Altered Endothelial Function Research Articles

Rap1 in endothelial biology.

Ubiquitously-expressed small GTPase Rap1 is a key modulator of integrin- and cadherin-regulated processes. In endothelium, Rap1 promotes angiogenesis and endothelial barrier function, acting downstream from cAMP-activated Rap1GEF, Epac. Recent in-vivo studies in mouse models have provided more information about the physiological role of Rap1 in vessel development and after birth under normal and pathologic conditions. Important molecular details of dynamic regulation of endothelial barrier are uncovered. Rap1 is not essential for initial vessel formation but is critical for vessel stabilization, as double knockout of the two Rap1 isoforms leads to hemorrhage and embryonic lethality. After development, Rap1 is not required for endothelial barrier maintenance but is critical for nitric oxide production and endothelial function. Radil and Afadin mediate Rap1 effects on endothelial barrier function by regulating connection with Rho GTPases, actomyosin cytoskeleton, and cell-cell adhesion receptors. Rap1 is critically required for nitric oxide release and normal endothelial function in vivo. Mechanistic studies lead to a novel paradigm of Rap1 as a critical regulator of endothelial cell shear stress responses and endothelial homeostasis. Increased understanding of molecular mechanisms underlying endothelial barrier regulation may identify novel pharmacological targets for retinopathies and conditions with altered endothelial barrier function or when increased endothelial barrier is desired.

Abstract WP148: Basilar Artery Displacement is Associated with Migraine with Aura

Background: Cerebrovascular dysregulation has long been associated with migraine pathophysiology, possibly mediated by hypoperfusion and/or endothelial dysfunction triggering cortical spreading depression. Vessel tortuosity has also been associated with altered hemodynamics and endothelial function. We sought to examine whether basilar artery (BA) tortuosity was altered in migraine. Methods: We performed the Anatomy and Cerebral Hemodynamic Evaluation of Migraine (ACHE-M) study, a prospective, observational, case-control study including high-resolution MR angiography, arterial spin labeled perfusion MRI, and structural MRI. Migraine with aura (MWA), migraine without aura (MwoA), and control subjects between the age of 25-50 were enrolled in a 1:1:1 ratio. Subjects with manifest vascular disease of any type were excluded. Vertebral and basilar artery diameters and BA total lateral displacement from MRI were correlated with regional perfusion and T2/FLAIR white matter lesions that were assessed using methods similar to the Cerebral Abnormalities in Migraine Epidemiologic Risk Analysis study. Results: 163 subjects were included (52 control/52 MWA/ 58 MwoA). Mean age was 33 ± 6 years, and 78% were female. BA diameter was similar across groups (3.6 ± 0.6 mm in all 3 groups). BA displacement was similar in MwoA (5.1±3.0 mm) and controls (4.9±3.1 mm), but tended to be greater in MWA (6.3±3.8 mm, p=0.055 vs. controls). In multivariate analysis incorporating migraine status, age, and sex, BA displacement was significantly associated with MWA (p=0.019), age (p<0.001), and sex (p=0.046). BA displacement was also significantly greater with increasing migraine frequency (p=0.003). There was no association with displacement and posterior cerebral artery territory cerebral blood flow or overall white matter lesion burden. Conclusions: Basilar artery lateral displacement is associated with MWA as well as headache frequency, but this association does not appear to be mediated by cerebral hypoperfusion. Further investigation of the physiological consequences of basilar artery lateral displacement may lead to new insights into the mechanisms of migraine.

Skin microvascular reactivity in patients with hypothyroidism.

Hypothyroidism is associated with impaired vascular function; however, little is known about its impact on microcirculation. We aimed to determine skin microvascular reactivity in hypothyroidism focusing on endothelial function and the sympathetic response. We measured skin laser Doppler (LD) flux (LDF) on the volar forearm and the finger pulp using LD flowmetry in hypothyroid patients (N = 13) and healthy controls (N = 15). Skin microvascular reactivity was assessed by a three-minute occlusion of the brachial artery, inducing postocclusive reactive hyperaemia (PRH), and by a four-minute local cooling of the hand. An electrocardiogram (ECG), digital artery blood pressure and skin temperature at the measuring sites were recorded. Baseline LDF, the digital artery blood pressure and the heart rate were comparable between patients and controls. On the other hand, patients exhibited significantly longer PRH duration, significantly higher blood pressure during cooling (unpaired t-test, p <0.05) and lower, albeit not significant, LDF in the ipsilateral finger pulp during cooling compared to controls. Unexpectedly, the results of the present study point to an increased vasodilator capacity of skin microcirculation and an apparent increase in sympathetic reactivity after local cooling in hypothyroid patients. Hypothyroidism induces subtle changes of some haemodynamic parameters in skin microcirculation implying altered endothelial function and altered sympathetic reactivity.

