Muscular Arteries Research Articles

Abstract 12393: Pexidartinib Ameliorates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

Background: Pulmonary arterial hypertension (PAH) is a life-threatening disease caused by pulmonary artery remodeling, inflammation, and altered immune responses. Lungs from PAH patients show that accumulation of perivascular macrophages is a key factor for the development of pulmonary artery remodeling, which leads to right ventricular failure. However, pharmacological inhibition of this pathway for treating PAH has not been thoroughly examined. Pexidartinib inhibits macrophage proliferation and polarization, thus can be a candidate for treating PAH. Objective: To investigate the effect of pexidartinib in PAH. Methods: Male Sprague-Dawley rats were divided into 4 groups: control, pexidartinib treated, monocrotaline (MCT)-exposed, pexidartinib treated and MCT-exposed rats. Right ventricular hemodynamic changes, right ventricular hypertrophy, and pulmonary artery morphological features were examined. Pulmonary artery perivascular macrophage infiltration was determined by immunofluorescence of CD68 and arginase-1 (M2 macrophage marker). Results: Immunofluorescence of lungs from MCT-exposed PAH rats showed perivascular CD68- and arginase-1-positive macrophage infiltration (P < 0.05, each) and muscularization of pulmonary arteries (P < 0.05) compared to controls. Treatment of pexidartinib inhibited perivascular CD68- and arginase-1-positive macrophage infiltration (P < 0.05, each) and attenuated right ventricular systolic pressure and the right ventricle to the left ventricle plus septum ratio (RV/LV+IVS) in MCT-exposed PAH rats (Figure 1). Conclusion: Pexidartinib treatment prevented MCT-induced PAH and right ventricular hypertrophy by inhibiting perivascular macrophage infiltration and M2 macrophage polarization in rat pulmonary arteries. Therefore, pexidartinib may be a promising drug for the treatment of PAH.

Wall Properties of Elastic and Muscular Arteries in Children and Adolescents at Increased Cardiovascular Risk.

Pulse wave velocity (PWV) assessment represents a simple method to estimate arterial distensibility. At present, carotid-femoral PWV (cf-PWV) is considered the gold standard method in the non-invasive evaluation of the elastic properties of the aorta. On the other hand, the mechanical properties of muscular arteries can be evaluated on the axillo-brachial-radia axis by estimating the carotid-radial PWV (cr-PWV). While a number of studies have addressed these issues in adults, limited information is available on the respective features of cf-PWV and cr-PWV and on their modulating factors in children and adolescents at increased cardiovascular risk. The mechanical properties of the predominantly elastic (aorta) and muscular (axillo-brachial-radial axis) arteries were evaluated in a pediatric population characterized by either elevated blood pressure (BP) or excess body weight, and the main factors affecting cf-PWV and cr-PWV values in these individuals were investigated. 443 children and adolescents (median age 11.5 years, 43.3% females) were enrolled; 25% had BP values >90th percentile and 81% were excess weight. The cf-PWV values were significantly lower than the cr-PWV values: median (Q1-Q3) = 4.8 m/s (4.3-5.5) and 5.8 m/s (5.0-6.5), respectively (p < 0.001). The pubertal development (p < 0.03), systolic BP and diastolic BP z-scores (p = 0.002), heart rate (p < 0.001), and waist-to-height ratio (p < 0.005) were significantly associated with cf-PWV values. No significant association was found between BMI z-score and cf-PWV. Predictors of high cf-PWV (>95th percentile) were the heart rate (OR 1.07, 95%CI 1.04-1.10, p < 0.001) and waist-to-height ratio (OR 1.06, 95%CI 1.0-1.13, p = 0.04). The variables significantly related with cr-PWV values were diastolic BP z-score (p = 0.001), heart rate (p < 0.01), and HOMA index (p < 0.02). No significant association was found between the cr-PWV and BMI z-score or waist-to-height ratio. Systolic and diastolic BP values and central obesity are associated with aortic stiffness in a population of children and adolescents at increased cardiovascular risk. In contrast, diastolic BP, heart rate, and levels of insulin resistance appear to be related to distensibility of the upper limb vascular district.

Arterial stiffness of the aorta and iliofemoral artery and their responses to nitroglycerin administration in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits.

