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Results for “Endothelialization”

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At least 235 records · Page 13Linked to original sources

PubMed2005

Monocyte-induced endothelial calcium signaling mediates early xenogeneic endothelial activation.

Hallmarks of delayed xenograft rejection include monocyte infiltration, endothelial cell activation and disruption of the endothelial barrier. The monocyte is an important initiator of this type of rejection because monocytes accumulate within hours after xenografting and prior monocyte depletion suppresses the development of this type of rejection. However, the mechanisms that mediate monocyte-induced xenograft injury are unclear at present. Here we report that human monocytes activate xenogeneic endothelial cells through calcium signals. Monocyte contact with porcine but not human endothelium leads to an endothelial calcium transient mediated via a G-protein-coupled receptor (GPCR) that results in up-regulation of porcine VCAM-1 and E-selectin. Although human monocyte adhesion was greater to porcine than to human endothelium, especially when studied under laminar flow, blockade of the xeno-specific endothelial calcium signals did not reduce adhesion of human monocytes to porcine endothelium. Human monocyte contact to porcine endothelium also resulted in reorganization of the F-actin cytoskeleton with a concomitant increase in endothelial monolayer permeability. In contrast to the effect on adhesion, these changes appear to be regulated through endothelial calcium signals. Taken together, these data suggest that human monocytes are capable of activating xenogeneic endothelial cells through calcium transients, as well as other distinct pathways.

Animals↗

PubMedDate not supplied

Inhibition of endothelial cell regrowth. Cessation of aortic endothelial cell replication after balloon catheter denudation.

Aortas of male rabbits (2.0 to 2.5 kg body weight) were denuded of endothelium with a 4F balloon catheter and killed 7, 14, 60, 90, and 180 days later. Aortic endothelial cells regrowth was determined using Evans blue dye and scanning electron microscopy. Early endothelial outgrowth was rapid, but by 14 days the regrowth slowed markedly so that no further increase of endothelial outgrowth was detected at other time periods. Another group of animals received 3H-thymidine 1 hour before death and were killed 4, 14, and 42 days later. The endothelial cells replication in the aortas of these animals was measured from Häutchen preparations. Endothelial cells replication was observed 4 days after balloon injury but was markedly reduced by 14 and 42 days. Intimal smooth muscle cell replication, however, was observed at both these later times. These result demonstrate that in vivo endothelial cells replication stops long before the aorta is repopulated and suggest that some mechanism other than contact between endothelial cells can prevent endothelial cell replication.

Animals↗

PubMed1996

Identification of authentic estrogen receptor in cultured endothelial cells. A potential mechanism for steroid hormone regulation of endothelial function.

BACKGROUND: Estrogen plays a major role in the delayed expression of coronary heart disease (CHD) in women, and recent data indicate that postmenopausal estrogen therapy reduces the incidence of CHD by > 40%. The mechanism or mechanisms through which estrogen exerts this benefit are unknown, although effects on blood pressure, carbohydrate and lipid metabolism, and coagulation have been suggested. We hypothesized that at least part of the effect of estrogen in reducing the incidence of CHD is due to an effect on endothelial cell function. METHODS AND RESULTS: In the present study, we examined human aortic and umbilical vein endothelial cells and bovine aortic endothelial cells for the presence of estrogen receptors (ERs) through immunoblot and mRNA analyses. Electrophoretic mobility shift assays were also performed to determine the DNA-binding properties of the putative ERs. Nuclear extracts from all three endothelial cell types were found to contain a 67-kD protein that reacted with anti-ER monoclonal antibodies specific to different domains of the ERs. Each of these types of cells expresses proteins that bind specifically to consensus estrogen-responsive elements. Finally, Northern blots verified that endothelial cells express abundant amount of mRNA for the ER. CONCLUSIONS: These data indicate that endothelial cells constitutively possess the potential for transcriptional regulation of target genes by estrogen. The evolutionary conservation of this receptor in bovine and human endothelial cells suggests a common mechanism for estrogen regulation of endothelial function.

Animals↗

PubMed2000

Origins of circulating endothelial cells and endothelial outgrowth from blood.

