small mesenteric arteries of ovariectomized hypertensive rats.

Cardiovascular diseases rank the top causes of death worldwide, with a substantial increase in women compared to men. Such increase can beexplained by the drastic decrease in 17-ß-estradiol hormone during menopause and associated with endothelium-dependent vascular dysfunction. The current treatments for cardiovascular diseases (e.g., hypertension), are only palliative and therefore, feasible, non-invasive options for preventing further vascular damage are needed. The polyphenol ellagic acid (EA) has risen as a candidate with possible vascular protection properties. This study evaluated the effects of EA in small mesenteric arteries of ovariectomized spontaneously hypertensive rats. Our findings showed that EA oral treatment for 4 weeks preserved vasodilation endothelial-dependent in acetylcholine pre-constricted arteries of spontaneously hypertensive rats to the same extent as 17-ß-estradiol treatment, an effect that was abolished in the presence of the nitric oxide synthase inhibitor L-NitroG-L-Arginine Methyl Ester. Moreover, EA induced vascular nitric oxide release, by increasing both the activitation site phosphorylation and total levels of the endothelial nitric oxide synthase. Finally, EA decreased superoxide anion while increased total levels of the antioxidant enzymes Superoxide Dismutase 2 and catalase. We concluded that EA has vasodilation properties acting via endothelial nitric oxide synthase activation and a potential antioxidant effect by stimulating the Superoxide Dismutase 2-catalase pathway.

The Contribution of Gut Microbiota and Endothelial Dysfunction in the Development of Arterial Hypertension in Animal Models and in Humans.

The maintenance of the physiological values of blood pressure is closely related to unchangeable factors (genetic predisposition or pathological alterations) but also to modifiable factors (dietary fat and salt, sedentary lifestyle, overweight, inappropriate combinations of drugs, alcohol abuse, smoking and use of psychogenic substances). Hypertension is usually characterized by the presence of a chronic increase in systemic blood pressure above the threshold value and is an important risk factor for cardiovascular disease, including myocardial infarction, stroke, micro- and macro-vascular diseases. Hypertension is closely related to functional changes in the endothelium, such as an altered production of vasoconstrictive and vasodilator substances, which lead to an increase in vascular resistance. These alterations make the endothelial tissue unresponsive to autocrine and paracrine stimuli, initially determining an adaptive response, which over time lead to an increase in risk or disease. The gut microbiota is composed of a highly diverse bacterial population of approximately 1014 bacteria. A balanced intestinal microbiota preserves the digestive and absorbent functions of the intestine, protecting from pathogens and toxic metabolites in the circulation and reducing the onset of various diseases. The gut microbiota has been shown to produce unique metabolites potentially important in the generation of hypertension and endothelial dysfunction. This review highlights the close connection between hypertension, endothelial dysfunction and gut microbiota.

Sex-Dependent Protective Effect of Combined Application of Solubilized Ubiquinol and Selenium on Monocrotaline-Induced Pulmonary Hypertension in Wistar Rats.

Ubiquinol exhibits anti-inflammatory and antioxidant properties. Selenium is a part of a number of antioxidant enzymes. The monocrotaline inducible model of pulmonary hypertension used in this study includes pathological links that may act as an application for the use of ubiquinol with high bioavailability and selenium metabolic products. On day 1, male and female rats were subcutaneously injected with a water-alcohol solution of monocrotaline or only water-alcohol solution. On days 7 and 14, some animals were intravenously injected with either ubiquinol's vehicle or solubilized ubiquinol, or orally with selenium powder daily, starting from day 7, or received both ubiquinol + selenium. Magnetic resonance imaging of the lungs was performed on day 20. Hemodynamic parameters and morphometry were measured on day 22. An increased right ventricle systolic pressure in relation to control was demonstrated in all groups of animals of both sexes, except the group of males receiving the combination of ubiquinol + selenium. The relative mass of the right ventricle did not differ from the control in all groups of males and females receiving either ubiquinol alone or the combination. Magnetic resonance imaging revealed impaired perfusion in almost all animals examined, but pulmonary fibrosis developed in only half of the animals in the ubiquinol group. Intravenous administration of ubiquinol has a protective effect on monocrotaline-induced pulmonary hypertension development resulting in reduced right ventricle hypertrophy, and lung mass. Ubiquinol + selenium administration resulted in a less severe increase in the right ventricle systolic pressure in male rats but not in females 3 weeks after the start of the experiment. This sex-dependent effect was not observed in the influence of ubiquinol alone.