The role of hypercholesterolemia in arterial stiffness, which usually reflects the progression of atherosclerosis has not been fully investigated. To clarify the meaning of arterial stiffness in hypercholesterolemia, we evaluated arterial stiffness in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits by using new arterial stiffness indices of the aorta and common iliac to femoral artery. The new arterial stiffness indices of both arteries were determined by the application of the theory of cardio-ankle vascular index (CAVI) to the aorta (aBeta) and ilio-femoral artery (ifBeta). Furthermore, the responses of both indices to nitroglycerin (NTG) administration were compared between WHHHMI and normal rabbits. aBeta and ifBeta of WHHLMI and normal rabbits were measured under anesthesia. Pulse wave velocity in the whole aorta (aPWV) and ilio-femoral artery (ifPWV), blood pressure, and other parameters were measured before and after administration of NTG (50-120 μg/kg/min) every 1 for 5 min. Atherosclerotic lesions were observed in the aorta, but a little in the ilio-femoral artery in WHHLMI rabbits. Compared with normal rabbits, aBeta was significantly higher, but ifBeta was lower in WHHLMI rabbits. When NTG was administered, ifBeta decreased significantly in both groups; however, aBeta increased in normal rabbits, but remained unchanged in WHHIMI rabbits. These findings suggested that hereditary hypercholesterolemia in rabbits did not uniformly enhance arterial stiffness in elastic artery and muscular artery. The responses to NTG were also different between two arteries. The mechanism of these different responses needs further studies.

Morphological features of basal laminas of enteral nervous system structures in chronic slow transit constipation

BACKGROUND: Studies on basal laminas in the tissues of the enteric nervous system are few and are carried out on experimental models in vivo and in vitro, performed on animals. The morphological features of the structure and localization of BL, their cellular sources of origin in various tissues of the gastrointestinal tract in normal and pathological conditions remain poorly studied.&#x0D; AIM: Study of morphological features and distribution of basal laminas in human colon tissues and their changes in pathology.&#x0D; MATERIALS AND METHODS: Fragments of the large intestine, obtained as a result of surgery for chronic slow-transit constipation, performed in S. M. Kirov Military Medical Academy were studied. The selective marker of basal laminas, type IV collagen, as well as neuronal and glial immunohistochemical markers (PGP 9.5, GFAP, S100 proteins) were used in the work&#x0D; RESULTS: It has been shown that the greatest immunoreactivity within the intestinal wall is observed in the myenteric membrane, weak in the vessels of the submucosa, locally expressed in the subepithelial region of the mucous membrane (in the upper sections of the crypts). In smooth muscle, basal laminas were found around the smooth muscle cells of the longitudinal and concentric layers of the muscular membrane, mucous membrane, veins and arteries, as well as in the endothelium. It has been shown that the ganglionic Auerbachs plexus is delimited from closely adjacent muscle layers of a continuous basal lamina, similar to the basal plate (glia limitans) of the brain and spinal cord of the CNS. It is clearly defined by its appearance it has the form of a continuous hollow tubular structure. The sources of the formation of the basal plate around the ganglia of Auerbach and Meissners plexuses are various glial elements: in the first plexus, astrocyte-like and non-myelinated Schwann cells (both types located in the neuropil), and in the second plexus, glia of the autonomic nervous system (satellite cells of neurons and neurolemmocytes of postganglionic nerve fibers).&#x0D; CONCLUSIONS: For the first time, the transition of basal lamina from the Auerbachs plexus to numerous basal plates of neurolemmocytes of the Remakov fibers of the main terminal nerve plexus, which are involved in the innervation of the smooth muscle cells of the muscular membrane, is shown. Signs of dystrophic changes in the basal lamina structure associated with pathological changes in chronic slow transit constipation (tissue edema, inflammatory reactions, manifestations of agangliosis, gliosis, focal denervation of muscle cells, degeneration of nerve endings of neuromuscular and ganglionic plexuses) are shown in the work.

MORPHOMETRIC FEATURES OF CHANGES IN THE MUSCLES OF THE ANTERIOR ABDOMINAL WALL AFTER IMPLANTATION OF THE CAPROMESH MESH COMBINED WITH PRP IN THE EXPERIMENT