Normal adults have a small number of circulating endothelial cells (CEC) in peripheral blood, and endothelial outgrowth has been observed from cultures of blood. In this study we seek insight into the origins of CEC and endothelial outgrowth from cultures of blood. Fluorescence in situ hybridization analysis of blood samples from bone marrow transplant recipients who had received gender-mismatched transplants 5-20 months earlier showed that most CEC in fresh blood had recipient genotype. Endothelial outgrowth from the same blood samples after 9 days in culture (5-fold expansion) was still predominantly of the recipient genotype. In contrast, endothelial outgrowth after approximately 1 month (102-fold expansion) was mostly of donor genotype. Thus, recipient-genotype endothelial cells expanded only approximately 20-fold over this period, whereas donor-genotype endothelial cells expanded approximately 1000-fold. These data suggest that most CEC in fresh blood originate from vessel walls and have limited growth capability. Conversely, the data indicate that outgrowth of endothelial cells from cultures of blood is mostly derived from transplantable marrow-derived cells. Because these cells have more delayed outgrowth but a greater proliferative rate, our data suggest that they are derived from circulating angioblasts.

Adult↗

PubMed2001

The chemokine receptor CCR8 mediates human endothelial cell chemotaxis induced by I-309 and Kaposi sarcoma herpesvirus-encoded vMIP-I and by lipoprotein(a)-stimulated endothelial cell conditioned medium.

The CC chemokine receptor 8 (CCR8) is expressed on monocytes and type 2 T lymphocytes. CCR8 is the sole receptor for the human CC chemokine I-309, as well as for viral monocyte inflammatory protein-I (vMIP-I), a human chemokine homologue induced in human cells by the Kaposi sarcoma-related human herpesvirus-8. Recently it was found that I-309 messenger RNA and protein are expressed by human umbilical vein endothelial cells (HUVECs) and that the secretion of endothelial I-309 is stimulated by apolipoprotein(a). I-309, vMIP-I, and the conditioned medium from apolipoprotein(a)-stimulated HUVECs induce endothelial chemotaxis. A polyclonal anti-CCR8 antibody and a newly developed murine monoclonal antibody against CCR8 inhibited this activity. The G-protein inhibitor pertussis toxin also inhibited endothelial chemotaxis, providing further evidence for a chemokine receptor-mediated effect. Endothelial cells contain CCR8 mRNA as shown by RNA blot analysis as well by direct sequence analysis. Immunohistochemical studies identified CCR8 and I-309 on the endothelium of human atherosclerotic plaques and in endothelial-derived spindle cells of Kaposi sarcoma. These results indicate that CCR8 is an endothelial receptor that may modulate endothelial function.

Antibodies↗

PubMed1998

Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration.

We studied endothelial-mediated microvascular blood flow in neuropathic diabetic patients to determine the association between endothelial regulation of the microcirculation and the expression of endothelial constitutive nitric oxide synthetase (ecNOS) in the skin. Vasodilation on the dorsal foot in response to heating and iontophoresis of acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) were measured using single-point laser Doppler and laser Doppler imaging in diabetic patients with neuropathy (DN), with neuropathy and vascular disease (DI), with Charcot arthropathy (DA), and without complications (D), and in healthy control subjects (C). The response to heat was reduced in the DN (321 [21-629] percentage of increase over the baseline, median [interquartile range]) and DI (225 [122-470]) groups but was preserved in the DA (895 [359-1,229]), D (699 [466-1,029]), and C (810 [440-1,064], P < 0.0001) groups. The endothelial-mediated response to acetylcholine was reduced in the DN (17 [11-25]), DA (22 [2-34]), and DI (13 [2-30]) groups compared with the D (47 [24-58]) and C (44 [31-70], P < 0.001) groups. The non-endothelial-mediated response to sodium nitroprusside was also reduced in the DI (4 [0-18]), DN (17 [9-26]), and DA (21 [11-31]) groups compared with the D (37 [19-41]) and C (44 [26-67], P < 0.0001) groups. There was a significant reduction in vasodilation in the DI group compared with all other groups (P < 0.0001). Full thickness skin biopsies from the dorsum of the foot of 15 DN, 10 DI, and 11 C study subjects were immunostained with antiserum to human ecNOS, the functional endothelial marker GLUT1, and the anatomical endothelial marker von Willebrand factor. The staining intensity of ecNOS was reduced in both diabetic groups. No differences were found among the three groups in the staining intensity of von Willebrand factor and GLUT1. We conclude that the endothelium-dependent and endothelium-independent vasodilations are impaired in diabetic patients predisposed to foot ulceration and that neuropathy is the main factor associated with this abnormality. Reduced expression of ecNOS may be a major contributing factor for endothelial dysfunction. These data provide support for a close association of neuropathy and microcirculation in the pathogenesis of foot ulceration.

