AbstractThe lymphatic system maintains tissue homeostasis by transporting the excess fluid from the interstitium and ultimately returning it to the venous circulation against an adverse pressure gradient and gravitational force. The spontaneous contractions of lymphangions, the building blocks of collecting vessels, and the secondary lymphatic valves play key roles in lymph propulsion. The aim of this study was to investigate lymph propulsion in a series of three contracting lymphangions in a 3D reconstructed model segmented from micro-CT scans of the collecting lymphatics in the hind limb of mice. Computational Fluid Dynamics and Fluid–Structure Interaction were used to study the behavior of flow within the collecting vessel, as well as the behavior and deformations of the vessel wall and the poroelastic interstitium. The secondary valves were modelled as porous membranes with closed or open states depending on their permeability. A sensitivity study revealed that the parameters having the most impact on the total volume of lymph propelled by active contraction of the lymphangions were the elastic modulus of the interstitium and the permeability of the secondary valves during the open states.

Arteries can stiffen via different mechanisms due to the distending effects of blood pressure, the extracellular (ECM) and vascular smooth muscle cells (VSMC). This short review discusses how these simple models can be applied to the complex biomechanics of arteries to gain physiological insight into why an individual’s arteries are stiff and identify new therapeutic strategies. In the Multi-Ethnic Study of Atherosclerosis, the important question of whether arteries stiffen with aging due to load-dependent or structural stiffening was investigated. Structural stiffening was consistently observed with aging, but load-dependent stiffening was highly variable. Importantly, the high load-dependent stiffness was associated with future cardiovascular disease events, but structural stiffness was not. Clinical studies in older, hypertensive adults surprisingly show that decreasing vascular smooth muscle tone can cause clinically significant increases in arterial stiffness. To understand this paradox, the author developed a model simple enough for clinical data but with biologically relevant extracellular matrix (ECM) and vascular smooth muscle cell (VSMC) stiffness parameters. The effect of VSMC tone on arterial stiffness depends on the ECM–VSMC stiffness ratio. Future research is needed to develop a framework that incorporates both the blood pressure dependence of arterial stiffness and the VSMC–ECM interaction on hemodynamics. This could result in personalized arterial stiffness treatments and improved CVD outcomes. The subtitle of this review is “Learning to De-Stiffen Arteries” because our results have so far only shown that we can acutely make arteries stiffer. We are optimistic though that the findings and the analytic techniques covered here will be one of the many steps along the path of the arterial stiffness research community learning how to de-stiffen arteries.

Endotheliopathy plays a role in the development of acute kidney and lung injury in COVID-19, probably due to inflammation, endothelial permeability, vascular leakage and edema formation. This study examined alterations in the circulation of patients with mild and severe COVID-19 on in vitro endothelial permeability and its relation to the endothelial angiopoietin/Tie2 system, which is involved in the regulation of endothelial permeability. Plasma was obtained from COVID-19 patients admitted to the ward (n = 14) or ICU (n = 20) at admission and after 1 and 2 weeks and healthy controls (n = 5). Human kidney and lung endothelial cells were exposed to patient plasma and treated with recombinant angiopoietin-1. In vitro endothelial barrier function was assessed using electric cell-substrate impedance sensing. Circulating markers of the angiopoietin/Tie2 system, endothelial dysfunction and glycocalyx degradation were measured by ELISA. Plasma from COVID-19 patients reduced endothelial resistance compared to healthy controls, but COVID-19 plasma-induced drop in endothelial resistance did not differ between ward and ICU patients. Circulating angiopoietin-2, soluble Tie2 and soluble Tie1 levels increased over time in ICU patients, whereas levels remained stable in ward patients. The increase in angiopoietin-2 was able to predict 90-day mortality (AUC = 0.914, p < 0.001). Treatment with recombinant angiopoietin-1 did not restore COVID-19 plasma-induced hyperpermeability. In conclusion, these results suggest that indirect effects of the virus represented in the circulation of COVID-19 patients induced endothelial hyperpermeability irrespective of disease severity and changes in the endothelial angiopoietin/Tie2 system. Nonetheless, angiopoietin-2 might be of interest in the context of organ injury and patient outcome in COVID-19.

BackgroundPrevious studies explored multifactorial interactions and sirtuin expression in the aortic cells of laboratory rodents and humans. Human studies were limited due to the availability of biological material exclusively in the advanced stage of the disease. The role of sirtuins in aortic pathology has not been explained extensively therefore the aim of the study was to assess the plasma concentrations of human sirtuin 1 (SIRT1) and human sirtuin 2 (SIRT2) in patients with ascending aortic dissection and ascending aortic aneurysm.Material and methodsThe study group included 43 adults (34 males and 9 females) aged 44–92 years with ascending aortic dissection (n = 10) or with ascending aortic aneurysm (n = 33). The SIRT1 and SIRT2 plasma concentrations in patients’ blood samples were determined, and the differences between groups were observed (p = 0.02 for SIRT1, p = 0.04 for SIRT2).ResultsLevels of both SIRT1 and SIRT2 were lower in patients with ascending aortic dissection (SIRT1: median = 6.5 ng/mL; SIRT2: median = 5.7 ng/mL) than in patients with ascending aortic aneurysm (SIRT1: median = 9.2 ng/mL; SIRT2: median = 7.8 ng/mL). The SIRT1 and SIRT2 cut-off levels differentiating both groups of patients were 6.7 ng/mL and 3.2 ng/mL, respectively.ConclusionsThe patients with ascending aortic dissection had lower plasma concentrations of SIRT1 and SIRT2 than the patients with ascending aortic aneurysm. Calculated cut-off values for both enzymes may be helpful in laboratory differentiation of ascending aortic dissection from ascending aortic aneurysm.

