Sickle erythrocytes increase prostacyclin and endothelin-1 production by cultured human endothelial cells under flow conditions

We investigated the effects of sickle erythrocytes on the production of vasotone mediators in endothelial cells (ECs) using an in vitro recirculating flow system. Sickle erythrocytes increased the EC production of two important vasoactivators, prostacyclin and endothelin-1, under venous wall shear stress conditions of 1dyncm2. The presence of interleukin-1 in the perfusion system, as a model for inflammatory cytokine effects, enhanced the overall amounts of released prostacyclin but did not affect the production of endothelin-1. This study demonstrates the effects of sickle erythrocytes on the function and metabolism of ECs under vascular flow environments. The altered production of vasoactivators may contribute to the vasotone instability and vasoocclusive crises in sickle cell anemia.     

Cytokines in sickle cell disease

Sickle red cells express adhesion molecules including integrin alpha4beta1, CD36, band 3 protein, sulfated glycolipid, Lutheran protein, phosphatidylserine and integrin-associated protein. The proadhesive sickle cells may bind to endothelial cell P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD36 and integrins leading to its activation. Monocytes also activate endothelium by releasing proinflammatory cytokines like tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Sickle monocytes also express increased surface CD11b and cytoplasmic cytokines TNFalpha and IL-1beta indicating activated state. Polymorphonuclear leukocytes (PMNs) are also activated with reduced L-selectin expression, enhanced CD64 expression and elevated levels of sL-selectin, sCD16 and elastase resulting in increased adhesiveness to the endothelium. Platelets are also activated and secrete thrombospondin (TSP) and cytokine IL-1. They also form platelet- monocytes aggregates causing endothelial cell P-selectin expression. Endothelial cell activation by these multiple mechanisms leads to a loss of vascular integrity, expression of leukocyte adhesion molecules, change in the surface phenotype from antithrombotic to prothrombotic, excessive cytokine production and upregulation of HLA molecules. Furthermore, contraction of these activated endothelial cells leads to exposure of extracellular matrix proteins, such as TSP, laminin, and fibronectin and their participation in adhesive interactions with bridging molecules from the plasma such as von Willebrand factor (vWf) released from endothelial cells, ultimately culminating in vasoocclusion and local tissue ischemia, the pathognomonic basis of vasoocclusive crisis.     

Cytokines in Sickle Cell Disease

Sickle red cells express adhesion molecules including integrin ₄β₁, CD36, band 3 protein, sulfated glycolipid, Lutheran protein, phosphatidylserine and integrin-associated protein. The proadhesive sickle cells may bind to endothelial cell P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD36 and integrins leading to its activation. Monocytes also activate endothelium by releasing proinflammatory cytokines like tumor necrosis factor alpha (TNF-) and interleukin 1β (IL-1β). Sickle monocytes also express increased surface CD11b and cytoplasmic cytokines TNF and IL-1β indicating activated state. Polymorphonuclear leukocytes (PMNs) are also activated with reduced L-selectin expression, enhanced CD64 expression and elevated levels of sL-selectin, sCD16 and elastase resulting in increased adhesiveness to the endothelium. Platelets are also activated and secrete thrombospondin (TSP) and cytokine IL-1. They also form platelet- monocytes aggregates causing endothelial cell P-selectin expression. Endothelial cell activation by these multiple mechanisms leads to a loss of vascular integrity, expression of leukocyte adhesion molecules, change in the surface phenotype from antithrombotic to prothrombotic, excessive cytokine production and upregulation of HLA molecules. Furthermore, contraction of these activated endothelial cells leads to exposure of extracellular matrix proteins, such as TSP, laminin, and fibronectin and their participation in adhesive interactions with bridging molecules from the plasma such as von Willebrand factor (vWf) released from endothelial cells, ultimately culminating in vasoocclusion and local tissue ischemia, the pathognomonic basis of vasoocclusive crisis.     