Acetylcholine↗

PubMed1999

[Pre-eclampsia--endothelial damage of endothelial activation?].

There is considerable evidence that endothelial damage, followed by the release of vasoactive substances contributes to the pathophysiology of preeclampsia. Because of controversial experiences in literature we wanted to evaluate the potential cytotoxic effect of preeclamptic sera on cultured endothelial cells. Therefore cultured human umbilical vein endothelial cells (HUVEC) were stimulated with sera obtained from preeclamptic patients, while sera from normotensive pregnant and nonpregnant women served as controls. To prove the viability of these cells we performed ethidiumbromide/acridinorange immunostaining and determined t-PA/PAI-1 release into the supernatant. These experiments could not show any cytotoxic effect on endothelial cells. In ongoing studies we measured the concentrations of adhesion molecules, markers of endothelial activation, in maternal sera, in the supernatant of cultured endothelial cells, and on cell surface after stimulation with the above mentioned sera. In the supernatant we couldn't determine any different concentrations of adhesion molecules after stimulation with the different sera, but using immunofluorescence-microscopy an increased concentration of those molecules could be detected on the endothelial surface after stimulation with preeclamptic sera than compared to sera from normotensive controls. In conclusion, our experiments support the hypothesis that sera from preeclamptic women may cause endothelial activation.

Cell Adhesion Molecules↗

PubMed2001

Individuals with cystic fibrosis do not display impaired endothelial function or evidence of oxidative damage in endothelial cells exposed to serum.

Heightened systemic oxidative stress is increasingly recognized as a feature of cystic fibrosis (CF). The consequences of long-term exposure to free radical attack include a predisposition to diseases such as cancer and atherosclerosis. An increased incidence of malignancy among adult patients with CF has been reported, but the absence of atherosclerotic disease is well described. The aim of the present study was to assess endothelial function in vivo and relate this to the potential of serum from patients with CF to induce oxidative-mediated damage in cultured human endothelial cells. A group of 11 CF patients was matched with a group of healthy volunteers with regard to age and sex. Endothelial function was assessed as endothelium-dependent and -independent vasodilation by measuring forearm blood flow in response to infused acetylcholine and sodium nitroprusside respectively. Confluent monolayers of cultured human endothelial cells were exposed to serum from CF patients and control subjects. Following exposure, cell death was assessed by lactate dehydrogenase release, and the degree of lipid peroxidation in the membrane was assessed by measuring the content of lipid hydroperoxides, malondialdehyde and 4-hydroxynonenal. Endothelial monolayers exposed to serum from CF patients released significantly less lactate dehydrogenase following exposure than those exposed to serum from healthy controls (1.8% and 3.0% respectively; mean difference -1.2%; 95% confidence intervals -1.9% to -0.1%; P<0.05) and contained significantly less 4-hydroxynonenal (0.75 and 3.41 micromol/g of protein respectively; mean difference -2.66 micromol/g; 95% confidence intervals -5.10 to -0.22 micromol/g; P<0.05). There was no significant difference between patients and controls in the extent of serum-induced membrane peroxidation, as assessed by malondialdehyde or lipid hydroperoxides, or in endothelial function, as assessed by forearm blood flow. In conclusion, despite evidence for heightened systemic oxidative stress in CF, patients displayed no impairment of endothelial function, and their serum caused significantly less damage to human endothelial cells than that from matched controls.

Adolescent↗

PubMed1990

Ability of human T lymphocytes to adhere to vascular endothelial cells and to augment endothelial permeability to macromolecules is linked to their state of post-thymic maturation.

