Background The vascular wall participates in the pathogenesisof sickle cell disease. To determine whether the endotheliumis activated in this disease, we studied the number, origin,and surface phenotype of circulating endothelial cells in patientswith sickle cell anemia.
Methods We used immunohistochemical examination of buffy-coatsmears to enumerate circulating endothelial cells, and we evaluatedthe surface phenotype by applying immunofluorescence microscopyto preparations of circulating endothelial cells. A panel ofantibodies was used, including a specific anti–endothelial-cellantibody, P1H12.
Results Mean (±SD) numbers of circulating endothelialcells in normal blood donors, patients with sickle cell trait,and patients with hemolytic anemias not due to hemoglobin Swere 2.6±1.6, 3.0±2.6, and 2.0±0.8 permilliliter of whole blood, respectively. Patients with sicklecell anemia who presented with acute painful episodes had 22.8±18.2circulating endothelial cells per milliliter of blood (P<0.001for the comparison with normal donors), and patients with nosuch events within one month before or after blood samplinghad 13.2±11.8 circulating endothelial cells per milliliterof blood (P = 0.002 for the comparison with normal donors andP = 0.019 for the comparison with patients with acute events).Serial observations of three patients showed a tendency towardhigher levels of circulating endothelial cells at the onsetof acute painful crises. The average viability of circulatingendothelial cells was 66±30 percent. In patients withsickle cell anemia, regardless of clinical status, the circulatingendothelial cells were predominantly microvascular in origin(CD36-positive), and most of the cells expressed four markersof endothelial-cell activation: intercellular adhesion molecule1, vascular-cell adhesion molecule 1, E-selectin, and P-selectin.
Conclusions Our studies suggest that the vascular endotheliumis activated in patients with sickle cell anemia, regardlessof the patients' clinical status. Adhesion proteins on activatedendothelial cells may have a role in the vascular pathologyof sickle cell disease.
The endothelial cell participates in numerous functions of vascularphysiology.1,2,3,4,5 Many factors, such as cytokines, can alterthe surface of the endothelial cell and thereby modulate therole of the endothelium in coagulation, inflammation, vaso-regulation,and adhesion.5,6,7 The endothelial cell may also have a keyrole in the vascular pathology of sickle cell anemia,5 includingthe vaso-occlusions that cause acute painful crises. However,research in this area has been hindered by the inaccessibilityof vascular endothelium in patients. Circulating endothelialcells might provide useful material for the study of this problem.In previous investigations increased numbers of circulatingendothelial cells have been found in sickle cell anemia8,9 andother conditions with vascular injury, such as that due to cytomegalovirusinfection,10,11 rickettsial infection,12,13 myocardial infarction,14,15intravascular instrumentation,16,17 and endotoxinemia.18 Becauseindirect evidence suggests perturbation and activation of vascular-wallendothelium in sickle cell disease,5 we examined the viability,origin, and surface phenotype of circulating endothelial cellsin patients with this disease.
Methods
Subjects and Blood Collection
Blood donors were volunteers, as approved by the human-subjectsreview boards of the participating institutions. Adults gaveinformed consent; for minors, the consent of both the parentsand the subjects was obtained, but only waste blood left overfrom clinical laboratory testing was used in the case of thesubjects who were less than 14 years old. The subjects consistedof 14 normal persons, 18 patients with sickle cell anemia whopresented with acute painful crises or were in a steady state(pain-free, with no acute clinical event within at least themonth before and the month after blood sampling), 3 donors withsickle trait, and 4 control patients with high reticulocytecounts that were not due to sickle cell disease. The patientswith sickle cell anemia ranged in age from 5 to 57 years (mean[±SD], 27±17) and included nine males and ninefemales; of these, six were less than 21 years old (mean, 12±7).Only two of these patients had received transfusions withinthree months before blood donation for this study. After theinitial blood obtained from venipuncture was discarded, venousblood was drawn into tubes treated with silicon and EDTA andstudied immediately.