Vascular cell adhesion molecule-1 is involved in mediating hypoxia- induced sickle red blood cell adherence to endothelium: potential role in sickle cell disease

We investigated the effects of hypoxia on red blood cell (RBC)- endothelial cell (EC) adherence and the potential mechanism(s) involved in mediating this effect. We report that hypoxia significantly increased sickle RBC adherence to aortic EC when compared with the normoxia controls. However, hypoxia had no effect on the adherence of normal RBCs. In additional studies, we found that the least dense sickle RBCs containing CD36+ and VLA-4+ reticulocytes were involved in hypoxia-induced adherence. We next evaluated the effects of hypoxia on the expression of EC surface receptors involved in RBC adherence to macrovascular ECs, including vascular cell adhesion molecule-1 (VCAM- 1), intracellular adhesion molecule-1 (ICAM-1), and the vitronectin receptor (VnR). Hypoxia upregulated the expression of both VCAM-1 and ICAM-1, whereas no effect on VnR was noted. Potential involvement of VCAM-1 and ICAM-1 in mediating hypoxia-induced sickle RBC-EC adhesion was next investigated using monoclonal antibodies against these receptors. Whereas anti-VCAM-1 had no effect on basal adherence, it inhibited hypoxia-induced sickle RBC adherence in a concentration- dependent manner, with 50% to 75% inhibition noted at 10 to 60 micrograms/mL antibody (n = 6, P < .05 to P < .01). Anti-ICAM-1 (10 to 60 micrograms/mL, n = 8) had no effect on either basal or hypoxia- induced adherence. As noted in the bovine aortic ECs, hypoxia stimulated the adherence of sickle RBCs to human retinal capillary ECs, and this response appeared to be mediated via mechanisms similar to those observed with macro-endothelium, ie, via the adhesive receptor combination VCAM-1-VLA-4. Our studies show that hypoxia enhances sickle RBC adhesion to both macrovascular and human microvascular ECs via the adhesive receptor VCAM-1. Our findings are of interest because hypoxia is an integral part of the pathophysiology of the vaso-occlusive phenomenon in sickle cell anemia.     

Adhesion of sickle red blood cells and damage to interleukin-1 beta stimulated endothelial cells under flow in vitro

Two factors that are hypothesized to contribute to vasoocclusive crises in sickle cell anemia are increased sickle red blood cell-endothelial cell interactions and damage to endothelium. Despite considerable study, the mechanisms by which erythrocyte-endothelial interactions occur and the role of endothelial damage have not yet been fully elucidated. In this report, we demonstrate that adhesion and damage may be related in a model of vasoocclusion in sickle cell anemia. Phase contrast microscopy coupled to digital image processing was used to determine the adhesion of sickle red blood cells to 1-, 4-, and 24-hour interleukin-I beta (IL-1 beta) stimulated endothelial calls in a parallel plate flow chamber. Morphological alterations to activated endothelial cells after the perfusion of sickle erythrocytes were also identified. Pretreatment of monolayers with 50 pg/mL of IL-1 beta for 1, 4, and 24 hours caused approximately 16-fold increases in adhesion of sickle cells to activated endothelium at all time points. Results with an Arginine-glycine aspartic acid (RGD) peptide and monoclonal antibodies indicated a role for three different endothelial cell receptors: alpha v beta 3 after 1 hour of IL-1 beta stimulation; E- selectin after 4 hours of IL-1 beta stimulation; and vascular cell adhesion molecule-1 after prolonged exposure to cytokines. Perfusion of sickle, but not normal, erythrocytes resulted in alteration of endothelial morphology. Approximately 6% to 8% damage was observed on 4- and 24-hour IL-1 beta stimulated endothelial cells after the perfusion of sickle cells. Damage to 24-hour activated endothelial cells showed a positive correlation (r = .899) with the number of adherent sickle erythrocytes.     

Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality

Endothelial cell adhesion molecules orchestrate the recruitment and binding of inflammatory cells to vascular endothelium. With endothelial dysfunction and vascular injury, the levels of endothelial bound and soluble adhesion molecules increase. Such expression is modulated by nitric oxide (NO), and in patients with sickle cell disease (SCD), these levels are inversely associated with measures of NO bioavailability. To further evaluate the role of endothelial dysfunction in a population study of SCD, we have measured the levels of soluble endothelium-derived adhesion molecules in the plasma specimens of 160 adult patients with SCD during steady state. Consistent with a link between endothelial dysfunction and end-organ disease, we found that higher levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were associated with markers indicating renal dysfunction and hepatic impairment. Analysis of soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin and sP-selectin levels indicated partially overlapping associations with sVCAM-1, with an additional association with inflammatory stress and triglyceride levels. Importantly, increased soluble adhesion molecule expression correlated with severity of pulmonary hypertension, a clinical manifestation of endothelial dysfunction. Soluble VCAM-1, ICAM-1, and E-selectin were independently associated with the risk of mortality in this cohort. Our data are consistent with steady state levels of soluble adhesion molecules as markers of pulmonary hypertension and risk of death.     

