EP3 (E-Prostanoid 3) Receptor Mediates Impaired Vasodilation in a Mouse Model of Salt-Sensitive Hypertension.

[Figure: see text].

Neutrophils Enhance Cutaneous Vascular Dilation and Permeability to Aggravate Psoriasis by Releasing Matrix Metallopeptidase 9.

Neutrophil infiltration and papillary vessel dilation are hallmarks of the initiation phase of psoriatic lesions. However, how neutrophils aggravate psoriasis development during transendothelial migration and the interaction between neutrophils and cutaneous vascular endothelial cells are less well-understood. In this study, we reported that neutrophils and cutaneous vascular endothelial cells activated each other when neutrophils migrated through the cutaneous endothelial barrier. In addition, neutrophil infiltration into skin lesions caused vascular remodeling including cutaneous vasodilation and enhanced vascular permeability in vivo and in vitro. Microarray gene profile data showed that matrix metallopeptidase (MMP)-9 was overexpressed in psoriatic neutrophils, and zymography assay further validated the bioactivity of MMP-9 secreted by psoriatic neutrophils. Moreover, MMP-9 activated vascular endothelial cells through the extracellular signal‒regulated kinase 1/2 and p38-MAPK signaling pathways, enhancing CD4+ T-cell transmigration in vitro. Correspondingly, an MMP-9 inhibitor significantly reduced cutaneous vasodilation, vascular permeability, and psoriatic symptoms in an imiquimod- or IL-23‒induced psoriasiform mouse model. Overall, our study demonstrates that neutrophil-derived MMP-9 induces cutaneous vasodilation and hyperpermeability by activating cutaneous vascular endothelial cells, thus facilitating psoriatic lesion development, which increases our knowledge on the role of neutrophils in the pathogenesis of psoriasis.

Group II innate lymphoid cells and microvascular dysfunction from pulmonary titanium dioxide nanoparticle exposure.

BACKGROUND: The cardiovascular effects of pulmonary exposure to engineered nanomaterials (ENM) are poorly understood, and the reproductive consequences are even less understood. Inflammation remains the most frequently explored mechanism of ENM toxicity. However, the key mediators and steps between lung exposure and uterine health remain to be fully defined. The purpose of this study was to determine the uterine inflammatory and vascular effects of pulmonary exposure to titanium dioxide nanoparticles (nano-TiO2). We hypothesized that pulmonary nano-TiO2 exposure initiates a Th2 inflammatory response mediated by Group II innate lymphoid cells (ILC2), which may be associated with an impairment in uterine microvascular reactivity. METHODS: Female, virgin, Sprague-Dawley rats (8-12 weeks) were exposed to 100 µg of nano-TiO2 via intratracheal instillation 24 h prior to microvascular assessments. Serial blood samples were obtained at 0, 1, 2 and 4 h post-exposure for multiplex cytokine analysis. ILC2 numbers in the lungs were determined. ILC2s were isolated and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) levels were measured. Pressure myography was used to assess vascular reactivity of isolated radial arterioles. RESULTS: Pulmonary nano-TiO2 exposure was associated with an increase in IL-1ß, 4, 5 and 13 and TNF- α 4 h post-exposure, indicative of an innate Th2 inflammatory response. ILC2 numbers were significantly increased in lungs from exposed animals (1.66 ± 0.19%) compared to controls (0.19 ± 0.22%). Phosphorylation of the transactivation domain (Ser-468) of NF-κB in isolated ILC2 and IL-33 in lung epithelial cells were significantly increased (126.8 ± 4.3% and 137 ± 11% of controls respectively) by nano-TiO2 exposure. Lastly, radial endothelium-dependent arteriolar reactivity was significantly impaired (27 ± 12%), while endothelium-independent dilation (7 ± 14%) and α-adrenergic sensitivity (8 ± 2%) were not altered compared to control levels. Treatment with an anti- IL-33 antibody (1 mg/kg) 30 min prior to nano-TiO2 exposure resulted in a significant improvement in endothelium-dependent dilation and a decreased level of IL-33 in both plasma and bronchoalveolar lavage fluid. CONCLUSIONS: These results provide evidence that the uterine microvascular dysfunction that follows pulmonary ENM exposure may be initiated via activation of lung-resident ILC2 and subsequent systemic Th2-dependent inflammation.