Summary. Despite the use of meshes and other improvements, currently popular methods of surgical treatment of diastasis recti of the abdominal muscles and umbilical hernia have certain disadvantages and risks, especially in the group of patients with morbid obesity. The priority surgical intervention for diastasis and umbilical hernia under the conditions of morbid obesity is the performance of E-Milos video assisted operation. However, this type of procedure does not involve suture or stapled fixation of the mesh in the retromuscular space, which can lead to a number of complications. The analysis of the obtained results determines the relevance of this study.&#x0D; Purpose. Carry out a quantitative morphometric assessment of the changes in the arteriomuscular-aponeurotic layer and muscles of the abdominal wall under the conditions of the E-Milos operation using meshes based on e-caprolactone treated with PRP (plasma enriched with growth factors) in the experiment.&#x0D; Materials and Methods. The morphometric study involved the analysis of the muscles of the anterior abdominal wall after the implantation of the Capromesh based on e-caprolactone treated with PRP into the retromuscular space under the light-optical examination of micronutrients. Experiments were conducted on 16 sexually mature male Vietnamese pigs, which were divided into 4 groups.&#x0D; Results. Measurements made in a group of intact animals showed that the outer diameter of small-caliber arteries was equal to (35.40±0.39) μm,, the inner diameter was (16.95±0.15) μm, the media thickness was (6.36±0 .06) μm, the Kernohan index (the ratio of the area of the lumen to the entire area of the vessel) was (22.90±0.18) %. The height of the endotheliocytes of these vessels reached (6.12±0.06) μm, the diameter of their nuclei – (3.12±0.03) μm. The nuclear-cytoplasmic ratio in the studied cells was equal to (0.260±0.003).&#x0D; The thickness of the media of small caliber arteries on day 7 of the experiment increased from (6.38±0.06) μm to (6.60±0.06) μm, i.e. by 3.4 % (р&lt;0.05), and adventitia thickness – by 24.7 % (р&lt;0.001). Thus, the Wogenvoort index increased from (436.20±4.20) % to (513.90±4.50) %, i.e. by 77.7 %. It is also worth noting that the given morphometric indicators were statistically significantly (p&lt;0.001) different from each other.&#x0D; On day 14 of the experiment, the relative volume of damaged endothelial cells was (4.20±0.03) %. This morphometric parameter exceeded the similar control by 1.8 times (p&lt;0.001). The morphometric parameters of the small-caliber arteries of the soft tissues of the anterior abdominal wall of male Vietnamese pigs on day 21 of the experiment did not differ significantly from similar quantitative morphological indicators of the control observations.&#x0D; Conclusions. On day 14 of the experiment, the structural rearrangement of small-caliber arteries did not significantly differ from similar vessels of control observations. The relative volume of damaged endothelial cells was equal to (4.20±0.03) %. The morphometric parameters of the small-caliber arteries of the soft tissues of the anterior abdominal wall of male Vietnamese pigs on day 21 of the experiment did not differ significantly from similar quantitative morphological indicators of the control observations.&#x0D; On day 21 of the experiment, the nuclear-cytoplasmic ratio in the studied muscle structures was equal to (0.055±0.002), and the given morphometric parameter did not differ from the similar control, which indicated the preservation and stability of cellular structural homeostasis.

Exercise training and vascular heterogeneity in db/db mice: evidence for regional- and duration-dependent effects.

Exercise training (ET) has several health benefits; however, our understanding of regional adaptations to ET is limited. We examined the functional and molecular adaptations to short- and long-term ET in elastic and muscular conduit arteries of db/db mice in relation to changes in cardiovascular risk factors. Diabetic mice and their controls were exercised at moderate intensity for 4 or 8weeks. The vasodilatory and contractile responses of thoracic aortae and femoral arteries isolated from the same animals were examined. Blood and aortic samples were used to measure hyperglycemia, oxidative stress, inflammation, dyslipidemia, protein expression of SOD isoforms, COX, eNOS, and Akt. Short-term ET improved nitric oxide (NO) mediated vasorelaxation in the aortae and femoral arteries of db/db mice in parallel with increased SOD2 and SOD3 expression, reduced oxidative stress and triglycerides, and independent of weight loss, glycemia, or inflammation. Long-term ET reduced body weight in parallel with reduced systemic inflammation and improved insulin sensitivity along with increased SOD1, Akt, and eNOS expression and improved NO vasorelaxation. Exercise did not restore NOS- and COX-independent vasodilatation in femoral arteries, nor did it mitigate the hypercontractility in the aortae of db/db mice; rather ET transiently increased contractility in association with upregulated COX-2. Long-term ET differentially affected the aortae and femoral arteries contractile responses. ET improved NO-mediated vasodilation in both arteries likely due to collective systemic effects. ET did not mitigate all diabetes-induced vasculopathies. Optimization of the ET regimen can help develop comprehensive management of type 2 diabetes.