Soluble intercelluar adhesion molecule-1, E-selectin, vascular cell adhesion molecule-1 and von Willebrand factor in stroke.

We investigated the role of endothelial cell and leukocyte adhesion in the pathophysiology of acute stroke. The immunocytochemical expression of adhesion molecules in brain tissue from six patients who died following acute ischaemic stroke showed weak endothelial expression of intercellular adhesion molecule-1 (ICAM-1), but intense expression of vascular cell adhesion molecule-1 (VCAM-1) by astrocytes and endothelial cells from the infarcted, but not the non-infarcted areas. We also measured soluble adhesion molecules E-selectin, ICAM-1, VCAM-1 and von Willebrand factor (all by enzyme-linked immunosorbent assay) in 21 patients after an acute ischaemic stroke (ictus < 12 h), and again 3 months later. Blood levels in the stroke patients were compared with 82 healthy controls and 22 subjects with carotid atherosclerosis. Compared with healthy controls, both patient groups had raised levels of von Willebrand factor (P < 0.02) but the level of soluble VCAM-1 was raised only in patients with acute stroke (P < 0.02). Levels of von Willebrand factor and soluble VCAM-1 in the stroke patients were still high at 3 months follow-up. We suggest that there might be changes in adhesion molecule expression and release in the acute and chronic stages of ischaemic stroke, where blood levels are related to immunocytochemical findings on infarcted brain. These changes may perhaps be part of the complex pathophysiological responses to infarction and repair of brain tissue following stroke.     

Intercellular adhesion molecule-1 (ICAM-1) expression is necessary for monocyte adhesion to the placental bed endothelium and is increased in type 1 diabetic human pregnancy

BACKGROUND: That adhesion molecule expression is upregulated in endothelial cells of the placental bed in pregnancies complicated by type 1 diabetes mellitus, and that this is associated with increased adherence of peripheral blood monocytes, which can be reversed by reduction in activity or expression of relevant adhesion molecules. Specific aims were to compare the adherence of monocytes from normal pregnancies to decidual endothelial cells from both normal and diabetic pregnancies, and to examine the involvement of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in regulation of such adhesion. METHODS: We examined adhesion of peripheral blood monocytes (isolated by density gradient centrifugation) of normal third trimester pregnant women, to cultured endothelial cells (isolated from decidual biopsies collected at elective caesarean section) from both normal women and those with type 1 diabetes. Adhesion molecule expression was determined by flow cytometry. The role of ICAM-1 was further investigated by monoclonal antibody-blocking experiments and gene-silencing methodology. RESULTS: There was a significant increase in monocyte adhesion to decidual endothelial cells from diabetic pregnancies, associated with increased endothelial cell expression of ICAM-1, but not VCAM-1. ICAM-1 expression in normal decidual endothelial cells was stimulated by pro-atherogenic and pro-inflammatory stimuli. Following ICAM-1 antibody blockade, monocyte adhesion was decreased by > 70%. ICAM-1 silencing by small interfering RNAs also inhibited monocyte adhesion and ICAM-1 expression. CONCLUSIONS: These findings implicate upregulation of ICAM-1 in decidual endothelial cells in the development of placental bed vascular pathology in diabetic pregnancy.     

No effect of acenocoumarol therapy on levels of endothelial activation markers in sickle cell disease

Sickle cell patients are characterized by a chronic inflammatory and hypercoagulable state, depicted by elevated levels of pro-inflammatory cytokines, endothelial adhesion molecules, and elevated markers of thrombin generation. We set out to determine whether anticoagulation with a coumadin derivative reduces inflammation in sickle cell disease. Therefore, serum levels of NFkappaB-regulated endothelial adhesion molecule soluble vascular cell adhesion molecule-1 and serum levels of non-NFkappaB-dependent markers of endothelial activation (soluble cellular fibronectin and von Willebrand factor antigen) were compared during treatment with acenocoumarol (INR 1.6-2.0) and placebo. No effect on circulating levels of the measured parameters was observed during treatment with acenocoumarol as compared to placebo. In the targeted INR range, anticoagulation of sickle cell patients with acenocoumarol does not seem to reduce endothelial activation.     

Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation.

The recruitment of mononuclear leukocytes and formation of intimal macrophage-rich lesions at specific sites of the arterial tree are key events in atherogenesis. Inducible endothelial cell adhesion molecules may participate in this process. In aortas of normal chow-fed wild-type mice and rabbits, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), but not E-selectin, were expressed by endothelial cells in regions predisposed to atherosclerotic lesion formation. En face confocal microscopy of the mouse ascending aorta and proximal arch demonstrated that VCAM-1 expression was increased on the endothelial cell surface in lesion-prone areas. ICAM-1 expression extended into areas protected from lesion formation. Hypercholesterolemia induced atherosclerotic lesion formation in rabbits, LDL receptor and apolipoprotein E knockout mice, and Northern blot analysis demonstrated increased steady-state mRNA levels of VCAM-1 and ICAM-1, but not of E-selectin. Immunohistochemical staining revealed that VCAM-1 and ICAM-1 were expressed predominantly by endothelium in early lesions and by intimal cells in more advanced lesions. In early and advanced lesions, staining was most intense in endothelial cells at and adjacent to lesion borders. ICAM-1 staining extended into the uninvolved aorta. These expression patterns were highly reproducible in both species. The only difference was that VCAM-1 expression in endothelium over the central portions of lesions was found frequently in rabbits and rarely in mice. The expression of VCAM-1 by arterial endothelium in normal animals may represent a pathogenic mechanism or a phenotypic marker of predisposition to atherogenesis.     

Infection of endothelium with E1(-)E4(+), but not E1(-)E4(-), adenovirus gene transfer vectors enhances leukocyte adhesion and migration by modulation of ICAM-1, VCAM-1, CD34, and chemokine expression

Intravascular introduction of replication-deficient adenoviral vectors (Advectors) provides an ideal model of delivery of transgenes for the treatment of various vascular abnormalities. On the basis of the knowledge that Advectors can induce inflammatory responses after intravascular administration, we speculated that cellular activation by Advector infection could directly modulate the endothelial cell (EC) adhesion molecule/chemokine expression repertoire. Infection of human umbilical vein ECs or bone marrow microvascular ECs with an E1(-)E4(+) Advector resulted in the upregulation of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and CD34, but not E-selectin, P-selectin, CD36, CD13, CD44, HLA-DR or PECAM. Upregulation of ICAM-1, VCAM-1, and CD34 was apparent 12 hours after infection and persisted for weeks after infection. Selective induction of adhesion molecules was mediated by the presence of the E4 gene in the Advector, because infection of ECs with an E1(-)E4(-) Advector had no effect on adhesion molecule expression. ECs infected with E1(-)E4(+) Advector, but not those infected with E1(-)E4(-) Advector, supported the adhesion of leukocytes. Monoclonal antibodies to ICAM-1 and VCAM-1 inhibited adhesion of leukocytes to E1(-)E4(+)-infected ECS: Infection of the ECs with E1(-)E4(+) Advector, but not E1(-)E4(-) Advector, resulted in downregulation of expression of chemocytokines, including interleukin-8, MCP-1, RANTES, and GM-CSF. Nonetheless, a large number of leukocytes migrated through ECs infected with E1(-)E4(+), but not those infected with E1(-)E4(l-), in response to exogenous chemokines. These results demonstrate that infection of ECs with E1(-)E4(+) Advectors, but not E1(-)E4(-) Advectors, may directly augment inflammatory responses by upregulating expression of adhesion molecules and enhancing migration through Advector-infected ECs and suggest that E1(-)E4(-) Advectors may be a better choice for gene-transfer strategies directed to the ECS:     

The effects of dipyridamole stress test on plasma levels of soluble adhesion molecules intracellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin and L-selectin in patients with ischemic heart disease and patients with syndrome X.