Involvement of Histamine and RhoA/ROCK in Penicillin Immediate Hypersensitivity Reactions.

The mechanism of penicillin immediate hypersensitivity reactions has not been completely elucidated. These reactions are generally considered to be mediated by IgE, but penicillin-specific IgE could not be detected in most cases. This study demonstrated that penicillin was able to cause vascular hyperpermeability in a mouse model mimicking clinical symptoms of penicillin immediate hypersensitivity reactions. The first exposure to penicillin also induced immediate edema and exudative reactions in ears and lungs of mice in a dose-dependent manner. Vasodilation was noted in microvessels in ears. These reactions were unlikely to be immune-mediated reactions, because no penicillin-specific IgE was produced. Furthermore, penicillin treatment directly elicited rapid histamine release. Penicillin also led to F-actin reorganization in human umbilical vein endothelial cells and increased the permeability of the endothelial monolayer. Activation of the RhoA/ROCK signaling pathway was observed in ears and lungs of mice and in endothelial cells after treatment with penicillin. Both an anti-histamine agent and a ROCK inhibitor attenuated penicillin immediate hypersensitivity reactions in mice. This study presents a novel mechanism of penicillin immediate hypersensitivity reactions and suggests a potential preventive approach against these reactions.

Mast cells are required for phototolerance induction and scratching abatement.

Dermal mast cells protect the skin from inflammatory effects of ultraviolet (UV) radiation and are required for UV-induced immune suppression. We sought to determine a potential mechanistic role of mast cells in reducing the sensitivity to UV radiation (i.e. phototolerance induction) through photohardening. We administered single UV exposures as well as a chronic UV irradiation regime to mast cell-deficient Kit(W-Sh/W-Sh) mice and their controls. The chronic irradiation protocol was similar to that given for prophylaxis in certain photodermatoses in humans. Compared to controls, UV-exposed Kit(W-Sh/W-Sh) mice were more susceptible to epidermal hyperplasia and dermal oedema which was linked to blood vessel dilation. Unexpectedly, Kit(W-Sh/W-Sh) mice exhibited an excessive scratching behaviour following broadband UVB plus UVA or solar simulated UV irradiation at doses far below their minimal skin-swelling dose. Protection from this UV-induced scratching phenotype was dependent on mast cells, as engraftment of bone marrow-derived cultured mast cells abated it entirely. Kit(W-Sh/W-Sh) mice were entirely resistant to phototolerance induction by photohardening treatment. Compared to controls, these mice also showed reduced numbers of regulatory T cells and neutrophils in the skin 24 h after UV irradiation. While it is well known that mast cell-deficient mice are resistant to UV-induced immune suppression, we have discovered that they are prone to develop photo-itch and are more susceptible to UV-induced epidermal hyperplasia and skin oedema.

The role of TRPV1 in improving VSMC function and attenuating hypertension.

The transient receptor potential vanilloid type 1 (TRPV1) channel, a ligand-gated cation channel of the TRP subfamily, can be activated by multiple stimuli, including capsaicin. Currently, cumulative studies have demonstrated an interesting link between TRPV1 and cardiovascular diseases, including hypertension. Additionally, the protective effect of TRPV1 against hypertension and its related disorders has been proved to be partly involved with the improved action of vascular smooth muscle cells (VSMCs). This review focuses on the current knowledge of TRPV1 in improving VSMC function and attenuating hypertension.

Perivascular adipose tissue, inflammation and vascular dysfunction in obesity.