Blood pressure regulation in stress: focus on nitric oxide-dependent mechanisms.

Stress is considered a risk factor associated with the development of various civilization diseases including cardiovascular diseases, malignant tumors and mental disorders. Research investigating mechanisms involved in stress-induced hypertension have attracted much attention of physicians and researchers, however, there are still ambiguous results concerning a causal relationship between stress and long-term elevation of blood pressure (BP). Several studies have observed that mechanisms involved in the development of stress-induced hypertension include increased activity of sympathetic nervous system (SNS), glucocorticoid (GC) overload and altered endothelial function including decreased nitric oxide (NO) bioavailability. Nitric oxide is well known neurotransmitter, neuromodulator and vasodilator involved in regulation of neuroendocrine mechanisms and cardiovascular responses to stressors. Thus NO plays a crucial role in the regulation of the stress systems and thereby in the BP regulation in stress. Elevated NO synthesis, especially in the initial phase of stress, may be considered a stress-limiting mechanism, facilitating the recovery from stress to the resting levels via attenuation of both GC release and SNS activity as well as by increased NO-dependent vasorelaxation. On the other hand, reduced levels of NO were observed in the later phases of stress and in subjects with genetic predisposition to hypertension, irrespectively, in which reduced NO bioavailability may account for disruption of NO-mediated BP regulatory mechanisms and accentuated SNS and GC effects. This review summarizes current knowledge on the role of stress in development of hypertension with a special focus on the interactions among NO and other biological systems affecting blood pressure and vascular function.

The relationship between sodium excretion and blood pressure, urine albumin, central retinal arteriolar equivalent.

BackgroundMany studies showed an association between dietary salt intake, blood pressure and increased CVD risk. The potential reason may be related to vascular structural and functional changes, through alterations in endothelial function. The central retinal arteriolar equivalent and urinary albumin reflected vascular endothelial dysfunction in different part of the body. The urinary sodium-creatinine ratio of causal urine specimens could represent the 24-h urinary sodium intake to estimate sodium intake.MethodsThe 24-h sodium excretion was estimated by urinary sodium-creatinine ratio. Urinary albumin-creatinine ratio (UACR), reflecting renal arterial damage, was also determined. The central retinal arteriolar equivalent (CRAE) was detected by fundus photography and was further analyzed by semi-quantitative software.ResultsParticipants included 951 hypertensive patients with the average sodium excretion of 11.62 ± 3.01 g. The sodium excretion was significantly higher (P < 0.01) in the hypertensive as compared to that of the non-hypertensive participants. Prevalence of hypertension was increased with increasing sodium excretion. The sodium excretion was positively correlated with systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively (r = 0.20 and 0.14; P < 0.01). Furthermore, UACR and CRAE were significantly (P < 0.01) different within the sodium excretion quartiles (Q1-Q4). After adjusting the confounding variables, such as age and sex, the binary logistic regression analysis showed that sodium excretion was an independent factor of UACR and CRAE (P < 0.01).ConclusionOur results suggest that sodium excretion in the hypertensive participants were higher. The high sodium excretion was related with the renal arterial damage as well as retinal arteriolar changes.

Assessment of serum Lactate Dehydrogenase in preeclamptic pregnant women

Background: Evidences prove that endothelial cell and altered endothelial cell function play an important role in the pathogenesis of preeclampsia. Therefore serum lactate dehydrogenase (LDH) is useful biochemical markers reflecting the severity of the occurrence of preeclampsia. Objective: Determination of serum lactate dehydrogenase (LDH) in severe preeclamptic pregnant women. Methods: This is the case-control hospital based study carried in the Al Azhar Medical College and Super speciality Hospital, Thodupuzha. Normal pregnant women (n=55) and women with severe preeclampsia (n=63) were included in the study. Both the groups were in their third trimester and of same age and same gestational age. Serum LDH levels were measured by continuous spectrophotometric pyruvate method for both groups. Results: Higher values of serum lactate dehydrogenase (LDH) were found in severe preeclamptic women compared with normal pregnant women in third trimester. Conclusion: Elevated levels of serum LDH indicates the tissue damage and might be the cause of the occurrence of preeclampsia.