Myeloid PTP1B deficiency protects against atherosclerosis by improving cholesterol homeostasis through an AMPK-dependent mechanism

ObjectiveAtherosclerosis is a chronic inflammatory process induced by the influx and entrapment of excess lipoproteins into the intima media of arteries. Previously, our lab demonstrated that systemic PTP1B inhibition protects against atherosclerosis in preclinical LDLR−/− models. Similarly, it was shown that myeloid-specific PTP1B ablation decreases plaque formation and ameliorates dyslipidaemia in the ApoE−/− model of atherosclerosis. We hypothesized that the relevant improvements in dyslipidaemia following modification of PTP1B activation may either result from changes in hepatic cholesterol biosynthesis and/or increased uptake and degradation by liver-resident macrophages. We examined this in animal models and patients with coronary artery disease.MethodsIn this study, we determined the cholesterol-lowering effect of myeloid-PTP1B deletion in mice fed a high-fat high-cholesterol diet and examined effects on total cholesterol levels and lipoprotein profiles. We also determined the effects of PTP1B inhibition to oxLDL-C challenge on foam cell formation and cholesterol efflux in human monocytes/macrophages.ResultsWe present evidence that myeloid-PTP1B deficiency significantly increases the affinity of Kupffer cells for ApoB containing lipoproteins, in an IL10-dependent manner. We also demonstrate that PTP1B inhibitor, MSI-1436, treatment decreased foam cell formation in Thp1-derived macrophages and increased macrophage cholesterol efflux to HDL in an AMPK-dependent manner. We present evidence of three novel and distinct mechanisms regulated by PTP1B: an increase in cholesterol efflux from foam cells, decreased uptake of lipoproteins into intra-lesion macrophages in vitro and a decrease of circulating LDL-C and VLDL-C in vivo.ConclusionsOverall, these results suggest that myeloid-PTP1B inhibition has atheroprotective effects through improved cholesterol handling in atherosclerotic lesions, as well as increased reverse cholesterol transport.Trial registration Research registry, researchregistry 3235. Registered 07 November 2017, https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5a01d0fce7e1904e93e0aac5/.

Intersystem interactions of physiological system indicators in students with different types of autonomic regulation

Studying not only individual students indicators of students, but complex intersystem interactions that reflect the specifics of adaptive capabilities is of scientific interest. The aim of the study. To reveal the features of intersystem interactions of indicators of the blood vessels functional state, morphological and neurodynamic characteristics of students with different types of autonomic regulation, living in the KhantyMansiysk Autonomous Okrug – Yugra. Methods. 429 first–fourth-year students (348 girls, 80 boys) of the Surgut State Pedagogical University were examined. The initial type of autonomic regulation was determined by the average duration of electrocardiogram RR intervals. Anthropometry parameters (body length and weight) and body composition were assessed using Tanita BC-601 device (Tanita, Japan), vascular wall elasticity – using AngioScan-01 (AngioScan-Electronics Ltd, Russia), neurodynamic indicators – using NS-PsychoTest device (Neurosoft, Russia). Statistical analysis was carried out using Statistica 7.0 software (StatSoft Inc., USA). We used the nonparametric Mann – Whitney U-test to evaluate differences and the nonparametric Pearson R-test to analyze correlations. Results. An increase in the stiffness of the vascular wall of large and small arteries in girls is accompanied by an increase in parasympathetic activity. In young men, an increase in the stiffness of large arteries raises with an increase in sympathoadrenal activity, while a compensatory increase in the stiffness of small muscular arteries is noted with an increase in parasympathetic activity. In persons with the sympathicotonic type of autonomic regulation, an excess content of fat mass, an increased frequency of visceral obesity, and a deficiency in water content were registered. With the predominance of the parasympathetic component contribution to the regulation of cardiac rhythm, an increase in the processes of inhibition in the central nervous system was noted. In young men, reduced sensorimotor reactions are consistent with sympathetic activation in the regulation of heart rate. Correlation analysis made it possible to establish some features in the interaction of the vascular, morphological and central nervous systems. Conclusion. Differences in indicators of functional systems (physical development, blood flow, neurodynamic characteristics) in the examined groups of students are shown, taking into account gender and autonomic regulation type. Features of intersystem interactions of indicators of physiological systems of students’ bodies with different types of autonomic regulation were revealed.