Adipocytes are no longer considered just as cells related to storage of energy and thermoregulation. Now we know that they release a huge number of paracrine and endocrine biologically active molecules. This is also the case for perivascular adipose tissue (PVAT) that surrounds almost all blood vessels in the organism. PVAT secretes the so-called adipo(cyto)kines that, because of its proximity, can easily influence vascular smooth muscle cells. The role of PVAT on vascular function can be both protective and deleterious. Normal healthy PVAT, as present in lean subjects, helps to keep the blood vessels dilated as its presence diminishes the effect of vasocontractile agents. Obesity is associated with an increased mass in PVAT. Excessive adipocyte hypertrophy may result in "adiposopathy" in which PVAT attracts macrophages and becomes a more inflammatory phenotype. This leads to a change in profile of the released adipo(cyto)kines, resulting in a decreased vasorelaxing effect of PVAT, which may be linked to obesity-induced hypertension. It also results in smooth muscle cell migration and proliferation and the development of atherosclerotic lesions. The increased knowledge of PVAT function brings up new targets that can be useful to develop novel therapeutic and preventive strategies for obesity-related cardiovascular diseases. This mini-review presents a general overview of the actual knowledge on the role of PVAT on vascular function and dysfunction in obesity.

Endothelial dysfunction, obesity and insulin resistance.

Obesity is a metabolic disorder of increasing prevalence worldwide and a risk factor for the development of insulin resistance (IR), metabolic syndrome and type 2 diabetes. Obesity is related to endothelial dysfunction through indirect mechanisms such as IR and the associated risk factors, and through direct mechanisms including the production of proinflammatory adipokines and elevated levels of free fatty acids (FFAs) by adipose tissue. Both clinical and experimental studies using genetic and diet-induced animal models of obesity have consistently shown impaired metabolic, agonistor flow-induced vasodilatations correlated with the amount of visceral adipose tissue and improved by dietary interventions and exercise. Compromised bioavailability of NO due to oxidative stress emerges as a main cause of endothelial dysfunction in obesity. Inflamed adipose tissue due to hypoxia, and in particular perivascular adipose tissue (PVAT), secrete larger amounts of reactive oxygen species (ROS) and adipokines that deteriorate NO signaling pathways. Abnormal production and activity of the vasoconstrictor/proatherogenic peptide endothelin-1 (ET-1) is also a hallmark of the obesity- associated endothelial dysfunction. Obesity, and in particular visceral obesity, is one of the main causes of IR, and the pathogenic factors that induce endothelial dysfunction in the earlier stages of obesity will further deteriorate the insulin signaling pathways in endothelial cells thus leading to blunted vasodilatation and abnormal capillary recruitment and substrate delivery by insulin to the target tissues. The present review is an attempt to summarize the current knowledge and the latest novel findings on the pathogenic mechanisms underlying endothelial dysfunction in obesity, in particular the local contribution of oxidative stress and inflammatory response from PVAT, and its role in the obesity-associated cardiovascular and metabolic complications.

An evaluation of potential correlations between pathophysiologic mechanisms, clinical manifestations, and management of rosacea.

This article discusses rosacea, a common facial dermatosis of uncertain etiology and recent investigations that have begun to shed considerable light on the sequence of events leading to clinical manifestations of rosacea. The article content is based on a dedicated meeting about rosacea sanctioned by the American Acne & Rosacea Society (AARS) and represents the consensus of the authors and AARS Board of Directors.

Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin.

Obesity is characterized by a chronic proinflammatory state that leads to endothelial dysfunction. Saturated fatty acids (SFA) stimulate Toll-like receptors (TLR) that promote metabolic insulin resistance. However, it is not known whether TLR2 mediates impairment of vascular actions of insulin in response to high-fat diet (HFD) to cause endothelial dysfunction. siRNA knockdown of TLR2 in primary endothelial cells opposed palmitate-stimulated expression of proinflammatory cytokines and splicing of X box protein 1 (XBP-1). Inhibition of unfolding protein response (UPR) reduced SFA-stimulated expression of TNFα. Thus, SFA stimulates UPR and proinflammatory response through activation of TLR2 in endothelial cells. Knockdown of TLR2 also opposed impairment of insulin-stimulated phosphorylation of eNOS and subsequent production of NO. Importantly, insulin-stimulated vasorelaxation of mesenteric arteries from TLR2 knockout mice was preserved even on HFD (in contrast with results from arteries examined in wild-type mice on HFD). We conclude that TLR2 in vascular endothelium mediates HFD-stimulated proinflammatory responses and UPR that accompany impairment of vasodilator actions of insulin, leading to endothelial dysfunction. These results are relevant to understanding the pathophysiology of the cardiovascular complications of diabetes and obesity.

