Maintenance Of Vascular Homeostasis Research Articles

Decreased Number of Circulating Endothelial Progenitor Cells in Hidradenitis Suppurativa Patients

Background: Hidradenitis suppurativa (HS) is nowadays regarded as a systemic disease associated with metabolic syndrome. Some recent studies have also demonstrated an increased cardiovascular risk in patients with HS. Circulating endothelial progenitor cells (EPCs) play an integral role in the regulation and protection of the endothelium and in the maintenance of vascular homeostasis. Objective: This study was undertaken to determine the possible alterations in the number of EPCs in patients with HS compared to controls. Methods: The number of EPCs, identified as CD133+/KDR+ cells, was determined with flow cytometry in the peripheral blood of 25 HS patients and 31 controls. Results: The number of EPCs was significantly reduced in HS sufferers compared with controls (p < 0.0001). The mean number of EPCs was assessed as 191.3 ± 118.5/ml and 672.4 ± 343.0/ml for patients and controls, respectively. Conclusion: A decreased number of EPCs among HS sufferers may contribute to endothelial malfunction resulting in increased cardiovascular risk in this group of patients.

A Methodological Approach to Non-invasive Assessments of Vascular Function and Morphology

The endothelium is the innermost lining of the vasculature and is involved in the maintenance of vascular homeostasis. Damage to the endothelium may predispose the vessel to atherosclerosis and increase the risk for cardiovascular disease. Assessments of peripheral endothelial function are good indicators of early abnormalities in the vascular wall and correlate well with assessments of coronary endothelial function. The present manuscript details the important methodological steps necessary for the assessment of microvascular endothelial function using laser Doppler imaging with iontophoresis, large vessel endothelial function using flow-mediated dilatation, and carotid atherosclerosis using carotid artery ultrasound. A discussion on the methodological considerations for each of the techniques is also presented, and recommendations are made for future research.

A methodological approach to non-invasive assessments of vascular function and morphology.

The endothelium is the innermost lining of the vasculature and is involved in the maintenance of vascular homeostasis. Damage to the endothelium may predispose the vessel to atherosclerosis and increase the risk for cardiovascular disease. Assessments of peripheral endothelial function are good indicators of early abnormalities in the vascular wall and correlate well with assessments of coronary endothelial function. The present manuscript details the important methodological steps necessary for the assessment of microvascular endothelial function using laser Doppler imaging with iontophoresis, large vessel endothelial function using flow-mediated dilatation, and carotid atherosclerosis using carotid artery ultrasound. A discussion on the methodological considerations for each of the techniques is also presented, and recommendations are made for future research.

Chronic hepatitis B: role of anti-platelet therapy in inflammation control.

Platelets play a known role in the maintenance of vascular homeostasis, but these cells are emerging as important cellular mediators of acute and chronic inflammatory diseases. Platelets are key elements in the pathogenesis of acute and chronic liver disease associated with hepatitis B virus (HBV) infection by promoting the accumulation of virus-specific CD8(+) T cells and nonspecific inflammatory cells into the liver parenchyma. This review discusses major platelet functions in immune and inflammatory responses, with an emphasis on recent pre-clinical studies that suggest that the inhibition of platelet activation pathways represent an alternative therapeutic strategy with potential use in the reduction of virus-specific T cell-mediated chronic inflammation, liver fibrosis and hepatocellular carcinoma in patients who are chronically infected with HBV.

Metabolic Adaptations in Diabetic Endothelial Cells

In healthy individuals, the endothelium plays a fundamental role in normal health in the maintenance of vascular homeostasis. Endothelial cell (EC) dysfunction results in the development of several pathologies. In diabetes, in particular, sustained hyperglycemia, a characteristic of diabetes, contributes to EC dysfunction and consequently mediates the pathogenesis of diabetes-associated micro- and macrovasculopathies. Hyperglycemia-induced EC dysfunction is triggered by elevated levels of oxidative stress derived from several mechanisms, with the mitochondria as a key source, and is exacerbated by a subsequent hyperglycemia-induced self-perpetuating cycle of oxidative stress and aberrant metabolic memory. Recent reports have highlighted the importance of metabolic pathways in EC and suggested the therapeutic potential of targeting EC metabolism. This review focuses on the current knowledge regarding differences in the metabolism of healthy ECs vs. diabetes-associated dysfunctional ECs, and outlines how EC metabolism may be targeted for therapeutic benefit.