BACKGROUND: Adhesion of activated leukocytes to the endothelium as a result of myocardial ischemia/reperfusion has been shown to be involved in the development of tissue injury. Leukocyte adhesion to the endothelium occurs via adhesion molecules expressed on the surface of both cell types. Upon cell activation these proteins may be released into the circulation and measured in a soluble form. AIM: To verify whether the dipyridamole stress test, performed in patients with ischemic heart disease (IHD) and in patients with syndrome X, modifies plasma levels of the soluble adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), E-selectin and L-selectin. METHODS: Plasma levels of the soluble endothelial adhesion molecules ICAM-1, VCAM-1 and E-selectin, as well as of the soluble leukocyte adhesion molecule L-selectin, were measured in venous blood samples taken before and 7 min after administration of dipyridamole in patients with IHD, patients with syndrome X and healthy individuals. Myocardial perfusion was evaluated using single photon emission tomography. The plasma levels of soluble VCAM-1, ICAM-1, E-selectin and L-selectin were all measured using enzyme-linked immunosorbent assays. RESULTS: After infusion of dipyridamole, plasma levels of ICAM-1 increased significantly in patients with IHD, whereas they remained unchanged in patients with syndrome X and in the control group. In patients with IHD, the initial plasma levels of VCAM-1, E-selectin and L-selectin, before administration of dipyridamole, were higher than those observed in patients with syndrome X and than those in the control group. Plasma levels of soluble VCAM-1, E-selectin and L-selectin decreased significantly in patients with IHD following the dipyridamole stress test, whereas they remained unchanged in patients with syndrome X, and in the control group. CONCLUSION: In patients with IHD, administration of dipyridamole induces myocardial ischemia resulting in modification of plasma levels of the soluble adhesion molecules.     

Migration inhibitory factor up-regulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 via Src, PI3 kinase, and NFkappaB

Cell adhesion molecules are critical in monocyte (MN) recruitment in immune-mediated and hematologic diseases. We investigated the novel role of recombinant human migration inhibitory factor (rhMIF) in up-regulating vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and their signaling pathways in human MNs. rhMIF-induced expression of VCAM-1 and ICAM-1 was significantly higher compared with nonstimulated MNs. rhMIF induced MN VCAM-1 and ICAM-1 expression in a concentration-dependent manner (P < .05). Antisense oligodeoxynucleotides (ODNs) and inhibitors of Src, PI3K, p38, and NFkappaB significantly reduced rhMIF-induced MN VCAM-1 and ICAM-1 expression (P < .05). However, Erk1/2 and Jak2 were not involved. Silencing RNA directed against MIF, and inhibitors of Src, PI3K, NFkappaB, anti-VCAM-1, and anti-ICAM-1 significantly inhibited rhMIF-induced adhesion of HL-60 cells to human dermal microvascular endothelial cells (HMVECs) or an endothelial cell line, HMEC-1, in cell adhesion assays, suggesting the functional significance of MIF-induced adhesion molecules (P < .05). rhMIF also activated MN phospho-Src, -Akt, and -NFkappaB in a time-dependent manner. rhMIF induced VCAM-1 and ICAM-1 up-regulation in 12 hours via Src, PI3K, and NFkappaB as shown by Western blotting and immunofluorescence. MIF and MIF-dependent signaling pathways may be a potential target for treating diseases characterized by up-regulation of cell adhesion molecules.     

Alpha 4 beta 1-integrin expression on sickle reticulocytes: vascular cell adhesion molecule-1-dependent binding to endothelium

Important complications in sickle cell anemia occur secondary to vascular occlusion, which is postulated to be initiated by interactions of erythrocytes with vascular endothelial cells. In patients with sickle cell anemia, up to 25% of reticulocytes express the alpha 4 beta 1-integrin complex. Furthermore, erythrocytes from patients with sickle cell anemia bind to endothelial cells activated by tumor necrosis factor alpha via (TNF alpha) via interactions between erythrocyte alpha 4 beta 1 and endothelial cell vascular cell adhesion molecule-1 (VCAM- 1). Thus, binding of alpha 4 beta 1-expressing reticulocytes to cytokine-activated endothelial cells may initiate vascular complications in sickle cell anemia and perhaps other hemolytic anemias during episodes of infection and inflammation.     