Myocardial Remodeling in Early Chronic Kidney Disease—Mineral and Bone Disorder Model with Low Bone Turnover

Chronic kidney disease—mineral and bone disorder (CKD-MBD) plays a significant role in causing cardiovascular morbidity and mortality related to CKD. CKD-MBD has been studied during advanced stages when changes in inorganic phosphate (Pi) and its hormonal regulation are obvious. The initial phases of myocardial remodeling (MR) in early CKD-MBD remain poorly understood. We induced mild CKD-MBD in spontaneously hypertensive rats using 3/4 nephrectomy. Animals were fed standard chow, containing 0.6% phosphate. In each animal, we analyzed indices of chronic kidney injury, bone turnover and Pi exchange, and assessed the myocardial histology and gene expression profile. Applied CKD-MBD models corresponded to human CKD S1-2 with low bone turnover and without an increase in systemic Pi-regulating factors (parathyroid hormone and fibroblast growth factor 23). In mild CKD-MBD models, we found MR features characterized by cardiomyocyte hypertrophy, interstitial and perivascular fibrosis, intramyocardial artery media thickening, along with alterations in Ppp3ca, Mapk1, Jag1, Hes1, Ptch1, Numb, Lgr4 and Bmp4 genes. Among other genes, the down-regulation of Jag1 was most tightly associated with either myocardial hypertrophy or fibrosis. Myocardial alterations concurrently occurred with mild CKD-MBD and comprised fibrosis preceding cardiomyocyte hypertrophy. The histological features of MR were associated with myocardial P accumulation in settings of low bone turnover, prior to a response of systemic Pi-regulating factors and with alterations in calcineurin, ERK1/2, Notch, BMP and Hedgehog genes.

Reimagining the Value of Brachial-Ankle Pulse Wave Velocity as a Biomarker of Cardiovascular Disease Risk-A Call to Action on Behalf of VascAgeNet.

This review critiques the literature supporting clinical assessment and management of cardiovascular disease and cardiovascular disease risk stratification with brachial-ankle pulse wave velocity (baPWV). First, we outline what baPWV actually measures-arterial stiffness of both large central elastic arteries and medium-sized muscular peripheral arteries of the lower limb. Second, we argue that baPWV is not a surrogate for carotid-femoral pulse wave velocity. While both measures are dependent on the properties of the aorta, baPWV is also strongly dependent on the muscular arteries of the lower extremities. Increased lower-extremity arterial stiffness amplifies and hastens wave reflections at the level of the aorta, widens pulse pressure, increases afterload, and reduces coronary perfusion. Third, we used an established evaluation framework to identify the value of baPWV as an independent vascular biomarker. There is sufficient evidence to support (1) proof of concept; (2) prospective validation; (3) incremental value; and (4) clinical utility. However, there is limited or no evidence to support (5) clinical outcomes; (6) cost-effectiveness; (8) methodological consensus; or (9) reference values. Fourth, we address future research requirements. The majority of the evaluation criteria, (1) proof of concept, (2) prospective validation, (3) incremental value, (4) clinical utility and (9) reference values, can be supported using existing cohort datasets, whereas the (5) clinical outcomes and (6) cost-effectiveness criteria require prospective investigation. The (8) methodological consensus criteria will require an expert consensus statement. Finally, we finish this review by providing an example of a future clinical practice model.

The Importance of Inflammatory and Angiogenic Markers in the Evaluation of Early Cardiovascular Disease Risk in Women with Hypertensive Disorders of Pregnancy.

Women with hypertensive disorders of pregnancy (HDP) have a significantly higher risk of developing cardiovascular diseases later in life. The stratification of this risk using biomarkers during pregnancy can help to identify these women and apply early prevention. We aimed to determine proinflammatory cytokines and angiogenic markers, echocardiographic parameter changes after delivery and predict early cardiovascular disease risk in women with arterial hypertension and its complications during pregnancy. We conducted a literature search using the PubMed database for the last ten years. A total of 17 articles were included to our study and full text reviewed. Four out of six studies found higher postpartum Interleukin-6 (IL-6) levels in women with HDP. IL-6 correlated positively with waist circumference, body mass index, and triglycerides, and negatively with high density lipoproteins (HDL). Two out of four studies found higher postpartum tumor necrosis factor alpha (TNF-α) levels in women with HDP but later concentration equalizes. One out of eight studies found higher placental growth factor (PlGF) and two out of eight found more elevated soluble fms-like tyrosine kinase-1 (sFlt-1) in women with HDP. With decreasing PlGF and increasing sFlt-1, common carotid artery intima and media thickness, aortic root diameter, left atrial diameter, left ventricle mass, systolic, diastolic, and mean blood pressure increased, whereas HDL decreased. One out of four studies found higher sFlt-1/PlGF. IL-6 remains significantly higher after delivery. Few studies found higher TNF-α, sFlt-1, PlGF and their ratio postpartum. All studies found a correlation between angiogenic factors, IL-6, and cardiovascular disease risk factors.