Temporal phosphoproteomics to investigate the mechanotransduction of vascular smooth muscle cells in response to cyclic stretch

Vascular smooth muscle cells (VSMCs) are exposed to mechanical cyclic stretch in vivo, which play important roles in maintenance of vascular homeostasis and regulation of pathological vascular remodeling. Reversible protein phosphorylation is crucial for intracellular signaling transduction. However, the dynamic phosphorylated profile induced by cyclic stretch in VSMCs is still unclear. Using the stable isotope labeling by amino acid in cell culture, VSMCs were labeled and exposed to 10% physiological cyclic stretch in vitro at 1.25Hz for 0min, 15min, 30min, 1h and 6h, respectively. Using TiO2 beads and liquid chromatography tandem mass spectrometry, the temporal phosphoproteomic profiles in response to cyclic stretch were then detected. Bioinformatics analysis including fuzzy c-means clustering, functional classifications, and Ingenuity Pathway Analysis were applied to further reveal the potential mechanotranduction networks. The results indicated that protein kinase C (PKCs) family, Rho-associated coiled-coil containing protein kinase 1 (ROCK1) and Akt may participate in cyclic-stretch induced VSMC functions. Cyclic stretch repressed the expression of ROCK1, while it had no significant effect on the phosphorylation of PKCα/βII, PKCζ/λ and PKCδ/θ. PKCθ was activated first at short time-phase (15min and 30min), and again at long time-phase (6h, 12h and 24h). The activation of p-PKCμ was immediate and short-term, similar to p-Akt. Our present in vitro work hence revealed that cyclic stretch activates complex mechanotransduction networks, suggesting that novel mechanoresponsive molecules, i.e., PKCθ, PKCμ, and ROCK1, may participate in the mechanotransduction and modulation VSMC functions.

Vascular-resident CD169-positive monocytes and macrophages control neutrophil accumulation in the kidney with ischemia-reperfusion injury.

Monocytes and kidney-resident macrophages are considered to be involved in the pathogenesis of renal ischemia-reperfusion injury (IRI). Several subsets of monocytes and macrophages are localized in the injured tissue, but the pathologic roles of these cells are not fully understood. Here, we show that CD169(+) monocytes and macrophages have a critical role in preventing excessive inflammation in IRI by downregulating intercellular adhesion molecule-1 (ICAM-1) expression on vascular endothelial cells. Mice depleted of CD169(+) cells showed enhanced endothelial ICAM-1 expression and developed irreversible renal damage associated with infiltration of a large number of neutrophils. The perivascular localization of CD169(+) monocytes and macrophages indicated direct interaction with blood vessels, and coculture experiments showed that the direct interaction of CD169(+) cell-depleted peripheral blood leukocytes augments the expression levels of ICAM-1 on endothelial cells. Notably, the transfer of Ly6C(lo) monocytes into CD169(+) cell-depleted mice rescued the mice from lethal renal injury and normalized renal ICAM-1 expression levels, indicating that the Ly6C(lo) subset of CD169(+) monocytes has a major role in the regulation of inflammation. Our findings highlight the previously unknown role of CD169(+) monocytes and macrophages in the maintenance of vascular homeostasis and provide new approaches to the treatment of renal IRI.