The accumulation of mononuclear cells at sites of chronic inflammation is dependent on a number of factors including localized adherence of lymphocytes to vascular endothelial cells (EC), cytokine-mediated increased adhesiveness of endothelium, chemotactic factors and endothelial permeability. The present study investigates two of the above attributes of lymphocyte-EC interaction: namely, the ability of maturationally distinct subpopulations of human T lymphocytes to adhere to vascular EC and to increase vascular endothelial permeability to macromolecules in an in vitro model. Thus, human T lymphocytes were separated into CD4+ CD8-helper/inducer, CD4- CD8+ cytotoxic/suppressor, CD29+ CD45RA- CD45RO+ memory, and CD29- CD45RA+ CD45RO- naive/virgin T subpopulations, were activated with PHA and PMA, and then examined for their adherence to EC and also for their effect on endothelial permeability. Upon activation, cells within each of the above four subpopulations exhibited increased adherence to EC. In contrast, resting CD29+ CD45RA- CD45RO+ memory T lymphocytes exhibited two to three times greater ability to adhere to EC than their CD29- CD45RA+ CD45RO- naive/virgin counterparts. Consistent with their increased adherence to EC, CD29+ CD45RO+ memory T lymphocytes, when activated, significantly increased endothelial permeability to albumin. Although activated CD45RA+ naive T lymphocytes exhibited increased adherence to EC, these cells failed to increase significantly endothelial permeability. Similar to their polyclonal counterparts, Ag-specific CD4+ CD29+ CD45RO+ T cell clones, but not their actively released mediators, also increased endothelial permeability via a noncytolytic mechanism(s). This ability of CD29+ CD45RO+ memory T lymphocytes to augment endothelial permeability may facilitate their transendothelial migration into extravascular space. These observations may provide additional insights into molecular mechanism(s) underlying pathophysiology of localized chronic inflammatory responses in general and more specifically selective accumulation of CD29+/CD45RO+ memory T lymphocytes at sites of chronic inflammation such as rheumatoid synovium.

Antigens, CD↗

PubMed1985

Effects of fibroblastic and endothelial extracellular matrices on corneal endothelial cells.

Extracellular matrices (ECM) isolated from chick embryo fibroblast and human and rabbit corneal stromal cells induce polarization and elongation of corneal endothelial cells in culture. ECM isolated from rabbit corneal or bovine aortic endothelial cells neither polarize nor elongate corneal endothelial cells in culture. By indirect immunofluorescence, fibronectin is seen as arrays of long fibers in fibroblastic ECM, whereas in endothelial ECM, fibronectin is found in discreet foci as short fibers. The morphology corneal endothelial cells in culture is associated with the structure of the ECM laid down; short fibers in clusters associated with a typical polygonal shape, long polarized fibers inducing a fibroblastic-like appearance. ECM isolated from both fibroblastic or endothelial sources promote cell growth. Since coating the plastic with plasma fibronectin or denatured collagen does not promote endothelial cell growth, the authors assume the polymerized fibronectin network or a component bound to this network enhances the growth of corneal endothelial cells cultured in the presence of serum.

Animals↗

PubMed1985

Effects of chemotherapeutic drugs on platelet and metastatic tumor cell-endothelial cell interactions as a model for assessing vascular endothelial integrity.

An in vitro assay for examining the sublethal effects of chemotherapeutic agents on vascular endothelial integrity is described. Using vascular endothelial cell monolayers, the kinetics of binding of radiolabeled platelets or metastatic tumor cells were altered when endothelial cells were pretreated for 2 hr with low, clinically relevant concentrations of certain drugs. Electron microscopic examination by scanning electron microscopy revealed that these same drugs caused endothelial cell retraction and exposure of subendothelial matrix. Platelets and tumor cells were found bound only to the exposed areas of subendothelial matrix. Some drugs (bleomycin, 1,3-bis(2-chloroethyl)-1-nitrosourea, vincristine) induced rapid endothelial cell retraction and increased platelet and tumor cell binding to exposed subendothelial matrix, while one of the drugs tested (Adriamycin) caused delayed (1 to 3 days after a 2-hr drug treatment) endothelial cell retraction and increased cell binding. Of the drugs tested, only 5'-fluoro-2'-deoxyuridine which interferes with DNA replication failed to induce endothelial cell retraction and increased tumor cell and platelet binding. The results suggest that certain drug effects on the vascular endothelium can be assessed using the vascular endothelial cell monolayer model.