The so-called ligamentum arteriosum is innervated.

The ductus arteriosus is a muscular artery connecting the pulmonary trunk directly to the aorta in fetal circulation in order to by-pass the fluid filled lungs. Post-natally, this vessel is speculated to undergo obliteration, fibrosis and ultimately metamorphosize into a band of ligament, thereby changing name from the ductus arteriosus to the ligamentum arteriosum (LA). Earlier studies into the innervation of the ductus arteriosus reported innervation from the left aortic and vagus nerves. However, information of what becomes of the innervation is scanty and contradictory. I hypothesized that; this fetal shunt still receives innervation even in post-uterine life. To test this, LA of human, pig, and wild-type mice were studied using double-immunofluorescence labeling using antibodies directed against structural and general neuronal marker proteins (Smooth muscle actin and Protein gene product 9.5 (PGP 9.5, respectively). Additionally, TEM studies were performed on mouse LA. Results from the present study demonstrates an extensive innervation of the LA in animals (mice and pigs) and in senescent humans validated by two independent methods, i.e., immunolabeling with antibody directed against PGP 9.5 and TEM. Intense immunoreactivity was clearly visible in samples subjected to PGP-immunolabeling. TEM revealed the presence of nerve terminals with about 30% of all nerve terminals observed less than 1 μm away from smooth muscle cells within the LA. This clearly differs from elastic arteries, where the distance between autonomic terminals and smooth muscle cells is rarely less than 1 μm. Conceivably, these results imply that the so- called LA receives innervation representative of that present within the ductus arteriosus during fetal life. This provides the first reliable study of innervation of the LA and makes room for further investigation into the neurochemistry of this innervation. This is crucial as the presence of nerve terminals may play a role in vessel compliance or impedance of the two great vessels related to this structure. The substances released by these fibers may also have an influence on cells and tissues in the immediate microenvironment of this structure.

Correlation Between the Level od Atherosclerosis and Pathological Features of Coronary Artery Disease: A Study of 100 Autopsy Cases

Objective: Atherosclerosis is a generalized, chronic disease of large and medium-sized muscular elastic arteries. Relation between intensity of atherosclerosis and coronary artery disease, and risk factors of atherosclerosis could not been revealed completely by autopsy studies. We aimed to renew this shortage of knowledge with our autopsy study prospectively. &#x0D; Methods: One hundred cases were autopsied within 48 h after death. Atherosclerotic risk factor data were collected including age, gender, height, weight, smoking and any chronic coronary artery disease. Atherosclerosis severity was evaluated macroscopically by examining the inner surfaces of the vascular lumens and revealed with postmortem pathological findings of coronary artery disease.&#x0D; Results: The mean age was 42 ± 22 years. Seventy-four percent of cases were male, while 26% were female. Smoking duration ranged from 1 to 50 years with a mean duration of 17 ± 12 years. Existence of atherosclerosis in main vessels were also in correlation with age, duration of smoking and BMI (Body Mass Index) (p

A viscoelastic constitutive model for human femoropopliteal arteries

High failure rates present challenges for surgical and interventional therapies for peripheral artery disease of the femoropopliteal artery (FPA). The FPA’s demanding biomechanical environment necessitates complex interactions with repair devices and materials. While a comprehensive understanding of the FPA’s mechanical characteristics could improve medical treatments, the viscoelastic properties of these muscular arteries remain poorly understood, and the constitutive model describing their time-dependent behavior is absent. We introduce a new viscoelastic constitutive model for the human FPA grounded in its microstructural composition. The model is capable of detailing the contributions of each intramural component to the overall viscoelastic response. Our model was developed utilizing fractional viscoelasticity and tested using biaxial experimental data with hysteresis and relaxation collected from 10 healthy human subjects aged 57 to 65 and further optimized for high throughput and automation. The model accurately described the experimental data, capturing significant nonlinearity and hysteresis that were particularly pronounced circumferentially, and tracked the contribution of passive smooth muscle cells to viscoelasticity that was twice that of the collagen fibers. The high-throughput parameter estimation procedure we developed included a specialized objective function and modifications to enhance convergence for the common exponential-type fiber laws, facilitating computational implementation. Our new model delineates the time-dependent behavior of human FPAs, which will improve the fidelity of computational simulations investigating device-artery interactions and contribute to their greater physical accuracy. Moreover, it serves as a useful tool to investigate the contribution of arterial constituents to overall tissue viscoelasticity, thereby expanding our knowledge of arterial mechanophysiology. Statement of significanceThe demanding biomechanical environment of the femoropopliteal artery (FPA) necessitates complex interactions with repair devices and materials, but the viscoelastic properties of these muscular arteries remain poorly understood with the constitutive model describing their time-dependent behavior being absent. We hereby introduce the first viscoelastic constitutive model for the human FPA grounded in its microstructures. This model was tested using biaxial mechanical data collected from 10 healthy human subjects between the ages of 57 to 65. It can detail the contributions of each intramural component to the overall viscoelastic response, showing that the contribution of passive smooth muscle cells to viscoelasticity is twice that of collagen fibers. The usefulness of this model as tool to better understand arterial mechanophysiology was demonstrated.