Pathophysiology of atherosclerosis: the role of inflammation.

Atherosclerosis is a disease of arteries and is characterized by endothelial dysfunction, vascular inflammation, and the build-up of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall. A number of factors commonly characterized as "risk factors" for atherosclerosis have been identified to facilitate the development of atherosclerosis by decreasing NO bioavailability in the vascular endothelium. The serious clinical manifestations of atherosclerosis (including coronary heart disease, stroke, and peripheral vascular disease) augment the need of performing the appropriate diagnostic methods to the patients. The most important diagnostic methods include the usage of biochemical markers and the invasive and non-invasive imaging techniques assessing endothelial function. The main drug categories that have been proved to ameliorate the inflammatory state in atherosclerosis are angiotensin converting enzyme inhibitors/angiotensin receptors blockers, statins, and antioxidants.

Neurovascular and neuroimmune aspects in the pathophysiology of rosacea.

Rosacea is a common skin disease with a high impact on quality of life. Characterized by erythema, edema, burning pain, immune infiltration, and facial skin fibrosis, rosacea has all the characteristics of neurogenic inflammation, a condition induced by sensory nerves via antidromically released neuromediators. To investigate the hypothesis of a central role of neural interactions in the pathophysiology, we analyzed molecular and morphological characteristics in the different subtypes of rosacea by immunohistochemistry, double immunofluorescence, morphometry, real-time PCR, and gene array analysis, and compared the findings with those for lupus erythematosus or healthy skin. Our results showed significantly dilated blood and lymphatic vessels. Signs of angiogenesis were only evident in phymatous rosacea. The number of mast cells and fibroblasts was increased in rosacea, already in subtypes in which fibrosis is not clinically apparent, indicating early activation. Sensory nerves were closely associated with blood vessels and mast cells, and were increased in erythematous rosacea. Gene array studies and qRT-PCR confirmed upregulation of genes involved in vasoregulation and neurogenic inflammation. Thus, dysregulation of mediators and receptors implicated in neurovascular and neuroimmune communication may be crucial at early stages of rosacea. Drugs that function on neurovascular and/or neuroimmune communication may be beneficial for the treatment of rosacea.

Endotoxin-induced cardiovascular dysfunction in mice: effect of simvastatin.

Lung infections are associated with acute lung injury (ALI), systemic inflammation, and vascular events. Clinical studies suggest that statins improve health outcomes of patients with pneumonia and ALI. The mechanisms by which this occurs are unknown. The aim of this study was to determine whether statins attenuate systemic inflammation and cardiovascular dysfunction related to ALI in mice. Simvastatin (SS; 20 mg/kg) or vehicle solution was instilled intraperitoneally into mice 24 h before and again just prior to intratracheal LPS instillation (1 µg/g). These mice were then anesthetized with 2.0% isoflurane and underwent a short surgical procedure to instill LPS. Four hours later, IL-6 levels in bronchoalveolar lavage fluid and in arterial and venous serum were measured. Cardiac function was evaluated using 2-D echocardiography, and endothelial function was determined using wire myography on aortic sections. LPS induced a significant increase in serum IL-6 levels. SS reduced venous (P = 0.040) but not arterial concentrations of IL-6 (P = 0.112). SS improved the maximal vasodilatory response of the aorta to ACh (P = 0.004) but not to sodium nitroprusside (P = 1.000). SS also improved cardiac output (P = 0.023). Vasodilatory response to ACh was impaired when aorta from untreated mice was incubated with ex vivo IL-6 (P = 0.004), whereas in the aorta from mice pretreated with SS, the vasodilatory response did not change with IL-6 incubation (P = 0.387). SS significantly improved LPS-induced cardiovascular dysfunction possibly by reducing systemic expression of IL-6 and its downstream signaling pathways. These findings may explain how statins improve health outcomes in patients with ALI.