Animals↗

PubMed1996

Towards endothelial-cell-directed cancer immunotherapy: in vitro expression of human recombinant cytokine genes by human and mouse primary endothelial cells.

Recent studies have demonstrated the feasibility of cytokine gene transfer to enhance the antitumor activities of host immune cells. Endothelial cells forming the vascular supply of tumors may be useful vehicles for the delivery of cytokine molecules in order to effect tumor immunotherapy. In order to determine whether primary endothelial cells can express cytokine transgenes efficiently, we constructed two retroviral vectors containing a cDNA encoding either recombinant human interleukin-1 alpha (rhIL-1 alpha) or recombinant human interleukin-2 (rhIL-2), called LNCIL-1 alpha and LNCIL-2 respectively, and studied the expression of the two cytokines in vitro in non-immortalized endothelial cells. Human umbilical vein endothelial cells (HUVEC) transduced with LNCIL-1 alpha or LNCIL-2 secreted 1.8-33 ng/10(6) cells/24 h and 40-246.7 ng/10(6) cells/24 h of biological active rhIL-1 alpha and rhIL-2 respectively. Mouse microvascular endothelial cells (MMEC) transduced with LNCIL-1 alpha and LNCIL-2 secreted 1.5 ng/10(6) cells/24 h and 5.8-24.7 ng/10(6) of biologically active rhIL-1 alpha and rhIL-2 proteins respectively. Cocultivation of HUVEC/IL-2 and MMEC/IL-2 with normal human bone marrow cells generated potent cytotoxic activity against K562, Daudi and other cell targets in a 51Cr-release assay. While IL-2 transgene-expressing HUVEC and MMEC retained their normal morphology, rhIL-1 alpha transgene expression inhibited the growth and altered the morphology of both HUVEC and MMEC in culture. The cytokine-gene-transduced endothelial cells retained other endothelial cell features, including uptake of acetylated low-density lipoprotein (Ac-LDL) and expression of von Willebrand factor, and were euploid as shown by flow cytometry. These results demonstrate that endothelial cells, by sustaining the production of biologically active rhIL-2 at levels that are sufficient for the activation of potent cytotoxic lymphocyte activity, may be useful agents for cancer gene therapy.

Animals↗

PubMed1998

Vascular endothelial growth factor (VEGF)-C synergizes with basic fibroblast growth factor and VEGF in the induction of angiogenesis in vitro and alters endothelial cell extracellular proteolytic activity.

Vascular endothelial growth factor-C (VEGF-C) is a recently characterized member of the VEGF family of angiogenic polypeptides. We demonstrate here that VEGF-C is angiogenic in vitro when added to bovine aortic or lymphatic endothelial (BAE and BLE) cells but has little or no effect on bovine microvascular endothelial (BME) cells. As reported previously for VEGF, VEGF-C and basic fibroblast growth factor (bFGF) induced a synergistic in vitro angiogenic response in all three cells lines. Unexpectedly, VEGF and VEGF-C also synergized in the in vitro angiogenic response when assessed on BAE cells. Characterization of VEGF receptor (VEGFR) expression revealed that BME, BAE, and BLE cell lines express VEGFR-1 and -2, whereas of the three cell lines assessed, only BAE cells express VEGFR-3. We also demonstrate that VEGF-C increases plasminogen activator (PA) activity in the three bovine endothelial cell lines and that this is accompanied by a concomitant increase in PA inhibitor-1. Addition of alpha2-antiplasmin to BME cells co-treated with bFGF and VEGF-C partially inhibited collagen gel invasion. These results demonstrate, first, that by acting in concert with bFGF or VEGF, VEGF-C has a potent synergistic effect on the induction of angiogenesis in vitro and, second, that like VEGF and bFGF, VEGF-C is capable of altering endothelial cell extracellular proteolytic activity. These observations also highlight the notion of context, i.e., that the activity of an angiogenesis-regulating cytokine depends on the presence and concentration of other cytokines in the pericellular environment of the responding endothelial cell.

Amino Acid Sequence↗

PubMed1998

Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation.