Mechanistic perspectives of calorie restriction on vascular homeostasis

Calorie restriction (CR) is a dietary regime based on low calorie intake. CR without malnutrition extends lifespan in a wide range of organisms from yeast to rodents, and CR can prevent and delay the onset of age-related functional decline and diseases in human and non-human primates. CR is a safe and effective intervention to reduce vascular risk factors in humans. In recent years, studies in rodents have provided mechanistic insights into the beneficial effects of CR on vascular homeostasis, including reduced oxidative stress, enhanced nitric oxide (NO) bioactivity, and decreased inflammation. A number of important molecules, including sirtuins, AMP-activated protein kinase, mammalian targets of rapamycin, endothelial nitric oxidase and their regulatory pathways are involved in the maintenance of vascular homeostasis. Evidence has shown that these pathways are responsible for many aspects of CR's effects, and that they may also mediate the effects of CR on vasculature.

Role of Biomechanical Forces in Stem Cell Vascular Lineage Differentiation

Mechanical forces have long been known to play a role in the maintenance of vascular homeostasis in the mature animal and in developmental regulation in the fetus. More recently, it has been shown that stem cells play a role in vascular repair and remodeling in response to biomechanical stress. Laminar shear stress can directly activate growth factor receptors on stem/progenitor cells, initiating signaling pathways leading toward endothelial cell differentiation. Cyclic strain can stimulate stem cell differentiation toward smooth muscle lineages through different mechanisms. In vivo, blood flow in the coronary artery is significantly altered after stenting, leading to changes in biomechanical forces on the vessel wall. This disruption may activate stem cell differentiation into a variety of cells and cause delayed re-endothelialization. Based on progress in the research field, the present review aims to explore the role of mechanical forces in stem cell differentiation both in vivo and in vitro and to examine what this means for the application of stem cells in the clinic, in tissue engineering, and for the management of aberrant stem cell contribution to disease.

Abstract 14: Caskin2 is a Novel Regulator of Endothelial Cell Quiescence

Maintenance of vascular homeostasis is an active process that is dependent on continuous signaling by the quiescent endothelial cells (ECs) that line mature vessels. The signaling pathways that are active in quiescent ECs are distinct from those that regulate angiogenesis but are comparatively poorly understood. Here we demonstrate that the previously uncharacterized scaffolding protein Caskin2 is a novel regulator of EC quiescence. Caskin2 is highly expressed in ECs from various vascular beds both in vitro and in vivo. Morpholino knockdown of Caskin2 in zebrafish results in abnormal vascular development characterized by overly branched intersegmental vessels and failure to form the dorsal longitudinal vessels. Interestingly, Caskin2 knockout mice are viable and fertile. However, compared to wild-type mice, adult Caskin2 knockout mice have significantly more abdominal adipose and higher fasting blood glucose levels even when fed a standard chow diet. In vitro, Caskin2 overexpression inhibits serum-induced EC proliferation and DNA synthesis but promotes EC survival during serum starvation. Caskin2 localizes to the nucleus as well as the cytoplasm and promotes the downregulation of genes associated with EC activation (e.g., IL-8, VEGFR2, ANG2) and the upregulation of genes associated with EC quiescence (e.g., Notch1, KLF2/4, ANG1). More broadly, pathway analysis of microarray data demonstrates that Caskin2 primarily regulates cell cycle and metabolic genes. Additional data suggest that these effects result from the interaction of Caskin2 with the Ser/Thr phosphatase PP1alpha, which is mediated by a consensus PP1 binding motif at the Caskin2 N-terminus. Taken together, our data demonstrate that Caskin2 is sufficient to suppress EC proliferation in vitro and necessary to prevent dysregulated angiogenesis in at least one in vivo model. These findings indicate that Caskin2 is a novel regulator of EC quiescence and suggest a role for Caskin2 in the prevention of EC dysfunction in vivo. Understanding Caskin2’s function on the molecular level may lead to the development of novel pharmacological approaches to prevent inappropriate angiogenesis, normalize dysfunctional vessels, and improve vascular function in a variety of cardiovascular diseases.

Implications of Klotho in vascular health and disease.