The indirect alloimmune response causes microvascular endothelial dysfunction-a possible role for alloantibody.

BACKGROUND: The causes of endothelial dysfunction after cardiac transplantation are unknown. Here, we have investigated whether the indirect alloimmune response mediates endothelial dysfunction in a major histocompatibility complex class I mismatch model. METHODS: PVG.RT1 rat hearts were transplanted into thymectomized CD8 T-cell-depleted allogeneic (PVG.R8) or syngeneic (PVG.RT1) recipients. Alloantibody was assessed at 2, 4, and 8 weeks. Cardiac allograft vasculopathy, the nature of the inflammatory infiltrate, and origin of endothelial cells were examined at 1, 2, 4, and 8 weeks. Endothelial function was assessed by Langendorff preparations at 1, 2, and 4 weeks. RESULTS: Recipients produced alloantibody and showed luminal occlusion at 1 (17.7%±8.0%), 2 (23.2%±4.9%), 4 (34.3%±5.0%), and 8 weeks (58.1%±1.8%) posttransplantation. The major inflammatory features of the allografts consisted of CD11b monocytes, CD4 T cells, and C4d deposition. At 1 week, the basal coronary flow and the vasodilator response to 5-hydroxytrytamine of syngeneic and allografted hearts were inhibited compared with normal hearts. At 4 weeks, the basal coronary flow of allografts was 54% lower than syngrafts (P<0.01), and 5- hydroxytrytamine and sodium nitroprusside did not evoke an increase in coronary flow in the allograft heart compared with syngeneic controls (P<0.01). Culture of aortic rings with antibody to major histocompatibility complex class I inhibited endothelium-dependent vasodilation to acetylcholine. CONCLUSION: Transient microvascular endothelial dysfunction occurred in syngeneic and allogeneic cardiac grafts after transplantation. Syngeneic but not allogeneic grafts recovered, suggesting the indirect immune response, consisting of CD4 T cells, monocytes, and antibody, mediates endothelial dysfunction. A possible role for alloantibody in endothelial dysfunction is discussed.

Pulmonary allergic reactions impair systemic vascular relaxation in ragweed sensitive mice.

Asthma is often associated with cardiovascular complications, and recent observations in animal models indicate that induction of pulmonary allergic inflammation increases susceptibility of the myocardium to ischemia and reperfusion injury. In this study, we used a murine model of allergen sensitization in which aspiration of allergen induces pulmonary and systemic inflammation, to test the hypothesis that pulmonary exposure to allergen alters vascular relaxation responses. BALB/C mice were sensitized by intraperitoneal injection of ragweed and challenged by intratracheal instillation of allergen. Airway hyperreactivity and pulmonary inflammation were confirmed, and endothelium-dependent and -independent reactivity of thoracic aorta rings were evaluated. Ragweed sensitization and challenge induced airway hyperreactivity to methacholine and pulmonary inflammation, but did not affect constrictor responses of the aortic rings to phenylephrine and K+ depolarization. In contrast, maximal relaxation of aortic rings to acetylcholine and sodium nitroprusside decreased from 87.6±3.9% and 97.7±1.2% to 32±4% and 51±6%, respectively (p<0.05). The sensitivity to acetylcholine was likewise reduced (EC50=0.26±0.05 µM vs. 1.09±0.16 µM, p<0.001). The results demonstrate that induction of allergic pulmonary inflammation in mice depresses endothelium-dependent and -independent vascular relaxation, which can contribute to cardiovascular complications associated with allergic inflammation.

Augmented venous responsiveness to leukotriene D(4) in nasal septal mucosae of repeatedly antigen-challenged rats.