Single-Cell RNA sequencing investigation of female-male differences under PAD conditions.

Peripheral arterial disease (PAD) is an age-related medical condition affecting mostly muscular arteries of the limb. It is the 3rd leading cause of atherosclerotic morbidity. The mechanical environment of endothelial cells (ECs) in PAD is characterized by disturbed blood flow (d-flow) and stiff extracellular matrices. In PAD, the stiffness of arteries is due to decreased elastin function and increased collagen content. These flow and stiffness parameters are largely missing from current models of PAD. It has been previously proven that ECs exposed to d-flow or stiff substrates lead to proatherogenic pathways, but the effect of both, d-flow and stiffness, on EC phenotype has not been fully investigated. In this study, we sought to explore the effect of sex on proatherogenic pathways that could result from exposing endothelial cells to a d-flow and stiff environment. We utilized the scRNA-seq tool to analyze the gene expression of ECs exposed to the different mechanical conditions both in vitro and in vivo. We found that male ECs exposed to different mechanical stimuli presented higher expression of genes related to fibrosis and d-flow in vitro. We validated our findings in vivo by exposing murine carotid arteries to d-flow via partial carotid artery ligation. Since women have delayed onset of arterial stiffening and subsequent PAD, this work may provide a framework for some of the pathways in which biological sex interacts with sex-based differences in PAD.

Photoplethysmography factors associated with undiagnosed hypertension in men with low and moderate cardiovascular risk

Aim. To study the functional state of the terminal arteries and arterioles of the skin using photoplethysmography (PPG) in men with hypertension (HTN) of low and moderate cardiovascular risk (CVR) and to identify morphofunctional diagnostic criteria associated with HTN.Material and methods. A total of 118 healthy men (30-60 years old) underwent clinical and biochemical blood tests, PPG, ultrasound of cardiac and main arteries, 24-hour blood pressure monitoring. According to 24-hour blood pressure monitoring, two groups were formed: the control group — 59 normotensive men, HTN group — 59 men with HTN.Results. According to the PPG data, men with HN had higher normalized augmentation index (Alp75) (3,8 and -5,25%; (p&lt;0,005)), stiffness index (SI) (7,6 and 7,35 m/s) (p&lt;0,05) and reflection index (RI) (36,5 and 28,4%) (p&lt;0,005), respectively. According to multivariate analysis, an increase in RI ≥30,6% (odds ratio, 4,6; p=0,0476) and SI ≥7,9 m/s (odds ratio, 3,69; p=0,019) was significantly associated with HTN. A regression model has been developed that includes age ≥35 years, RI ≥30,6% and SI ≥7,9 m/s, which allows predicting HTN in men with low and moderate cardiovascular risk with a sensitivity of 78% and a specificity of 62,1%.Conclusion. Men with HTN of low and moderate CVR are characterized by an increase in vascular stiffness, tone of smooth muscle cells, terminal muscular arteries and arterioles, and an increase in pulse wave velocity. The developed model can be used to predict hypertension in these patients and determine indications for further examination.

Exercise intensities modulate ACE2/MasR/eNOS pathway in male Wistar rat's lung.