Cardiovascular disease (CVD) is a prevalent condition in general population and the first cause of death overall. Klotho, a pleiotropic protein related to longevity that acts as a co-receptor of the fibroblast growth factor 23, has been proposed as a key regulator of the development of CVD. In the few clinical studies made, it has been observed a relationship between low levels of soluble Klotho and the occurrence and severity of CVD, as well as a reduction of cardiovascular risk when they are high. Also, different polymorphisms of human Klotho gene have been related to the incidence of cardiovascular events. Moreover, several experimental studies indicate that this protein acts in the maintenance of vascular homeostasis. Klotho improves endothelial dysfunction through promotion of NO production and mediates anti-inflammatory and anti-aging effects such as suppression of adhesion molecules expression, attenuation of nuclear factor-kappa B or inhibition of Wnt signaling. Furthermore, this protein is related to the attenuation of vascular calcification as well as prevention of cardiac hypertrophy. The expression of this protein in the vascular wall implies a new scenario for the treatment of vascular disorders. The purpose of this review is to provide an overview of the relationship between the Klotho protein and CVD, in addition to its role in the maintenance of functional vascular integrity.

Expression Of Nitric Oxide Synthase, Vascular Cell Adhesion Molecule and C- Reactive Protein Receptor In Sickle Cell Leucocytes: Relationship With Chronic Inflammation

IntroductionChronic and acute inflammatory phenomenon's can contribute to activate several cells types and may play important role in the steady- and crisis-states of sickle cell anemia (HbSS) patients. Under normal circumstances, the nitric oxide synthase (NOS) constitutively produces low levels of nitric oxide (NO) that are important in the maintenance of vascular homeostasis, but in HbSS this balance is disrupted, mainly because the lack of arginine and the depletion of NO. This molecule also has an anti-inflammatory role in the vascular system and the state of resistance of NO can lead to deregulation of several other factors and interaction with many molecules. The aim of this study was correlate the expression of NOS, vascular cell adhesion molecule (VCAM), c-reactive protein receptor (rCRP) genes and biochemical profile of HbSS patients. Patients and MethodsWe studied 21 HbSS patients from Northeast Brazil, at steady state and were transfusion free. Blood samples were obtained during regular clinical visits. The expression of NOS, VCAM and rCRP genes were performed by real time PCR with Taqman assays from leucocytes RNA in trizol reagent. Serum biochemical analysis was determined using commercially available biochemical kits. The study was approved by the FIOCRUZ ethical committee and informed consents were signed by patients or official responsible. ResultsOur results showed a positive correlation among the expression of NOS and VCAM (p= 0.031, r=0.525), NOS and rCRP (p< 0.001, r=0.816) and VCAM and rCRP (p=0.003, r=0.659). Analyses of biochemical profile of HbSS individuals showed a correlation of NOS and serum calcium (p=0.044, r=0.456) as well as NOS and alkaline phosphatase (p=0.036, r=0.472).Discussion and ConclusionIn this study, the correlation among genetic expression of NOS, VCAM and rCRP molecules suggests how factors involved to inflammation in HbSS are linked. In response to inflammation, the liver releases a variety of acute phase proteins. One such product, CRP, serves as a dominating diagnostic marker of inflammation. Chronic inflammatory reflects in the up-regulation of VCAM and VOC susceptibility, can increase the release of alkaline phosphatase, as well as deregulation of NOS expression due to impaired constitutive NOS activity with loss of endothelial NOS dimerization, increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Also, NOS couples electron flux for NO production by binding calmodulin, which is calcium-dependent, which explain the positive correlation between NOS and serum calcium. Furthermore, additional studies will elucidate the mechanism involved with the interaction of this complex network of molecule and the endothelial activation and dysfunction described in the pathophysiology of HbSS chronic and acute inflammatory. Disclosures:No relevant conflicts of interest to declare.