BackgroundChronic kidney disease (CKD) manifested as reduced GFR and/or albuminuria, has been known to accelerate arterial stiffness and early vascular aging (EVA). Diabetes, hypertension, and glomerular disorders are the leading causes of CKD and renal failure.The question which etiology contributes more to this vascular phenomenon-hypertensive and diabetic CKD or CKD secondary to immune-mediated glomerulonephritis—remained unclear.ObjectiveTo compare pulse wave velocity (PWV), a marker of arterial stiffness, between CKD patients of different etiologies: hypertensive and diabetic nephrosclerosis. vs. CKD secondary to glomerular disorders.MethodsClinical data were collected on 56 patients followed at the Nephrology and Hypertension Institute in Samson Assuta Ashdod University Hospital. All patients had at least one visit at our Nephrology clinics prior to recruitment. All patients with a glomerular disorder had a clinical-pathological diagnosis based on a recent kidney biopsy.Pulse wave velocity (PWV) was measured using a validated Sphygmocor XCEL® device. Univariate and multivariate analyses were performed to compare PWV between hypertensive/diabetic CKD and CKD secondary to glomerular disorders.ResultsPWV was significantly higher in the hypertensive/diabetic CKD group, compared to the CKD-GN group, with an average of. 12.2 m/s vs 8.3 m/s, respectively (p < 0.001).In a multivariate linear regression model, having CKD secondary to glomerulonephritis was associated with a significantly lower PWV (B = − 3.262, p < 0.001), compared with CKD secondary to hypertension and diabetes, with adjustment of age, creatinine, and comorbidities.ConclusionCKD Patients secondary to glomerulonephritis, have lower PWV when compared to CKD patients with diabetes and/or hypertension, even after adjusting for age, renal function, and the presence of comorbidities. It is intriguing to further study the possible protective role of immunosuppression on the arterial properties of CKD patients.

BackgroundPrevious physics-based analyses of arterial morphology in relation to pulsatile pressure and flow, with pulse wave reflection, focused on the large arteries and required assumptions about the relative thicknesses of arterial walls and the velocities of pulse waves in the arteries. A primary objective of this study was to analyze arterial morphology and pulse wave reflection, using physics-based wave propagation, which explicitly includes arterial stiffness, with potential autonomic flow regulation, for both large and small arteries.MethodsPulse wave reflections that occur at arterial bifurcations, and their impact on macrocirculation and microcirculation pulse pressures and flows, are analyzed using the physics of wave propagation and impedance matching.ResultsThe optimum combinations of arterial dimensions and stiffnesses which minimize pulsatile reflections at arterial bifurcations are identified for both macrocirculation and microcirculation. The optimum ratio of arterial bifurcations’ branch-to-trunk luminal areas is predicted to have a value of 1.26, (with corresponding optimum stiffnesses) based on the principle that autonomic flow regulation minimizes pulsatile reflections. This newly predicted value of area ratio compares favorably with the Murray Scaling Law value of 1.26. For an area ratio of 1.26, the optimum bifurcation stiffness ratio is predicted to have a value of 1.12 for bifurcations in the macrocirculation and a value of 0.89 in the microcirculation. The analysis predicts that minimal pulsatile reflections may occur for area ratios not equal to 1.26, when vasodilation adjusts arterial stiffness to compensate for non-optimal arterial area ratios. The analysis predicts that the capillaries have about one-tenth the stiffness of the aorta, and the capillary bed possesses about one thousand times more total luminal area than the aorta. The analysis predicts there are about thirty generations, aorta to capillaries, of arterial bifurcations in an arterial tree.ConclusionsThe optimum arterial morphologies predicted by this physics-based analysis correspond to those observed in human vascular physiology. The contributions that arterial stiffnesses and dimensions make to optimal pulsatile flow are relevant to the development of pharmaceuticals related to autonomic vasodilation, to the development of optimally designed stents and to surgical procedures related to vascular modification.