One possible mechanism of the nasal obstruction observed in allergic rhinitis is thought to be a dilatation of veins in nasal mucosa, although the exact mechanism(s) is not fully understood. An involvement of cysteinyl leukotrienes (CysLTs) in the nasal obstruction has also been suggested. In addition to the specific antigen-induced nasal symptoms, nasal hyperresponsiveness to non-specific stimuli is one of the characteristic features of patients with allergic rhinitis. Augmentation of LTD(4)-induced venodilatation (a part of nasal hyperresponsiveness) of nasal mucosae in antigen-challenged rats was investigated. The LTD(4)-induced venodilatation was significantly increased in antigen-challenged rats, although venodilatation by application of LTD(4) was not induced in nasal mucosae of control rats. The LTD(4)-induced venodilatation was significantly inhibited by pretreatment with L-NMMA [an inhibitor of nitrix oxide synthase (NOS)]. Although mRNA of CysLT1 receptor of nasal mucosa was within control level, the LTD(4)-induced production of NOx in nasal cavity was augmented in repeatedly antigen challenge rats. In addition, the level of iNOS mRNA was also significantly augmented in nasal mucosae of repeatedly antigen-challenged rats. Interestingly, sodium nitroprusside (SNP; an NO donor)-induced venodilatation itself was significantly augmented in nasal mucosae of repeatedly antigen challenge rats. In conclusion, we here suggest that the sensitivity of venodilatation to LTD(4) was augmented in nasal mucosae of challenged rats. Therein, not only increased NO production but also enhanced NO responsiveness might be involved in the development of nasal hyperresponsiveness in allergic rhinitis.

Blockade of endogenous proinflammatory cytokines ameliorates endothelial dysfunction in obese Zucker rats.

To study the role of endogenous proinflammatory cytokines in endothelial dysfunction in diabetes, we administered semapimod, an inhibitor of proinflammatory cytokine production, to obese Zucker (OZ) rats, and examined its effect on endothelium-dependent vasorelaxation. Endothelium-dependent vasorelaxation induced by acetylcholine and adrenomedullin (AM) was significantly reduced in OZ rats compared to a control group of lean Zucker rats. Semapimod significantly restored endothelium-dependent vasorelaxation in OZ rats. This effect of semapimod was well correlated with the reduction in the serum concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and C-reactive protein, as well as with the recovery of AM-induced Akt phosphorylation and cGMP production. Furthermore, acute administration of TNF-alpha significantly suppressed endothelium-dependent vasorelaxation and AM-induced cGMP production. These results implicate endogenous proinflammatory cytokines, especially TNF-alpha, in endothelial dysfunction in diabetes, and indicate that blockade of these cytokines will be a promising strategy for inhibiting the progression of vascular inflammation.

Endothelial dysfunction and atherosclerosis in rheumatoid arthritis: a multiparametric analysis using imaging techniques and laboratory markers of inflammation and autoimmunity.

OBJECTIVE: Cardiovascular disease is a leading cause of mortality in rheumatoid arthritis (RA). Endothelial dysfunction often precedes manifest atherosclerosis. We assessed endothelial dysfunction and atherosclerosis in RA in context with laboratory markers. METHODS: Fifty-two patients with RA and 40 matched healthy controls were studied. We assessed common carotid intima-media thickness (ccIMT) and flow- (FMD) and nitroglycerine-mediated vasodilation (NMD). We also assayed numerous immunological and metabolic laboratory markers. RESULTS: FMD was significantly lower in RA (5.32% +/- 4.66%) compared to controls (8.30% +/- 3.96%) (p = 0.001). NMD was preserved in RA. ccIMT was significantly greater in patients with RA (0.63 +/- 0.14 mm) versus controls (0.54 +/- 0.15 mm) (p = 0.012). In patients with RA, ccIMT correlated with FMD% (R = -0.318, p = 0.022), age (R = 0.831, p < 0.001), and anti-dsDNA levels (R = 0.463, p = 0.006). FMD% correlated with serum interferon-gamma (IFN-gamma) levels (R = 0.516, p = 0.014). NMD% correlated inversely with the percentage of Th0 lymphocytes (R = -0.636, p = 0.006), serum immune complex (R = -0.692, p < 0.001), and IgM levels (R = -0.606, p = 0.003). Patients with RA were divided as "low" (< 0.65 mm) versus "high" (> 0.65 mm) ccIMT groups, and into "normal" (> 5%) versus "impaired" (< 5%) FMD% subsets. Low and high ccIMT groups differed significantly in age and serum interleukin 1 (IL-1) and anti-dsDNA levels. RA patients with normal versus impaired FMD% differed significantly in age, disease duration, and serum IFN-gamma levels. Lipoprotein(a) [Lp(a)] also correlated with rheumatoid factor (RF) and C-reactive protein (CRP); homocysteine (HCy) correlated with CRP and correlated inversely with folate and vitamin B12 production. Paraoxonase-1 (PON-1) activity correlated with serum tumor necrosis factor-alpha(TNF-alpha) and IL-6 levels. CONCLUSION: This was a well characterized RA population, where FMD and ccIMT were impaired, indicating early endothelial dysfunction and accelerated atherosclerosis, respectively. RA-related autoimmune-inflammatory mechanisms and metabolic factors including anti-CCP, RF, CRP, circulating immune complexes, IgM, TNF-alpha, IL-6, Th0/Th1 ratio, HCy, folate, vitamin B12, and PON-1 may all be involved in the development of vascular disease in RA. Although ccIMT and FMD, as well as some laboratory factors, have been assessed by other investigators in RA-associated atherosclerosis, our results regarding the possible involvement of anti-CCP, anti-dsDNA, Lp(a), some cytokines, and PON-1 activity are novel. Early determination of FMD% and ccIMT may be useful to assess RA patients with high cardiovascular risk.