Coronary heart disease risk equivalence in diabetes and arterial diseases characterized by endothelial function and endothelial progenitor cell

AimsPeripheral Arterial Disease (PAD), Carotid Artery Disease (CAD), and Type 2 Diabetes Mellitus (DM) were considered as “Coronary Heart Disease (CHD) risk equivalents”. Vascular endothelial dysfunction was recognized as an early event in the development of atherosclerosis. Involved in neovasculogenesis and maintenance of vascular homeostasis, endothelial progenitor cell (EPC) has been considered as a biological marker of cardiovascular disease. The purpose of this study was to assess the CHD risk equivalents concept by investigating the endothelial function and circulating EPC number in patients with CHD, PAD, CAD and T2DM. MethodsThere were four groups in the study: CHD (n=19), AD [PAD and CAD (n=17)], DM (n=21) and healthy controls (HC, n=20). PAD and CAD were assessed by ultrasonography. Coronal artery angiography was used to identify CHD. The diagnosis of T2DM was based on oral glucose tolerance test and medical history. Vascular endothelial function was assessed by flow-mediated brachial artery dilatation (FMD). Circulating EPC was quantified by flow cytometry. ResultsThe circulating EPC numbers in four groups were CHD, 973±96; AD, 1048±97; T2DM, 1210±125; HC, 1649±112 cells/ml. There were no significant differences in circulating EPC numbers between CHD and AD groups (P>0.05). Compared with CHD or AD group, T2DM group was associated with a slight increase in circulating EPC numbers (P<0.05). The results of FMD were almost similar to the circulating EPC numbers(CHD, 4.06±0.54; AD, 3.90±0.48; DM, 3.85±0.57; HC, 5.52±0.67%)except that there was no significant difference among the CHD, AD and T2DM groups (P>0.05). Age, glycosylated hemoglobin, low density lipoprotein cholesterol, systolic blood pressure, body mass index (BMI) and medical history were the independent risk factors of circulating EPC number in all the patients (P<0.05). Age, total cholesterol, BMI and medical history were the independent risk factors of FMD in all of the patients (P<0.05). ConclusionsThe results of this study supported the equivalents hypothesis and revealed that “CHD risk equivalents” were characterized by the consistent physiological changes of blood vessels in angiogenesis, repairing ability and endothelial function.

YIA2: A NOVEL CROSS-TALK BETWEEN PERIVASCULAR ADIPOSE TISSUE AND THE ARTERIAL WALL CONTROLS REDOX STATE IN HUMAN ATHEROSCLEROSIS

Background Endothelial nitric oxide synthase (eNOS) plays a crucial role in maintenance of vascular homeostasis. However, loss of eNOS co-factor tetrahydrobiopterin (BH4) due to oxidative degradation leads to uncoupling of the enzyme, that is turned into a source of superoxide radicals (O 2 − ) instead of nitric oxide (NO). Adipose tissue has been identified as the source of hormone-like molecules termed adipokines, which can exert endocrine and paracrine effects on the vascular wall. However, little is known about the role of adipokines such as adiponectin (AdN) in the regulation of vascular redox signalling in the human arterial wall or the mechanisms regulating their synthesis in perivascular adipose tissue (PVAT). Methods In Study 1, 677 patients undergoing coronary bypass surgery (CABG) were recruited. Blood samples were obtained preoperatively and internal mammary artery (IMA) segments as well as PVAT surrounding them were harvested during surgery. Serum AdN was quantified ELISA, vascular O 2 − was determined by lucigenin chemiluminescence (+/−LNAME to estimate eNOS coupling) and qRTPCR was performed to determine AdN gene expression in PVAT. In Study 2, IMA segments from 17 patients undergoing CABG were exposed to AdN (10 µg/ml, 6h)±wortmannin (W, a PI3K/Akt inhibitor) ex vivo to determine the effects of AdN on vascular redox state, eNOS phosphorylation status and BH4 content. In addition, PVAT was exposed to 4-hydroxynonenal (4HNE, a peroxidation product released by the vascular wall in the presence of high vascular oxidative stress) ex vivo to determine its effects on AdN gene expression. Results In Study 1, serum AdN was inversely related with resting O 2 − (p 2 − (p ex vivo . This was due to Akt-dependent eNOS phosphorylation at Ser1177 (C&D) and an increase in vascular BH4 (p 2 − triggered the release of 4HNE, while ex vivo exposure of PVAT to 4HNE up-regulated the expression of PPARγ (P Conclusions We describe a novel cross-talk between adipose tissue and the vascular wall in humans. Oxidative stress triggers the release of 4HNE from the vascular wall, which in turn up-regulates the expression of AdN in PVAT; then AdN exerts a paracrine effect on the vascular wall by activating eNOS and improving its BH4-mediated coupling.