BackgroundPerivascular adipose tissue (PVAT) in obesity critically contributes to vascular dysfunction, which might be restored by long-term exercise. Protein kinase B/nitric oxide synthase/nitric oxide (Akt/eNOS/NO) down-regulation within PVAT might be involved in the impaired anti-contractile function of arteries. Therefore, the present study evaluated the effect of long-term aerobic exercise on PVAT function and the potential regulator during this process.MethodsMale Sprague Dawley rats were divided into normal diet control group (NC), normal diet exercise group (NE), high-fat diet control group (HC), and high-fat diet exercise group (HE) (n = 12 in each group). Upon the establishment of obesity (20 weeks of high-fat diet), exercise program was performed on a treadmill for 17 weeks. After the intervention, circulating biomarkers and PVAT morphology were evaluated. Vascular contraction and relaxation were determined with or without PVAT. Production of NO and the phosphorylations of Akt (Ser473) and eNOS (Ser1177) within PVAT were quantified.ResultsMetabolic abnormalities, systemic inflammation, and circulating adipokines in obesity were significantly restored by long-term aerobic exercise (P < 0.05). The anti-contractile effect of PVAT was significantly enhanced by exercise in obese rats (P < 0.05), which was accompanied by a significant reduction in the PVAT mass and lipid droplet area (P < 0.05). Furthermore, the production of NO was significantly increased, and phosphorylation levels of Akt (Ser473) and eNOS (Ser1177) were also significantly promoted in PVAT by long-term aerobic exercise (P < 0.05).ConclusionLong-term aerobic exercise training restored PVAT morphology and anti-contractile function in obese rats, and enhanced the activation of the Akt/eNOS/NO signaling pathway in PVAT.

The early life programming of adult health and disease (Developmental Origins of Adult Health and Disease; DOHaD) concept has attracted increased attention during recent years. In this review evidence is presented for epidemiological associations between early life factors (birth weight, prematurity) and cardiometabolic traits and risk of disease in adult life. Even if not all studies concur, the evidence in general is supporting such links. This could be due to either nature or nurture. There is evidence to state that genetic markers influencing birth weight could also be of importance for offspring hypertension or risk of coronary heart disease, this supporting the nature argument. On the other hand, several studies, both historical and experimental, have found that the change of maternal dietary intake or famine in pregnancy may cause permanent changes in offspring body composition as well as in hemodynamic regulation. Taken together, this also supports the strategy of preventive maternal and child health care, starting already during the preconception period, for lowering the risk of adult cardiometabolic disease in the affected offspring. Further studies are needed to better understand the mediating mechanisms, for example concerning arterial function, hemodynamic regulation, renal function, and neuroendocrine influences, related to the development of early vascular aging (EVA) and cardiovascular disease manifestations.

ObjectivesThere is evidence that pulse wave velocity (PWV) can predict the occurrence of abdominal aortic calcification (AAC), while the association between estimated PWV (ePWV) and AAC has not been reported, so our study aimed to analyze the association between ePWV and AAC.MethodsThe study enrolled 3140 adults between the ages of 40 and 80 who participated in the 2013–2014 National Health and Nutrition Examination Survey. Using multivariate logistic regression analysis, multivariate linear regression and receiver operating characteristic (ROC) curve to evaluate the association between ePWV and AAC.ResultsThe ePWV was significantly higher in participants with AAC compared with those without AAC. And ePWV had a high correlation with age and AAC (correlation coefficient = 0.906 and 0.332, both P < 0.001). Individuals in high ePWV group had significantly higher percentage of AAC compared to low ePWV group (OR = 2.971, 95% CI 2.529–3.490, P < 0.001) in the crude model. After adjusting for all confounding variables, ePWV was still significantly higher (Model 3, OR = 1.962, 95% CI 1.612–2.389, P < 0.001). While after adjusting for all confounding variables plus age (Model 4), ePWV, when as a categorical variable, was no longer significantly positively associated with AAC. Additionally, the ROC curve indicated that both ePWV and age had some diagnostic value for AAC (AUC = 0.690, P < 0.001; AUC = 0.708, P < 0.001).ConclusionsIn the age range of 40–80 years, ePWV did have an association with AAC but did not have predictive power beyond age.

PurposeWhether antiphospholipid antibodies (aPLs) cause atherosclerosis in certain arteries with specific compositions and locations remains unknown. We investigated the relationship between aPLs and their association with locations of atherosclerosis in the arteries of the abdomen and lower extremities.MethodsOf 2273 patients, 697 who underwent computed tomography angiography of the abdomen and lower extremities and aPL evaluation were included. Atherosclerosis distribution score (ADS) was employed to quantify atherosclerosis severity. Multiple linear regression analysis was performed using the ADS of the suprainguinal elastic and infrainguinal muscular arteries as dependent variables and all aPLs, conventional risk factors of atherosclerosis, and coagulation-related factors as independent variables.ResultsIn the suprainguinal elastic and infrainguinal muscular arteries, common risk factors for higher ADS were age, smoking, hypertension, higher glycated hemoglobin, male sex, decreased protein S, and increased homocysteine. Lupus anticoagulant (LA) and increased triglyceride level in the suprainguinal elastic arteries and anticardiolipin antibody (aCL) immunoglobulin (Ig)G, longer alcohol consumption duration, and increased fibrinogen level in the infrainguinal muscular arteries were also risk factors for higher ADS.ConclusionLA and aCL IgG were associated with atherosclerosis in the suprainguinal elastic and infrainguinal muscular arteries, respectively. aPLs could predict the location of atherosclerosis.