Vascular smooth muscle cell dysfunction in diabetes: nuclear receptors channel to relaxation.

Endothelial dysfunction and impaired vascular relaxation represent a common cause of microvascular disease in patients with diabetes. Although multiple mechanisms underlying altered endothelial cell function in diabetes have been described, there is currently no specific and approved pharmacological treatment. In this edition of Clinical Science, Morales-Cano et al. characterize voltage-dependent K(+) (Kv) channels as genes regulated by pharmacological activation of peroxisome proliferator-activated receptor-b/d (PPARb/d). Diabetes altered Kv channel function leading to impaired coronary artery relaxation, which was prevented by pharmacological activation of PPARb/d. These studies highlight an important mechanism of vascular dysfunction in diabetes and point to a potential approach for therapy, particularly considering that PPARb/d ligands have been developed and tested in small clinical trials.

Endothelial function and sympathetic nervous system activity in patients with Takotsubo syndrome

BackgroundTakotsubo syndrome (TTS) is an acute cardiomyopathy associated with intense physical or emotional stress. The precise mechanisms of the disease remain unclear. The aim of this study was to study alterations in endothelial function, vascular compliance and structure and muscle sympathetic activity in the stable phase of the disease. MethodsIn this prospective observational study, patients with TTS and controls matched for age, sex, cardiovascular risk factors and medications were recruited. Flow-mediated vasodilatation (FMD) as a measure of endothelial dysfunction was the primary endpoint. Secondary endpoints included measurements of arterial stiffness, carotid atherosclerosis, quality of life and laboratory parameters. In a subset of patients, muscle sympathetic activity was measured before and after stress tests. ResultsThe study included 22 TTS patients and 21 matched controls. A significant increase in endothelial dysfunction was seen in TTS compared to controls (FMD 3.4±2.4% vs. 4.8±1.9%, p=0.016). No significant differences in arterial stiffness, intima-media thickness, quality of life and laboratory markers including endothelin-1 were noted. TTS patients showed a reduced carotid total plaque area compared to controls (TPA 17.3±15.1 vs 24.7±12.8mm2, p=0.02). A trend of increased muscle sympathetic activity at rest was observed in TTS patients vs. controls (53.5±28.4 vs. 29.4±16.5 bursts/100 heart beats, p=0.09) with no significant differences in muscle sympathetic activity in response to stress. ConclusionsOur findings underscore the importance of endothelial dysfunction in patients with TTS which may be involved in the pathophysiology of this syndrome. ClinicalTrials.gov identifierNCT01249599

Inflammatory Biomarkers Predict Domain-Specific Cognitive Decline in Older Adults.

Vascular risk factors, including inflammation, may contribute to dementia development. We investigated the associations between peripheral inflammatory biomarkers and cognitive decline in five domains (memory, construction, language, psychomotor speed, and executive function). Community-dwelling older adults from the Ginkgo Evaluation of Memory Study (n = 1,159, aged 75 or older) free of dementia at baseline were included and followed for up to 7 years. Ten biomarkers were measured at baseline representing different sources of inflammation: vascular inflammation (pentraxin 3 and serum amyloid P), endothelial function (endothelin-1), metabolic function (adiponectin, resistin, and plasminogen activating inhibitor-1), oxidative stress (receptor for advanced glycation end products), and general inflammation (interleukin-6, interleukin-2, and interleukin-10). A combined z-score was created from these biomarkers to represent total inflammation across these sources. We utilized generalized estimating equations that included an interaction term between z-scores and time to assess effect of inflammation on cognitive decline, adjusting for demographics (such as age, race/ethnicity, and sex), cardiovascular risk factors, and apolipoprotein E ε4 carrier status. A Bonferroni-adjusted significance level of .01 was used. We explored associations between individual biomarkers and cognitive decline without adjustment for multiplicity. The combined inflammation z-score was significantly associated with memory and psychomotor speed (p < .01). Pentraxin 3, serum amyloid P, endothelin-1, and interleukin-2 were associated with change in at least one cognitive domain (p < .05). Our results suggest that total inflammation is associated with memory and psychomotor speed. In particular, systemic inflammation, vascular inflammation, and altered endothelial function may play roles in domain-specific cognitive decline of nondemented individuals.