Periodontitis increases vascular cyclooxygenase-2: potential effect on vascular tone

It has been demonstrated that periodontitis induces a systemic inflammation, which may impair endothelial function. Cyclooxygenase-2 (COX-2) is an important enzyme in the inflammatory process and is responsible for prostacyclin production. We hypothesised that in periodontitis, an increase in vascular COX-2 expression may occur, which in turn may have a role in vascular homeostasis. Thus, we evaluated the vascular effects of COX-2 inhibition in an experimental rat model of periodontitis. Experimental periodontitis was induced in rats by placing a cotton ligature around the cervix of both sides of the mandibular first molars and maxillary second molars. Sham-operated rats had the ligature removed immediately after the procedure. Mesenteric vessels were obtained for the study of COX-2 expression, and blood samples were collected for nitric oxide quantification. In another set of experiments, animals received etoricoxib (10mg/kg/d, v.o.) or vehicle, and alveolar bone loss and cardiovascular parameters were evaluated. We observed an increase in COX-2 expression in mesenteric vessels harvested from animals with periodontitis, which was accompanied by a reduction in nitric oxide content. Etoricoxib treatment impaired the endothelium-dependent reduction in blood pressure in rats with periodontitis. Periodontitis increases vascular COX-2 expression, which is important in the maintenance of vascular homeostasis in this model. Despite the limitations of an animal study, these findings may have important implications regarding the safety of using selective COX-2 inhibitors in patients with periodontitis.

ASSA13-10-13 Cellular Repressor E1A-Stimulated Genes Controls Phenotypic Switching of Adventitial Fibroblasts by Blocking p38MAPK Activation

Background Phenotypic modulation of adventitial fibroblasts (AFs) plays an important role in the pathogenesis of proliferative vascular diseases. The current study aimed to identify the role of cellular repressor E1A-stimulated genes (CREG), a critical mediator in the maintenance of vascular homeostasis, in AF phenotypic modulation and adventitial remodelling. Methods Two models of AF phenotypic modulation were used: the in vivo injury-induced adventitial remodelling and the in vitro Ang II-induced AF phenotypic modulation. CREG’s function in AFs was investigated after over-expression of CREG with infection with adenovirus expressing full-length human CREG cDNA. Results Using in situ double-immunofluorescence staining, we ascertained that CREG expression was significantly downregulated in the adventitia after vascular injury, and its expression pattern was conversely correlated with the expression of smooth muscle α-actin (α-SMA), a marker for differentiation of AFs into myofibroblasts. In vitro data confirmed the association of CREG in angiotensin II (Ang II)-induced AF differentiation. Additionally, over-expression of CREG attenuated Ang II-induced α-SMA expression in AFs. CREG over-expressing AFs showed decreased levels of proliferation on days 2 to 5 following stimulation by Ang II compared with controls, with changes in the cell cycle profile as shown by BrdU incorporation assay and fluorescence activated cell sorting analysis. Moreover, wound healing assay and transwell migration model demonstrated that upregulation of CREG expression inhibited Ang II-induced AF migration. We found that CREG mediated its counterbalancing effects in Ang II-induced phenotypic modulation, proliferation and migration by inhibition of the p38MAPK signalling pathway, validated by pharmacological blockade of p38MAPK with SB 203580 and by over-expression of p38MAPK with transfectants expressing constitutively active p38αMAPK. Conclusions Our findings suggest that CREG is a novel AF phenotypic modulator in a p38MAPK-dependent manner. Modulating CREG on the local vascular wall may become a new therapeutic target against proliferative vascular diseases.