Specific exercise intensities could improve lung vascular function by increasing nitric oxide (NO). The ACE2/MasR/eNOS axis is one of the pathways facilitating NO synthesis. This study examines the effect of different intensities of aerobic training on the ACE2/MasR/eNOS axis and histology of lung muscular arteries. Male Wistar rats were used in this study and randomized into control and exercise groups receiving low-, moderate-, and high-intensity training. The training was conducted for 30 min daily, five times a week, for 8 weeks. We observed that different exercise intensities affect the ACE2/MasR/eNOS pathway differently. Compared to control, high-intensity aerobic exercise significantly increased ACE2, Mas receptor (MasR), and eNOS mRNA expressions (p < 0.01). Moderate-intensity exercise significantly increased MasR and eNOS mRNA expressions compared to the control (p < 0.05), and this intensity also increased ACE2 mRNA but not significantly. Low-intensity exercise increased ACE2, MasR, and eNOS mRNA expressions but not significantly. Low-, moderate-, or high-intensity exercises reduced the medial wall thickness of the lung muscular arteries but not significantly. In conclusion, high-intensity exercise may induce NO synthesis in the lung by increasing mRNA expression of ACE2, MasR, and eNOS without decreasing the medial wall thickness of the muscular artery. Thus, high-intensity exercise may be the optimal intensity to improve NO synthesis and vascular function in the lung.

Myocardial infarction impaired wall mechanics and hemodynamics in peripheral arteries.

Myocardial infarction (MI) impaired both cardiac functions and peripheral arteries. The changes in normal and shear stresses in the peripheral artery wall are of importance for understanding the progression of MI-induced heart failure (HF). The aim of the study is to investigate the corresponding changes of normal and shear stresses. The coronary artery ligation was used to induce the MI in Wistar rats. The analysis of wall mechanics and hemodynamics was performed based on in vivo and in vitro measurements. Myocardial infarction increased wall stiffness in elastic carotid and muscular femoral arteries significantly albeit different changes occurred between the two vessels from 3 to 6weeks postoperatively. Moreover, the hemodynamic analysis showed the gradually deteriorated wall shear stress, oscillatory shear index and relative residence time in the two arteries. This study probably shed light on understanding the interaction between abnormal systemic circulation and peripheral mechanics and hemodynamics during the development of MI-induced HF.

Persistent Hypoxia with Intermittent Aggravation Causes Imbalance in Smad3/Myocardin-Related Transcription Factor Signaling with Consequent Endothelial Senescence and Pulmonary Arterial Remodeling.

Loss of Smad3 and the consequent activation of myocardin-related transcription factor (MRTF) are associated with vascular pathologies. This study aimed to examine the impact of persistent hypoxia with intermittent aggravation (PI hypoxia) on cellular senescence and pulmonary arterial remodeling mediated by the Smad3/MRTF imbalance. We examined the effects of PI hypoxia on the Smad3/MRTF pathway and cellular senescence using human pulmonary artery endothelial cells (HPAECs) and in vivo studies in rats. The senescent degree was evaluated using β-galactosidase staining, p16 quantitation and the measurement of senescence-associated secretory phenotype. Structural data in the pathological analysis of pulmonary artery remodeling were collected. Compared to the control, HPAECs and pulmonary tissue from rats exposed to PI hypoxia showed a significantly higher senescent degree, lower expression of Smad3, and higher MRTF levels. The overexpression of Smad3 significantly mitigated HPAECs senescence in vitro. Further, treatment with CCG-203971, which inhibits MRTF, increased Smad3 levels and reduced β-galactosidase positive cells in rat lung tissue. This intervention also alleviated PI hypoxia-induced pathological changes, including remodeling indices of pulmonary arterial thickening, muscularization, and collagen formation. In conclusion, imbalanced Smad3/MRTF signaling is linked to PI hypoxia-induced senescence and pulmonary arterial remodeling, making it a potential therapeutic target for patients with sleep apnea and chronic obstructive pulmonary disease.

Axon guidance genes control hepatic artery development.

Earlier data on liver development demonstrated that morphogenesis of the bile duct, portal mesenchyme and hepatic artery is interdependent, yet how this interdependency is orchestrated remains unknown. Here, using 2D and 3D imaging, we first describe how portal mesenchymal cells organize to form hepatic arteries. Next, we searched for intercellular signalling active during portal area development and found that axon guidance genes are dynamically expressed in developing bile ducts and portal mesenchyme. Using tissue-specific gene inactivation in mice, we show that the Repulsive guidance molecule BMP co-receptor A (Rgma)/Neogenin 1 (Neo1) receptor/ligand pair is dispensable for portal area development, but that deficient Roundabout 2 (Robo2)/Slit2 signalling in the portal mesenchyme causes reduced maturation of the vascular smooth muscle cells that form the tunica media of the hepatic artery. This arterial anomaly does not impact liver function in homeostatic condition but is associated with significant tissular damage following partial hepatectomy. In conclusion, our work identifies new players in development of the liver vasculature in health and liver regeneration.