Vascular endothelial growth factor (VEGF) has been found to have various functions on endothelial cells, the most prominent of which is the induction of proliferation and differentiation. In this report we demonstrate that VEGF or a mutant, selectively binding to the Flk-1/KDR receptor, displayed high levels of survival activity, whereas Flt-1-specific ligands failed to promote survival of serum-starved primary human endothelial cells. This activity was blocked by the phosphatidylinositol 3'-kinase (PI3-kinase)-specific inhibitors wortmannin and LY294002. Endothelial cells cultured in the presence of VEGF and the Flk-1/KDR-selective VEGF mutant induced phosphorylation of the serine-threonine kinase Akt in a PI3-kinase-dependent manner. Akt activation was not detected in response to stimulation with placenta growth factor or an Flt-1-selective VEGF mutant. Furthermore, a constitutively active Akt was sufficient to promote survival of serum-starved endothelial cells in transient transfection experiments. In contrast, overexpression of a dominant-negative form of Akt blocked the survival effect of VEGF. These findings identify the Flk-1/KDR receptor and the PI3-kinase/Akt signal transduction pathway as crucial elements in the processes leading to endothelial cell survival induced by VEGF. Inhibition of apoptosis may represent a major aspect of the regulatory activity of VEGF on the vascular endothelium.

Amino Acid Chloromethyl Ketones↗

PubMed2005

Glycogen-Synthase Kinase3beta/beta-catenin axis promotes angiogenesis through activation of vascular endothelial growth factor signaling in endothelial cells.

Glycogen-Synthase Kinase 3beta (GSK3beta) has been shown to function as a nodal point of converging signaling pathways in endothelial cells to regulate vessel growth, but the signaling mechanisms downstream from GSK3beta have not been identified. Here, we show that beta-catenin is an important downstream target for GSK3beta action in angiogenesis and dissect the signal transduction pathways involved in the angiogenic phenotype. Transduction of human umbilical vein endothelial cells (HUVECs) with a kinase-mutant form of the enzyme (KM-GSK3beta) increased cytosolic beta-catenin levels, whereas constitutively active GSK3beta (S9A-GSK3beta) reduced beta-catenin levels. Lymphoid enhancer factor/T-cell factor promoter activity was upregulated by KM-GSK3beta and diminished by S9A-GSK3beta, whereas manipulation of Akt signaling had no effect on this parameter. beta-Catenin transduction induced capillary formation in a Matrigel-plug assay in vivo and promoted endothelial cell differentiation into network structures on Matrigel-coated plates in vitro. beta-Catenin activated the expression of vascular endothelial growth factor (VEGF)-A and VEGF-C in endothelial cells, and these effects were mediated at the levels of protein, mRNA, and promoter activity. Consistent with these data, beta-catenin increased the phosphorylation of the VEGF receptor 2 (VEGF-R2) and promoted its association with PI3-kinase, leading to a dose-dependent activation of the serine-threonine kinase Akt. Inhibition of PI3-kinase or Akt signaling led to a significant reduction in the pro-angiogenic activity of beta-catenin. Collectively, these data show that the growth factor-PI3-kinase-Akt axis functions downstream of GSK3beta/beta-catenin signaling in endothelial cells to promote angiogenesis.

Animals↗

PubMed1994

A new communication system between hepatocytes and sinusoidal endothelial cells in liver through vascular endothelial growth factor and Flt tyrosine kinase receptor family (Flt-1 and KDR/Flk-1).

Hepatocyte Growth Factor (HGF)/Scatter Factor secreted from sinusoidal endothelial cells and Kupffer cells in liver activates the c-Met tyrosine kinase receptor expressed on hepatocytes. Here we report yet another possible communication system through a different ligand and tyrosine kinase receptor in an opposite direction. We isolated and determined the primary structure of the entire coding region of rat flt-1 (fms-like tyrosine kinase), a receptor for Vascular Endothelial Growth Factor (VEGF). Using rat flt-1 cDNA as a probe we found that the flt-1 mRNA was expressed at very high levels in sinusoidal endothelial cells in normal rat liver, but was hardly detectable in hepatocytes. The transcripts of another VEGF receptor KDR/Flk-1 structurally related to Flt-1 was also expressed specifically in sinusoidal endothelial cells. On the other hand, VEGF mRNA was expressed weakly in hepatocytes, but not in the nonparenchymal cell fraction. Furthermore, in an in vitro culture system, VEGF demonstrated a remarkably specific growth-stimulatory activity as well as maintenance activity on the sinusoidal endothelial cells. These results suggest that hepatocytes regulate the proliferation and survival of the sinusoidal endothelial cells in liver in a paracrine manner. Therefore two reciprocal communication systems, VEGF-Flt receptor family and HGF-Met receptor, may exist in hepatic tissue.