Endothelial-Cell Cultures
Preliminary studies to perfect and verify the techniques usedin this investigation were performed on cultured human dermalmicrovascular endothelial cells (MVEC) obtained from human foreskins19and large-vessel endothelial cells (HUVEC) obtained from humanumbilical veins.20
Antibodies
We used the following antibodies: rabbit polyclonal antibodiesagainst von Willebrand factor (Sigma Chemical, St. Louis) orthrombomodulin (Biplex, Richmond, Calif.); two murine monoclonalantibodies against CD36, OKM5 (Ortho Diagnostic Systems, Raritan,N.J.) and FA6-152 (Immunotech, Westbrook, Me.); fluorochrome-labeledmurine monoclonal antibodies against intercellular adhesionmolecule 1 (ICAM-1) or vascular-cell adhesion molecule 1 (VCAM-1)(South Biotechnology, Birmingham, Ala.); and murine monoclonalantibodies against E-selectin (Genzyme, Cambridge, Mass.) orP-selectin (Novocastra Laboratories, Newcastle upon Tyne, UnitedKingdom). The antibodies used as controls for nonspecific bindingby these primary antibodies were polyclonal rabbit antichickenimmunoglobulin for the rabbit polyclonal antibodies and antibodieswith irrelevant binding specificities but the same isotype forthe murine monoclonal antibodies (Sigma). As a positive controlantibody for endothelial cells, we used a murine monoclonalantibody to beta2-microglobulin (Sigma). Secondary antibodieswere used as required: goat antimouse immunoglobulin conjugatedto lissamine rhodamine (Jackson IRL, Westgrove, Pa.) or fluoresceinisothiocyanate (Sigma), rhodamine-conjugated goat antirabbitimmunoglobulin (Jackson IRL), and alkaline phosphatase–conjugatedantimouse immunoglobulin (Sigma or Chemicon International, Temecula,Calif.).
Identification of Endothelial Cells
To identify circulating endothelial cells, we used the antibodyP1H12. This murine IgG1 monoclonal antibody was obtained byimmunizing mice with HUVEC, generating a hybridoma line, andseparating IgG from supernatants of hybridoma-cell cultureswith a protein G column. For some studies we used fluoresceinisothiocyanate–labeled P1H12, prepared with the FluoroTag FITC Conjugation kit (Sigma).
P1H12 reacts specifically with endothelial cells. It stainsprimary HUVEC and MVEC cultures and the endothelial cells ofall vessels in frozen sections of human skin, intestine, ovary,tonsil, lymph node, lung, and kidney. It does not stain anyother type of cell in those tissues. It does not stain carcinomacell lines HT-29 and COLO205, melanoma cell lines A-375 andM21, the T-cell lines Jurkat and HuT78, fibroblasts, HL-60 orChinese-hamster-ovary cells, or Epstein–Barr virus–transformedB-cell lines. It does not stain monocytes, granulocytes, redcells, platelets, T cells, or B cells from marrow or peripheralblood; nor does it react with marrow megakaryocytes or the megakaryoblastline HU3. The peripheral-blood cells that do stain with P1H12are also positive for both von Willebrand factor and thrombomodulin(the combined expression of which is limited to endothelium),and they stain for flt and flk (receptors for the endothelial-specificvascular endothelial growth factor). Subgroups of P1H12-positiveblood cells also stain for CD34 and two endothelial-specificactivation markers (VCAM and E-selectin, as reported here).
Quantitation of Circulating Endothelial Cells
We used immunohistochemical examination of buffy-coat smearsto enumerate circulating endothelial cells. One milliliter ofwhole blood was diluted by a factor of 4 with Hanks' balancedsalt solution without calcium and with 1 mM EDTA and 0.5 percentbovine serum albumin. Diluted blood was layered on one-halfvolume of Histopaque 1077 (Sigma) and centrifuged for 30 minutesat 250xg. The supernatant and the interface were pooled in polypropylenetubes (precoated with 0.5 percent bovine serum albumin) andcentrifuged for 5 minutes at 1200xg. After the removal of thesupernatant, the resulting "buffy-coat" pellet was gently resuspendedand transferred to microslides in volumes containing the cellsharvested from 0.25 ml of whole blood. Smears were air-driedovernight and fixed with 4 percent paraformaldehyde for 10 minutes.
For staining, the smears were rehydrated and pretreated withTRIS-buffered saline containing 2 percent bovine serum albuminfor 30 minutes, after which 5 µg of P1H12 per milliliterof TRIS-buffered saline was applied. The samples were then washedwith TRIS-buffered saline containing 2 percent bovine serumalbumin and a secondary antibody, alkaline phosphatase–conjugatedrabbit antimouse IgG, was applied. After the samples were washed,fast red substrate (Sigma) was added for color development.The samples were then counterstained with Mayer's hematoxylin(Biomeda, Foster City, Calif.) and examined by light microscopy.All nucleated circulating endothelial cells contained withinthe original 1-ml sample of whole blood were directly counted.Negative controls were provided by the white cells on the smearsand by parallel slides prepared with control primary antibodies.Positive controls consisted of cultured MVEC and HUVEC.