The eNOS signalosome and its link to endothelial dysfunction.

Endothelial nitric oxide synthase (eNOS) plays an essential role in the regulation of endothelial function and acts as a master regulator of vascular tone and homeostasis through the generation of the gasotransmitter nitric oxide (NO). The complex network of events mediating efficient NO synthesis is regulated by post-translational modifications and protein-protein interactions. Dysregulation of these mechanisms induces endothelial dysfunction, a term often used to refer to reduced NO bioavailability and consequent alterations in endothelial function, that are a hallmark of many cardiovascular diseases. Endothelial dysfunction is linked to eNOS uncoupling, which consists of a switch from the generation of NO to the generation of superoxide anions and hydrogen peroxide. This review provides an overview of the eNOS signalosome, integrating past and recently described protein-protein interactions that have been shown to play a role in the modulation of eNOS activity with implications for cardiovascular pathophysiology. The mechanisms underlying eNOS uncoupling and clinically relevant strategies that were adopted to influence them are also discussed.

Comparison of Endothelial Function in Pre‐ and Post‐exercise States between Obese and Normal‐weight Children

Background and RationaleMicroangiopathy is a common comorbidity associated with adult obesity. We hypothesize that microvascular function may be altered following an age‐specific pattern in pediatric obesity, occurring well before any clinical sign of vascular impairment. As exercise provides a strong, relatively homogeneous vasodilatory stimulus, these early alterations in endothelial function may be more easily detected in the post‐exercise state. We therefore designed the present study with the objective to detect differences between obese (Ob) and normal‐weight (Nw) children in endothelial function, via Laser Doppler Flowmetry (LDF), both at rest and following a standard incremental exercise test to exhaustion.MethodsThirteen Ob children (13 ± 2 yrs, 97 ± 0.8 BMI%, 6F) and 11 Nw children (14 ± 2 yrs, 61 ± 14 BMI%, 6F) participated in the study. An optical probe connected with a Periflux 5000 Laser Doppler system (Perimed, Sweden) was placed on the base of the middle finger, and LDF measurements of skin perfusion were obtained before, during, and after a 1‐min occlusion induced at the wrist with a blood pressure cuff inflated at 200 mmHg. Subjects then performed a standard incremental cycling exercise test to exhaustion, using a commercial metabolic cart/cycle ergometer system (Carefusion, San Diego, USA). The incremental phase of the test was tailored to last ~ 10 min after 2 min of unloaded pedaling. LDF measurements were then repeated 8 min after exercise cessation. Baseline pre‐occlusive perfusion (Plat1), post‐occlusive hyperemic peak (pMax), and the time from release of occlusion to reach pMax (PkT) were obtained from perfusion tracings. Comparisons were made using two‐tailed, independent Student's t‐tests.ResultsPerfusion variables (in arbitrary perfusion Units) were greater in Ob throughout the study (Plat1, pre‐exercise 76 ± 13 vs. 43 ± 12 in Nw, p = 0.068; post‐exercise, 86 ± 13 vs. 41 ± 6 in Nw, p&lt;0.05; pMax, pre‐exercise, 165 ± 16 vs. 99 ± 21, p&lt;0.05, post‐exercise, 164 ± 16 vs. 117 ± 13, p&lt;0.05). The magnitude of the hyperemic peak relative to baseline, while quantitatively larger in Nw in the pre‐exercise state, only reached significance in the post‐exercise state (pMax/Plat1, post‐exercise, 3.0 ± 0.3 vs. 2.1 ± 0.2, p&lt;0.05). In general, therefore, a similar pattern of differences was present in all studies, but significance was more clearly delineated in the post exercise state. PkT was similar across weight groups, and unchanged by prior exercise.ConclusionsOverall, our cohort of Ob children displayed characteristic perfusion alterations relative to Nw children, possibly including a state of chronic baseline vascular dilation, and reduced responsiveness to additional vasodilatory stimuli, such as physical exercise. Our findings are consistent with the concept that obesity, even in its very early stages in pediatric populations, is associated with microvascular dysfunction.Support or Funding InformationNIH NICHD P01HD048721 &amp; UL1 TR000153

Blood Brothers: Hemodynamics and Cell-Matrix Interactions in Endothelial Function.