Amino Acid Sequence↗

PubMed2005

Soluble vascular endothelial growth factor, soluble VEGF receptor Flt-1 and endothelial function in healthy smokers.

OBJECTIVE: To relate levels of vascular endothelial growth factor (VEGF) and its soluble receptor, sFlt-1, with endothelial function in healthy smokers. METHODS: Plasma levels of VEGF and sFlt-1 were measured by ELISA in 22 healthy smokers and 22 matched healthy non-smoking controls, and compared to flow- (FMD) and acetylcholine-mediated (AMD) vasodilatation (endothelial-dependent) (EDV) and nitroglycerine-mediated (NMD) vasodilatation (endothelial-independent) of lower extremities were measured with plethysmography. RESULTS: Smokers and controls had similar plasma VEGF levels, but sFlt-1 levels were lower in smokers than in controls (p<0.01). AMD was lower in smokers compared to controls (p<0.05), but FMD and NMD levels were similar. Smokers and controls with high AMD (>12 ml/100 ml tissue/min) had significantly lower plasma VEGF levels (p<0.001). An inverse correlation was found in both groups, between VEGF and AMD (smokers: r=-0.6, p<0.01; controls: r=-0.71, p<0.005) and with FMD (smokers: r=-0.56, p<0.05; controls: r=-0.58, p<0.005). There were no significant correlations between sFlt-1 with VEGF levels or endothelial-dependent dilatation. CONCLUSION: In conclusion, healthy smokers demonstrate abnormal AMD, and an inverse correlation between plasma VEGF levels (but not sFlt-1) with indices of endothelial dysfunction (FMD and AMD) exists. VEGF, and not sFlt-1, may be related to the pathogenesis of endothelial dysfunction in healthy smoking individuals.

Adult↗

PubMed1998

Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C.

Vascular endothelial growth factor (VEGF) is a prime regulator of normal and pathological angiogenesis. Three related endothelial cell growth factors, VEGF-B, VEGF-C, and VEGF-D were recently cloned. We have here studied the regulation of VEGF-C, a lymphatic endothelial growth factor, by angiogenic proinflammatory cytokines. Interleukin (IL)-1beta induced a concentration- and a time-dependent increase in VEGF-C, but not in VEGF-B, mRNA steady-state levels in human lung fibroblasts. The increase in VEGF-C mRNA levels was mainly due to increased transcription rather than elevated mRNA stability as detected by the nuclear run-on method and by following mRNA decay in the presence of an inhibitor of transcription, respectively. In contrast, angiopoietin-1 mRNA, encoding the ligand for the endothelial-specific Tek/Tie-2 receptor, was down-regulated by IL-1beta. Tumor necrosis factor-alpha and IL-1alpha also elevated VEGF-C mRNA steady-state levels, whereas the IL-1 receptor antagonist and dexamethasone inhibited the effect of IL-1beta. Experiments with cycloheximide indicated that the effect of IL-1beta was independent of protein synthesis. Hypoxia, which is an important inducer of VEGF expression, had no effect on VEGF-B or VEGF-C mRNA levels. IL-1beta and tumor necrosis factor-alpha also stimulated the production of VEGF-C protein by the fibroblasts. Cytokines and growth factors have previously been shown to down-regulate VEGF receptors in vascular endothelial cells. We found that the mRNA for the VEGF- and VEGF-C-binding VEGFR-2 (KDR/Flk-1) was stimulated by IL-1beta in human umbilical vein endothelial cells, whereas the mRNA levels of VEGFR-1 (Flt-1) and VEGFR-3 (Flt-4) were not altered. Our data suggest that in addition to VEGF, VEGF-C may also serve as an endothelial stimulus at sites of cytokine activation. In particular, these results raise the possibility that certain proinflammatory cytokines regulate the lymphatic vessels indirectly via VEGF-C.

Cell Hypoxia↗