Qualitative Studies of Circulating Endothelial Cells
Assessment of the surface phenotype of circulating endothelialcells required enrichment of the samples with Dynabeads carryinggoat antimouse immunoglobulin (Dynal, Oslo, Norway). These werecoated with P1H12 according to the manufacturer's instructionsand were used after being washed with Hanks' balanced salt solutionwithout calcium and with 1 mM EDTA and 0.5 percent bovine serumalbumin. To isolate circulating endothelial cells from blood,we used two different methods.
To detect antigens that are constitutively expressed by endothelialcells, whole blood diluted by a factor of 4 with Hanks' balancedsalt solution without calcium and with EDTA and 0.5 percentbovine serum albumin was mixed with 4 million P1H12-coated beadsfor each milliliter of undiluted blood and incubated for onehour at 4°C with gentle agitation. After incubation, beadswith circulating endothelial cells were collected with a magneticconcentrator (Dynal). The harvested cells were washed with medium199 and then transferred to slides with chambered coverslips(Nunc, Naperville, Ill.) at 37°C. The circulating endothelialcells were then washed with phosphate-buffered saline and fixedwith 4 percent paraformaldehyde in phosphate-buffered salinefor 10 minutes at room temperature. (For studies of von Willebrandfactor, the circulating endothelial cells were made permeableby additional treatment with 0.4 percent Triton X-100 in phosphate-bufferedsaline for 10 minutes.) Before undergoing staining, cells werepretreated with phosphate-buffered saline with 3 percent bovineserum albumin for at least 30 minutes.
To detect antigens that endothelial cells express only or toa markedly greater extent on activation (P-selectin, E-selectin,VCAM, and ICAM), we fixed cells immediately after venipunctureby adding 0.25 percent paraformaldehyde to whole blood, incubatingthe sample for 10 minutes, and washing it three times with phosphate-bufferedsaline. Samples were restored to four times the initial volumewith Hanks' balanced salt solution without calcium and withEDTA and 0.5 percent bovine serum albumin and mixed with P1H12-coatedbeads as described above. For P-selectin studies we made thecells permeable, as described for studies of von Willebrandfactor.
We analyzed the phenotype of circulating endothelial cells usingeither direct or indirect immunofluorescence staining with antibodiesin empirically determined concentrations (always between 1 and10 µg per milliliter). Direct immunofluorescence was usedto detect dual binding of fluorescein isothiocyanate–labeledP1H12 and R-phycoerythrin–conjugated antibodies to ICAM-1or VCAM-1, and indirect immunofluorescence was used to detectthe other antigens. After the staining procedures were completed,preparations of circulating endothelial cells were viewed withan inverted fluorescence microscope (Olympus, Tokyo, Japan).Specific positive controls were provided by cultured HUVEC andMVEC (stimulated in vitro if necessary with histamine or thrombin).Negative controls were provided by the white cells contaminatingpreparations of circulating endothelial cells and by smearsof circulating endothelial cells stained with primary or secondarycontrol antibodies. Preliminary studies indicated that our enrichmentmethod recovered more than 85 percent of the endothelial cellsin the original sample of whole blood, suggesting that the resultsreflect the entire population of circulating endothelial cells.Control experiments using HUVEC and MVEC demonstrated that thesample-handling procedures caused no artifactual expressionof the activation markers.
Viability of Circulating Endothelial Cells
Three independent criteria were used to assess the viabilityof circulating endothelial cells. First, we tested the responsivenessof circulating endothelial cells to histamine by incubatingdonor blood with or without 100 µM histamine at 37°Cfor 10 minutes, followed by immediate fixation with 0.25 percentparaformaldehyde. Viability was indicated by the inducibilityof the expression of P-selectin on the surface of circulatingendothelial cells in the histamine-treated sample.
Second, we identified live and dead cells with a kit (MolecularProbes, Eugene, Oreg.) that uses calcein AM, which stains thecytosol of live cells green, and ethidium homodimer, which stainsthe nuclei of dead cells red. Cultured endothelial cells stainedaccording to the manufacturer's directions had either greencytoplasm or red nuclei, but not both. To assess the circulatingendothelial cells, cells on slides were stained with P1H12 andwith only the ethidium homodimer component of the kit, whichallowed the identification of total and dead circulating endothelialcells. To determine the proportion of circulating endothelialcells with any given surface phenotype of interest that weredead, we combined staining with the ethidium homodimer withthe detection of P1H12 and the second epitope of interest.