Cellular repressor E1A-stimulated genes controls phenotypic switching of adventitial fibroblasts by blocking p38MAPK activation

AimsPhenotypic modulation of adventitial fibroblasts (AFs) plays an important role in the pathogenesis of proliferative vascular diseases. The current study aimed to identify the role of cellular repressor E1A-stimulated genes (CREG), a critical mediator in the maintenance of vascular homeostasis, in AF phenotypic modulation and adventitial remodeling. Method and resultsUsing in situ double-immunofluorescence staining, we ascertained that CREG expression was significantly down-regulated in the adventitia after vascular injury, and its expression pattern was conversely correlated with the expression of smooth muscle α-actin (α-SMA), a marker for differentiation of AFs into myofibroblasts. In vitro data confirmed the association of CREG in angiotensin II (Ang II)-induced AF differentiation. Additionally, overexpression of CREG attenuated Ang II-induced α-SMA expression in AFs. CREGoverexpressing AFs showed decreased levels of proliferation on days 2–5 following stimulation by Ang II compared with controls, with changes in the cell cycle profile as shown by BrdU incorporation assay and fluorescence activated cell sorting analysis. Moreover, wound healing assay and transwell migration model demonstrated that upregulation of CREG expression inhibited Ang II-induced AF migration. We found that CREG-mediated its counterbalancing effects in Ang II-induced phenotypic modulation, proliferation and migration by inhibition of the p38MAPK signaling pathway, validated by pharmacological blockade of p38MAPK with SB 203580 and by overexpression of p38MAPK with transfectants expressing constitutively active p38αMAPK. ConclusionOur findings suggest that CREG is a novel AF phenotypic modulator in a p38MAPK-dependent manner. Modulating CREG on the local vascular wall may become a new therapeutic target against proliferative vascular diseases.

Reduced Number of Circulating Endothelial Progenitor Cells (CD133+/KDR+) in Patients with Plaque Psoriasis

Background: Psoriasis is associated with an increased cardiovascular risk. Circulating endothelial progenitor cells (CEPCs) play a significant role in the maintenance of vascular homeostasis. Objective: The aim of this study was to evaluate the number of CEPCs in patients with psoriasis compared to controls and assess possible correlations between the number of these cells and the plasma levels of vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and clinical features of psoriasis. Methods: The number of CEPCs, identified as CD133+/KDR+ cells, was determined with flow cytometry in peripheral blood of psoriatic patients (n = 63) and controls (n = 31). The plasma levels of VEGF and sVEGFR-1 were measured with enzyme-linked immunosorbent assay. Results: The number of CEPCs was significantly reduced in psoriatic patients compared with controls (p = 0.000026) and inversely correlated with disease severity (R = –0.283; p = 0.0248). Conclusion: A reduced number of CEPCs may contribute to endothelial dysfunction in patients with psoriasis.

Regulation and Maintenance of Vascular Tone and Patency in Cardiovascular Health and Disease