Alterations in endothelial function contribute to a variety of vascular diseases. In pathological conditions, the endothelium shows a reduced ability to regulate vasodilation (endothelial dysfunction) and a conversion toward a proinflammatory and leaky phenotype (endothelial activation). At the interface between the vessel wall and blood, the endothelium exists in a complex microenvironment and must translate changes in these environmental signals to alterations in vessel function. Mechanical stimulation and endothelial cell interactions with the vascular matrix, as well as a host of soluble factors, coordinately contribute to this dynamic regulation. Blood hemodynamics play an established role in the regulation of endothelial function. However, a growing body of work suggests that subendothelial matrix composition similarly and coordinately regulates endothelial cell phenotype such that blood flow affects matrix remodeling, which affects the endothelial response to flow. Hemodynamics and soluble factors likely affect endothelial matrix remodeling through multiple mechanisms, including transforming growth factor β signaling and alterations in cell-matrix receptors, such as the integrins. Likewise, differential integrin signaling following matrix remodeling appears to regulate several key flow-induced responses, including nitric oxide production, regulation of oxidant stress, and activation of proinflammatory signaling and gene expression. Microvascular remodeling responses, such as angiogenesis and arteriogenesis, may also show coordinated regulation by flow and matrix. Identifying the mechanisms regulating the dynamic interplay between hemodynamics and matrix remodeling and their contribution to the pathogenesis of cardiovascular disease remains an important research area with therapeutic implications across a variety of conditions. Antioxid. Redox Signal. 25, 415-434.

Perioperative Management of Pediatric Pulmonary Hypertension

Perioperative management of patients with pulmonary hypertension or those at risk for increased pulmonary vascular reactivity should focus on supporting the patient through the vulnerable period of physiologic derangements surrounding surgery, including acute alterations in pulmonary blood flow, altered pulmonary endothelial function following cardiopulmonary bypass, invasive mechanical ventilation, and adaptation to new hemodynamics following correction or palliation of congenital heart disease lesions. These patients require careful attention to each step of perioperative management by teams experienced in the care of pediatric patients with pulmonary hypertension. This article will focus on preoperative evaluation, pulmonary hypertensive crises, general principles of perioperative management, and specific pulmonary vasodilator therapies.

Different Obese Phenotypes and Progenitor Endothelial Cell Dysfunction: The Missed Link to Cardiovascular Risk

Obesity has been remained a leading factor of metabolic and cardiovascular (CV) events worldwide. It has suggesting that obesity might effect on CV risk through several metabolic abnormalities including white adipose tissue and adipocytokines’ dysfunction, insulin resistance, impaired glucose metabolism and worsening of an endogenous repair system affected endothelial progenitor cells (EPCs). However, there are serious controversies regarding the level and functionality of EPCs in obese, metabolic syndrome, while EPCs dysfunction is considered a powerful risk factor of CV complications. By now, clinically use of EPC dysfunction as biomarker of altered endothelial function with high predictive ability to risk stratification in obese patients appears to be promised. The mini review is discussed differences in EPC between healthy obese and non-healthy people.

Porphyromonas gingivalis infection modifies oral microcirculation and aortic vascular function in the stroke-prone spontaneously hypertensive rat (SHRSP)

The functional modulation of vascular endothelial cells associated with stroke and periodontal disease has not yet been clarified. The objective of this study is to analyze the vascular endothelial function of periodontitis and stroke animal models. We examined endothelial function and gingival blood flow in oral microcirculation in vivo and measured the isometric tension in vitro of the aorta in animal models for lifestyle-related diseases, such as periodontitis and stroke. Gingival reactive hyperemia (GRH) was measured using laser Doppler flowmetry. Wistar Kyoto rats (WKY) were used as control animals; Porphyromonas gingivalis (P. gingivalis) infected WKY (WKY + Pg) as the periodontitis model; stroke-prone spontaneously hypertensive rat (SHRSP) as the stroke model; and a final group consisting of P. gingivalis infected SHRSP (SHRSP + Pg). Furthermore, for each group, the relaxation of descending aortic ring preparations was measured using a force transducer. The GRH was estimated by maximum response (peak), time taken for the maximum response to fall to one half (T1/2), and increased total amount of blood flow (mass). The relative change in T1/2 and mass increased in SHRSP + Pg compared to WKY. However, mass significantly increased in WKY (758.59 ± 88.21 ml/min/100 g s to 1755.55 ± 226.10 ml/min/100 g s) and SHRSP (1214.87 ± 141.61 ml/min/100 g s to 2674.32 ± 675.48 ml/min/100 g s) after treatment with acetylcholine. In addition, T1/2 and mass significantly increased in WKY + Pg (624.18 ± 96.36 ml/min/100 g s to 2629.90 ± 612.01 ml/min/100 g s) and SHRSP + Pg (1116.36 ± 206.24 ml/min/100 g s to 1952.76 ± 217.39 ml/min/100 g s) after treatment with nitroglycerin. Furthermore, the endothelium-dependent relaxation of ring preparations, evoked by acetylcholine, was attenuated in SHRSP compared with WKY, but not in SHRSP + Pg. This attenuation effect in SHRSP could be prevented by superoxide dismutase pretreatment. Our results suggest altered endothelial function may occur in gingival tissue in animal models experiencing both periodontitis and stroke. Therefore, these results indicate the disruption of vascular function in oral microcirculation may be caused by the interaction between the oxidative stress induced by periodontitis and nitric oxide in periodontitis, similar to the interactions present in stroke cases.