The Potential of Dietary Bioactive Compounds against SARS-CoV-2 and COVID-19-Induced Endothelial Dysfunction.

COVID-19 is an endothelial disease. All the major comorbidities that increase the risk for severe SARS-CoV-2 infection and severe COVID-19 including old age, obesity, diabetes, hypertension, respiratory disease, compromised immune system, coronary artery disease or heart failure are associated with dysfunctional endothelium. Genetics and environmental factors (epigenetics) are major risk factors for endothelial dysfunction. Individuals with metabolic syndrome are at increased risk for severe SARS-CoV-2 infection and poor COVID-19 outcomes and higher risk of mortality. Old age is a non-modifiable risk factor. All other risk factors are modifiable. This review also identifies dietary risk factors for endothelial dysfunction. Potential dietary preventions that address endothelial dysfunction and its sequelae may have an important role in preventing SARS-CoV-2 infection severity and are key factors for future research to address. This review presents some dietary bioactives with demonstrated efficacy against dysfunctional endothelial cells. This review also covers dietary bioactives with efficacy against SARS-CoV-2 infection. Dietary bioactive compounds that prevent endothelial dysfunction and its sequelae, especially in the gastrointestinal tract, will result in more effective prevention of SARS-CoV-2 variant infection severity and are key factors for future food research to address.

Uremic toxins activate CREB/ATF1 in endothelial cells related to chronic kidney disease.

Uremic toxins, such as p-cresyl sulfate (PCS) and indoxyl sulfate (IS), contribute to endothelial dysfunction in chronic kidney disease (CKD). This process is mediated by several cellular pathways, but it is unclear whether cAMP-responsive element-binding protein (CREB) and activating transcription factor 1 (ATF1) participate in endothelial dysfunction in uremic conditions despite playing roles in inflammatory modulation. This study aimed to evaluate the expression, activation, and transcriptional activity of CREB/ATF1 in endothelial cells exposed to PCS, IS, and uremic serum (US). In vitro, ATF1 protein levels were increased by PCS and IS, whereas CREB levels were enhanced only by IS. Activation through CREB-Ser133 and ATF1-Ser63 phosphorylation was induced by PCS, IS, and US. We evaluated the CREB/ATF1 transcriptional activity by analyzing the expression of their target genes, including ICAM1, PTGS2, NOX1, and SLC22A6, which are related to endothelial dysfunction through their roles in vascular inflammation, oxidative stress, and cellular uptake of PCS and IS. The expression of ICAM1, PTGS2 and NOX1 genes was increased by PCS, IS, and US, whereas that of SLC22A6 was induced only by IS. KG-501, a CREB inhibitor, restored the inductive effects of PCS on ICAM1, PTGS2, and NOX1 expression; IS on ICAM1, PTGS2 and SLC22A6 expression; and US on NOX1 expression. The presence of CREB and ATF1 was observed in healthy arteries and in arteries of patients with CKD, which were structurally damaged. These findings suggest that CREB/ATF1 is activated by uremic toxins and may play a relevant role in endothelial dysfunction in CKD.

Luteoloside protects the vascular endothelium against iron overload injury via the ROS/ADMA/DDAH II/eNOS/NO pathway.

Iron overload injury is considered to be a part of blood stasis syndrome of arthralgia in traditional Chinese medicine. Its primary therapies include clearing heat and detoxification, activating blood circulation, and removing blood stasis. Lonicera japonica flos (LJF) has long been known as an excellent antipyretic and antidote. Luteoloside (Lut) is one of the main components of LJF and exhibits antioxidant, anti-inflammatory, and cytoprotective properties. However, the protection of Lut against iron overload injury and its underlying mechanisms remain unclear. Therefore, HUVECs were exposed to 50 µmol·L-1 iron dextran for 48 h to establish an iron overload damage model and the effects of Lut were assessed. Our results showed that 20 µmol·L-1 Lut not only increased cell viability and weakened LDH activity, but also significantly up-regulated DDAHⅡ expression and activity, increased p-eNOS/eNOS ratio and NO content, and reduced ADMA content in HUVECs exposed to iron overload. Furthermore, Lut significantly attenuated intracellular/mitochondrial ROS generation, improved SOD, CAT, and GSH-Px activities, reduced MDA content, maintained MMP, inhibited mPTP opening, prevented cyt c from mitochondria released into cytoplasm, reduced cleaved-caspase3 expression, and ultimately decreased cell apoptosis induced by iron overload. The effects of Lut were similar to those of L-arginine (an ADMA competitive substrate), cyclosporin A (a mPTP blocker agent), and edaravone (a free radical scavenger) as positive controls. However, addition of pAD/DDAH II-shRNA adenovirus reversed the above beneficial effects of Lut. In conclusion, Lut can protect HUVECs against iron overload injury via the ROS/ADMA/DDAH II/eNOS/NO pathway. The mitochondria are the target organelles of Lut's protective effects.