PAR-2 mediates increased inflammatory cell adhesion and neointima formation following vascular injury in the mouse.

Activation of PAR-2 in the vasculature affects vascular tone and adhesion of leukocytes to the endothelium. Since adhesion of leukocytes is increased following vascular injury and is important in determining the extent of neointima formation, we hypothesised that mice lacking PAR-2 may have reduced neointima formation following vascular injury. PAR-2 activating peptides and trypsin induced endothelium-dependent relaxation of mouse carotid artery which was absent in the knockout mouse. Lack of a PAR-2 receptor did not affect lymphocyte adhesion under basal conditions, but reduced the contractile response produced by lymphocytes. Twenty-eight days after denuding injury, vessel contraction to lymphocytes was reduced in both strains while lymphocyte adhesion was significantly greater in PAR-2(+/+) mice compared to the PAR-2 knockout mice. Neointimal area was markedly reduced in the PAR-2 knockout mouse. Our data show that PAR-2 modulates inflammatory cell adhesion when stimulated and in mice lacking the PAR-2 receptor, adhesion to injured vessels is reduced with a consequent reduction in neointima formation.

C-reactive protein and e-selectin levels are related to vasodilation in resistance, but not conductance arteries in the elderly: the prospective investigation of the Vasculature in Uppsala Seniors (PIVUS) study.

BACKGROUND: Divergent results have emerged in the past when relating single markers of inflammation to measures of vascular reactivity. The aim of the present study is to relate a wide range of inflammatory markers to vasoreactivity in both resistance and conductance arteries. METHODS: In the Prospective Investigation of the Vasculature in Uppsala Seniors (the PIVUS study), endothelium-dependent vasodilation was evaluated by the invasive forearm technique with acetylcholine given in the brachial artery (EDV), the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD) and the pulse wave analysis method with beta-2 receptor agonist (terbutaline) provocation in 1016 subjects aged 70. A panel of 14 inflammatory markers, including cytokines, chemokines, adhesion molecules, CRP, sCD40 ligand and leukocyte count, was measured. RESULTS: After adjustment for gender and coronary risk factors, EDV was independently related to CRP levels and e-selectin in an inverse way (p<0.006 for both). FMD was not significantly related to any marker of inflammation after adjustment. Endothelium-independent vasodilation evaluated by the invasive forearm technique with sodium nitroprusside was also found to be related to both CRP and e-selectin in an inverse way (p=0.005 and p=0.045, respectively). CONCLUSION: Acetylcholine-induced vasodilation in the forearm, but not FMD, was inversely related to CRP and e-selectin levels independently of traditional risk factors in elderly subjects. As also endothelium-independent vasodilation was related to CRP and e-selectin, general vasoreactivity in resistance arteries seems to be effected by low-grade inflammation in elderly subjects.