Abstract 12177: Important Roles of Endothelial Caveolin-1/eNOS Complex in Maintaining Microvascular Homeostasis Through Endothelium-dependent Hyperpolarization Mediated Mechanism

Background: The endothelium plays important roles in maintaining cardiovascular homeostasis by synthesizing and releasing several vasodilators, including prostacyclin (PGI2), nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) factor. It is widely accepted that EDH plays important roles especially in microcirculation. We have previously demonstrated that endothelial NO synthase (eNOS) plays diverse roles depending on vessel size, as a NO generating system in conduit arteries and an EDH-mediated system in resistance arteries. Recently, we also have reported that caveolin-1 is involved in enhanced EDH-mediated mechanisms in resistance arteries through functional inhibition of eNOS. However, the detailed functions of caveolin-1 in the endothelium remain to be elucidated. Material and Results: We newly generated endothelium-specific caveolin-1-knockout mice (eCav-1-KO) under the control of Tie2 promoter. We confirmed that caveolae is absent in endothelial cells of those mice. Co-immunoprecipitation experiments showed the eNOS/Cav-1 complex formation in control mice, but not in eCav-1-KO mice. Western blot experiments demonstrated that the extent of eNOS phosphorylation at Ser1177 (stimulatory site) was comparable, whereas that at Thr495 (inhibitory site) was significantly reduced in mesenteric arteries from eCav-1-KO mice as compared with control mice, demonstrating hyperactivation of eNOS. Isometric tension experiments and Langendorff experiments showed that NO-mediated responses were significantly enhanced, whereas EDH-mediated responses were significantly reduced in microcirculations in eCav-1-KO mice. Importantly, eCav-1-KO mice showed altered endothelial functions and cardiac hypertrophy despite normal blood pressure level. Furthermore, the hearts from eCav-1-KO mice showed enhanced staining for nitrotyrosine, a marker of nitrosative stress in microvessels and epicardial arteries, whereas those from control mice only showed mild staining in epicardial arteries alone. Conclusions: These results indicate that endothelial Cav-1/eNOS complex plays important roles in maintaining microvascular homeostasis through EDH-mediated mechanisms in mice in vivo.

Endothelial biomarker soluble CD146 suggests that angiogenesis plays an important role in progression of fibrosis in liver disease

CD146, an element of the endothelial junction- has been evaluated in several pathological conditions with altered endothelial function but never before in patients with liver disease. As angiogenesis and inflammation were implicated in the development of liver fibrosis, we have explored this suggestion by evaluating levels of sCD146 in a group of patients with chronic liver diseases (CLD) and in cirrhotic patients. The results indicated that there is a clear connection between sCD146 levels and the progression of liver disease. They can differentiate noncirrhotic patients with CLD from cirrhotics, supporting the usefulness of CD146 in the noninvasive diagnosis of liver cirrhosis. Furthermore, our findings provided evidence of sCD146 upregulation in decompensated compared to compensated cirrhosis and sCD146 values were clearly associated with Model for End Stage Liver Disease (MELD) score. Thus, by using an easy to perform ELISA method, we demonstrated that sCD146 can accurately distinguish advanced fibrosis and prognosticate decompensation in cirrhosis.

Phenotypic and molecular characterization of intrauterine fetal growth restriction in interspecies sheep pregnancy.