Despite numerous advances in health care practices, cardiovascular disease still remains the leading cause of morbidity and mortality worldwide. Perhaps the most important consequence of cardiovascular disease is the interruption of blood flow to organs such as the heart and brain, resulting in the clinical presentation of a heart attack or stroke. As such, the regulation of vascular tone and the maintenance of vascular patency are vital for the preservation of cardiovascular health. Central to this process is the vascular endothelium. The endothelium is vital for the regulation of vascular tone and the maintenance of vascular homeostasis, as it releases factors such as nitric oxide, hydrogen sulfide, endothelial-dependent hyperpolarizing factor, and prostacyclin that induce vasodilatation and keep the vasculature free of obstructions [1]. Therefore, it should be of no surprise that a number of the risk factors for the development of cardiovascular disease, such as hypertension, hypercholesterolemia, diabetes, smoking, ageing, and atherosclerosis, correlate with an impaired endothelium [2]. This impairment, termed endothelial dysfunction, is characterized by the reduction in the bioavailability of vasodilators, particularly nitric oxide, and/or an increase in endothelium-derived contracting factors [3]. The resulting imbalance leads to an impairment of endothelium-dependent vasodilation, as well as a compromised state of endothelial activation characterized by proinflammatory, proliferative, and procoagulatory conditions that favor all stages of atherogenesis [4]. Therefore, it is critically important to develop and implement therapeutic strategies that will combat endothelial dysfunction in an effort to reduce the mortality and morbidity associated with cardiovascular diseases. However, before therapeutic strategies can be implemented it is important to have a clear understanding of the pathological mechanisms that lead to the endothelial dysfunction in the first place. This special issue of highlights the latest findings related to the role of endothelial dysfunction in cardiovascular disease and comprises five review articles and one original report. The first three articles share the common theme of endothelial dysfunction in diabetes. Each paper offers unique insights into the mechanisms underlying diabetes-induced changes in endothelial biology and highlights specific pathways that could be novel therapeutic targets. The review article in this series by S. D. Funk et al. discusses the mechanisms that contribute to the development of atherosclerosis in diabetics. This paper highlights the central role of hyperglycemia in promoting endothelial dysfunction and discusses how cellular and animal studies have translated to clinical development of therapeutics targeting endothelial dysfunction in diabetes. The next paper by A. Sharma et al. highlights the importance of alterations in endothelium-derived nitric oxide (EDNO) production in the pathogenesis of vascular complications in both type 1 and type 2 diabetes. The interrelationship between reactive oxygen species (ROS) and EDNO is described, with emphasis on the cellular and molecular mechanisms that give rise to altered NO bioavailability in diabetes. In their paper, G. K. Kolluru et al. emphasize the importance of angiogenesis in diabetes and chronicle studies that have yielded mechanistic insights into the development of endothelial dysfunction in diabetes. This comprehensive paper, entitled “Endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and wound healing,” discusses how ROS and deficiencies in NO bioavailability contribute to altered angiogenesis in diabetes. Therapeutic management of angiogenesis in diabetes is also discussed. In another review article in this series, M. Murakami provides a comprehensive overview of the mechanisms contributing to the active maintenance of the vasculature. The role of growth factors and cytokines in mediating endothelial and mural cell maintenance is described, with an analysis of how genetic alterations in these pathways give rise to blood vessel abnormalities and susceptibility to vascular disease. The molecular and cellular mechanisms leading to restenosis and the potential for new therapeutics targeting vascular smooth muscle cell (VSMC) proliferation are the topic of a review article in this series. L. Denes et al. highlight the importance of VSMC phenotype switching and proliferation in vascular disease and discuss the clinical diagnosis and management of restenosis. The original report by I. Liesmaa et al. is entitled “Bradykinin type-2 receptor expression correlates with age and is subjected to transcriptional regulation.” This study demonstrates that bradykinin type-2 receptor (BK-2R) mRNA is positively correlated with age, but is significantly reduced in human patients with idiopathic dilated cardiomyopathy (IDC) compared with healthy individuals. The study further examines the relationship between polymorphisms in the BK-2R promoter and the presence of IDC and coronary heart disease.

Nox enzymes and oxidative stress in atherosclerosis

Oxidative stress is a major contributor to the etiology of all severe vascular pathologies, such as atherosclerosis. NADPH oxidases (Nox) are a class of multicomponent enzymes whose unique function is the generation of reactive oxygen species (ROS) in the vascular cells and in circulating immune cells interacting with blood vessels. Physiological production of Nox-derived ROS contributes to the maintenance of vascular homeostasis. In pathological states, hyperactivity of Nox induces oxidative stress. Nox-derived ROS interact and stimulate other enzymatic sources of oxygen/nitrogen reactive intermediates, and amplify the initial response to insults. In atherosclerosis, Nox-induced lipid peroxidation is highly deleterious and expands the free radical reactions initially produced by activated Nox. Therefore, understanding the molecular mechanisms of Nox regulation, vascular and subcellular compartmentalization of ROS production and its subsequent biological significance, may lead to a focused and effective anti-oxidative stress therapy. We present here, recent advances in Nox regulation in the vasculature and discuss novel potential intrinsic feedback mechanisms and current and pharmacological perspectives to target Nox, which may have an impact in vascular health and disease.