Interferon-gamma and interleukin-4 differentially regulate ICAM-1 and VCAM-1 expression on human lung fibroblasts.

The expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and more specifically vascular adhesion molecule-1 (VCAM-1) on lung fibroblasts may be important for migration of inflammatory cells through the submucosa to the airway lumen in the asthmatic inflammatory response. This study aimed to assess which cytokines are regulating ICAM-1 and VCAM-1 expression on human lung fibroblasts. For this purpose, confluent fibroblast cultures (derived from lung tissue from a nonasthmatic donor) were stimulated for 4 h with interleukin (IL)-1beta, tumour necrosis factor (TNF)alpha, interferon (IFN)gamma, IL-4, IL-5 or transforming growth factor (TGF)beta. IL-1beta (optimal concentration (OC) 1 U x mL(-1)) and TNFalpha (OC 100 U x mL(-1)) both increased ICAM-1 and VCAM-1 expression. IFNgamma (OC 2 U x mL(-1)) increased only ICAM-1 expression and IL-4 (OC 5 ng x mL(-1)) increased only VCAM-1 expression, whereas IL-5 (20 ng x mL(-1)) and TGFbeta (10 ng x mL(-1)) did not influence ICAM-1 or VCAM-1 expression. ICAM-1 expression reached a plateau at 8-12 h after cytokine stimulation and remained constant for at least 24 h. VCAM-1 showed a transient increased expression within 24 h after IL-1beta and TNFalpha stimulation. In contrast, VCAM-1 expression did not decrease after maximal expression at 4 h upon IL-4 stimulation. It is concluded that the Helper-1T-cell, type cytokine interferon gamma and the Helper-2 T-cell type cytokine interleukin-4 differentially regulate intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression on human lung fibroblasts. The proinflammatory cytokines interleukin-1beta and tumour necrosis factor alpha increase both intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, without differential regulation of the expression of these adhesion molecules.     

胰高血糖素样肽1受体激动剂对高糖诱导的血管内皮细胞NF-κB、ICAM-1和VCAM-1表达的影响

目的观察胰高血糖素样肽1受体激动剂艾塞那肽对高糖诱导的人脐静脉内皮细胞核因子κB(NF-κB)活性及细胞间黏附分子1(ICAM-1)、血管细胞黏附分子1(VCAM-1)表达的影响,探讨胰高血糖素样肽1受体激动剂降糖外对改善糖尿病患者血管内皮损伤的作用及其可能的机制。方法体外培养人脐静脉内皮细胞,以不同浓度艾塞那肽和高糖共同孵育48 h,应用酶联免疫吸附法检测细胞培养上清液中ICAM-1和VCAM-1浓度,应用逆转录聚合酶链反应测定NF-κB p65、ICAM-1和VCAM-1的mRNA表达。结果与正常对照组比较,高糖组NF-κB p65、ICAM-1和VCAM-1的表达显著升高(P<0.01)。艾塞那肽干预后,NF-κB p65、ICAM-1及VCAM-1的表达较高糖组显著降低(P<0.01),并呈剂量依赖性。结论艾塞那肽可能通过抑制高糖环境下NF-κB活性影响其下游黏附分子ICAM-1和VCAM-1的高表达,由此稳定血管内皮环境,减轻高糖引起的内皮细胞损伤,有助于延缓糖尿病动脉粥样硬化病程。     

Angiopoietin-1 reduces VEGF-stimulated leukocyte adhesion to endothelial cells by reducing ICAM-1, VCAM-1, and E-selectin expression

Vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) are potent vasculogenic and angiogenic factors that hold promise as a means to produce therapeutic vascularization and angiogenesis. However, VEGF also acts as a proinflammatory cytokine by inducing adhesion molecules that bind leukocytes to endothelial cells, an initial and essential step toward inflammation. In the present study, we used human umbilical vascular endothelial cells (HUVECs) to examine the effect of Ang1 on VEGF-induced expression of three adhesion molecules: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Interestingly, Ang1 suppressed VEGF-induced expression of these adhesion molecules. Furthermore, Ang1 reduced VEGF-induced leukocyte adhesion to HUVECs. These results demonstrate that Ang1 counteracts VEGF-induced inflammation by reducing VEGF-induced endothelial adhesiveness.