Interspecies pregnancies between closely related species are usually performed in livestock to obtain improved and enriched offspring. Indeed, different hybrids have been obtained for research purposes since many years ago, and the maternal-fetal interactions have been studied as a possible strategy for species preservation. The aim of this study was to characterize by physiological and molecular approaches the interspecies pregnancy between bighorn sheep () and domestic sheep (). Hybrids were obtained by artificial insemination; the blood pressure and protein urine levels were measured during the last two-thirds of gestation. After parturition, offspring and placentas were weighed and measured and cotyledons were counted and weighed and their surface area determined. Plasma samples were obtained between wk 8 and 21 of gestation to assess progesterone (P4), vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) levels and cell-free RNA was isolated during the same period to assess hypoxia-inducible factor-1 α (α) gene expression. Hybrid and normal pregnancies were analyzed using physiological and molecular parameters during the last two-thirds of gestation (wk 8-21). The results show that during the measurement period, ewes with a hybrid pregnancy presented normal blood pressure and no alteration in urinary protein content. However, compared with sheep with a normal pregnancy, those with a hybrid pregnancy had a decrease in fetal and placental growth as well as in the cotyledonary surface area. Furthermore, in the hybrid group, there was placental insufficiency, characterized by a decrease in P4 production, as well as indications of endothelial dysfunction, characterized an increase in plasma levels of VEGF and PlGF as well as in plasma gene expression of α. Overall, the results indicate that hybrids of and presented intrauterine growth restriction, essentially due to altered endothelial function and chronic placental insufficiency. Further studies are necessary to overcome this primary placental dysfunction and thus obtain improved offspring for future molecular and genomic evaluations.

Lipoprotein(a) and livedoid vasculopathy: A new thrombophilic factor?

Livedoid vasculopathy is a chronic disorder characterised by recurrent reticulated purpura on lower extremities, associated with painful purpuric or necrotic macules and ulcerations. Current knowledge indicates LV to be a thrombo-occlusive vasculopathy of cutaneous blood vessels; exact pathogenesis is yet to be understood. Elevated levels of lipoprotein(a) have been found in LV patients.To date, elevated plasma levels of lipoprotein(a) are considered an independent and causal genetic risk factor for the development of cardiovascular disease, as well as a relevant factor in hypercoagulable states. Because of its structural homology with plasminogen, Lp(a) might have important anti-fibrinolytic properties. Altered endothelial function and participation in immune and autoimmune processes, such as antiphospholipid syndrome, are also potential mechanisms of Lp(a) involvement in LV pathogenesis. Lp(a) is part of the wound healing process; the possibility of Lp(a) serum elevation to reflect an acute-phase reagent in LV scenario is also considered.The objective of this review is to examine the possible association of lipoprotein(a) with LV pathogenesis, based on its effects on thrombogenesis, fibrinolysis and autoimmunity.

Sex differences and blood pressure regulation in humans.

What is the topic of this review? Over the past decade, our team has investigated interindividual variability in human blood pressure regulation. What advances does it highlight? In men, we have found a tight relationship between indices of sympathetic activity and vascular resistance across the age span. This relationship is absent in young women but seen in postmenopausal women. These sex and age differences in vascular resistance are largely a result of changes in the balance of vasodilating and vasoconstricting adrenergic receptor tone. When these changes are considered along with cardiac output, a coherent picture is beginning to emerge of why blood pressure rises more with age in women than men. Arterial pressure is a key regulated variable in the cardiovascular system with important health implications. Over the last 12 years, we have used physiological measurements, including muscle sympathetic nerve activity (MSNA), to explore the balance among mean arterial blood pressure, cardiac output and total peripheral resistance (TPR) in normotensive humans. We have shown that these determinants of blood pressure can vary widely in different subjects and how they vary depends on sex and age. In young men, there is a direct relationship between MSNA and TPR but no relationship with blood pressure. This is because cardiac output is proportionally lower in those with high MSNA and TPR. In contrast, in young women there is no relationship between MSNA and TPR (or cardiac output); this is because β-adrenergic vasodilator mechanisms offset α-adrenergic vasoconstriction. Thus, blood pressure is unrelated to MSNA in young women. In older women, β-adrenergic vasodilator mechanisms are diminished, and a direct relationship between MSNA and TPR is seen. In older men, the relationships among these variables are less clear cut, perhaps owing to age-related alterations in endothelial function. With ageing, the relationship between MSNA and blood pressure becomes positive, more so in women than in men. The finding that the physiological control of blood pressure is so different in men and women and that it varies with age suggests that future studies of mechanisms of hypertension will reveal corresponding differences among groups.