Rheopheresis Performed in Hemodialysis Patients Targets Endothelium and Has an Acute Anti-Inflammatory Effect.

Background: Rheopheresis is a double-filtration plasmapheresis that removes a defined spectrum of high-molecular-weight proteins to lower plasma viscosity and improves microcirculation disorders. This technique can be performed in hemodialysis (HD) patients with severe microischemia. Interestingly, some studies showed that rheopheresis sessions improve endothelial function. Methods: Our study evaluated the inflammatory and endothelial biomarker evolution in 23 HD patients treated or not with rheopheresis. A p value ≤ 0.001 was considered statistically significant. Results: Thirteen HD patients treated by rheopheresis either for a severe peripheral arterial disease (N = 8) or calciphylaxis (N = 5) were analyzed. Ten control HD patients were also included in order to avoid any misinterpretation of the rheopheresis effects in regard to the HD circuit. In the HD group without rheopheresis, the circulating endothelial adhesion molecules, cytokines, angiogenic factor concentrations, and circulating levels were not modified. In the HD group with rheopheresis, the circulating endothelial adhesion molecules (sVCAM-1, sP-selectin, and sE-selectin) experienced a significant reduction, except sICAM-1. Among the pro-inflammatory cytokines, TNF-α was significantly reduced by 32.6% [(−42.2)−(−22.5)] (p < 0.0001), while the anti-inflammatory cytokine IL-10 increased by 674% (306−1299) (p < 0.0001). Among the angiogenic factors, only sEndoglin experienced a significant reduction. The CEC level trended to increase from 13 (3−33) cells/mL to 43 (8−140) cells/mL (p = 0.002). We did not observe any difference on the pre-session values of the molecules of interest between the first rheopheresis session and the last rheopheresis session. Conclusion: Rheopheresis immediately modified the inflammation balance and the endothelial injury biomarkers. Further studies are needed to understand the mechanisms underlying these biological observations.

Aging-induced impaired endothelial wall shear stress mechanosensing causes arterial remodeling via JAM-A/F11R shedding by ADAM17.

Physiological and pathological vascular remodeling is uniquely driven by mechanical forces from blood flow in which wall shear stress (WSS) mechanosensing by the vascular endothelium plays a pivotal role. This study aimed to determine the novel role for a disintegrin and metalloproteinase 17 (ADAM17) in impaired WSS mechanosensing, which was hypothesized to contribute to aging-associated abnormal vascular remodeling. Without changes in arterial blood pressure and blood flow rate, skeletal muscle resistance arteries of aged mice (30-month-old vs. 12-week-old) exhibited impaired WSS mechanosensing and displayed inward hypertrophic arterial remodeling. These vascular changes were recapitulated by in vivo confined, AAV9-mediated overexpression of ADAM17 in the resistance arteries of young mice. An aging-related increase in ADAM17 expression reduced the endothelial junction level of its cleavage substrate, junctional adhesion molecule-A/F11 receptor (JAM-A/F11R). In cultured endothelial cells subjected to steady WSS ADAM17 activation or JAM-A/F11R knockdown inhibited WSS mechanosensing. The ADAM17-activation induced, impaired WSS mechanosensing was normalized by overexpression of ADAM17 cleavage resistant, mutated JAM-AV232Y both in cultured endothelial cells and in resistance arteries of aged mice, in vivo. These data demonstrate a novel role for ADAM17 in JAM-A/F11R cleavage-mediated impaired endothelial WSS mechanosensing and subsequently developed abnormal arterial remodeling in aging. ADAM17 could prove to be a key regulator of WSS mechanosensing, whereby it can also play a role in pathological vascular remodeling in diseases.