Third, we determined whether P1H12-positive cells isolated fromthe blood of patients with sickle cell anemia remain alive incell culture. The freshly isolated population of cells containingcirculating endothelial cells was first labeled with the intracellularfluorescent dye PKH26 (Molecular Probes) and then cultured withprimary MVEC19 for up to 28 days. Staining for both PKH26 andP1H12 was used as a marker to identify circulating endothelialcells that were alive in the culture.
Results
Quantitative Studies
We enumerated circulating endothelial cells by using antibodyP1H12 for immunohistochemical examination of buffy-coat smears(Figure 1A). The P1H12-positive cells in these smears were alsopositive for both intracellular von Willebrand factor (Figure 1B)and surface thrombomodulin (data not shown), demonstratingthat they were endothelial cells. Even minimally manipulatedsamples often contained some small anucleate P1H12-positivecell fragments, but we report only the number of nucleated circulatingendothelial cells. The circulating endothelial cells identifiedin the blood of patients with sickle cell anemia and the controlswere in the form of single cells dispersed throughout the buffy-coatsmears.
Figure 1. Examples of Immunohistochemical and Immunofluorescence Analysis of Circulating Endothelial Cells.
Each panel, except Panel C, shows circulating endothelial cells isolated from donors with sickle cell anemia. In Panel A, a buffy-coat smear stained with alkaline phosphatase–conjugated P1H12 has a single circulating endothelial cell (red staining). The nuclei were counterstained with hematoxylin (x1500). Panel B shows a circulating endothelial cell that is staining for both P1H12 (red area) and intracellular von Willebrand factor (brown area), obtained with peroxidase-conjugated antibody against von Willebrand factor (x1000). Panel C shows live HUVEC (green-stained cytoplasm) and dead HUVEC (red-stained nuclei) (x600). Panel D shows live circulating endothelial cells after 11 days in cell culture (x600). Before being added to the culture, circulating endothelial cells from blood were labeled with a cytoplasmic dye so they could be distinguished from the primary MVEC with which they were cultured. Live circulating endothelial cells stain with both P1H12 (green area) and the cytoplasmic dye (orange areas). A cell identified as an endothelial cell by staining with fluorescein isothiocyanate–conjugated P1H12 (Panel E; x1000) is also positive for CD36 (Panel F; x1000), detected with lissamine-conjugated anti-CD36. Panel G shows a circulating endothelial cell with the punctate pattern of expression of intracellular P-selectin that is typical of unstimulated cells (x1000), and Panel H shows the diffuse pattern of expression of surface P-selectin that is typical of activated cells (x900). The out-of-focus round object with the halo in Panel G is one of the immunomagnetic beads used to isolate circulating endothelial cells. Numerous beads are evident in Panel H.
Blood from normal subjects contained a very small number ofcirculating endothelial cells (mean [±SD], 2.6±1.6per milliliter of whole blood) (Table 1). The number of circulatingendothelial cells was close to this value in three donors withsickle cell trait (3.0±2.6 per milliliter) and four patientswith hemolytic anemias other than sickle cell disease (2.0±0.8per milliliter), including two patients with persistently highreticulocyte counts after splenectomy, one with a microangiopathichemolytic anemia, and one with paroxysmal nocturnal hemoglobinuria.In contrast, patients with sickle cell anemia who were not acutelyill (i.e., in a steady state) had significantly elevated numbersof circulating endothelial cells (13.2±11.8 per milliliter;P = 0.002 for the comparison with normal subjects). Patientspresenting on the first day of an acute painful crisis had evengreater numbers (22.8±18.2; P = 0.019 for the comparisonwith patients in a steady state; P<0.001 for the comparisonwith normal donors). Because of the large variation betweenpatients in the number of circulating endothelial cells, wealso examined three patients serially. Figure 2 shows the tendencyin these patients for the number of circulating endothelialcells to increase further at the onset of a painful crisis.
Figure 2. Longitudinal Quantitation of Circulating Endothelial Cells.
The numbers of circulating endothelial cells were monitored in three patients. The onset of every acute painful crisis that occurred during the study is indicated by an arrow.
We found no relation between the number of circulating endothelialcells and the sex or age of the patients (which ranged from5 to 57 years). There was no relation between the number ofcirculating endothelial cells and the use of particular medications.
Viability of Circulating Endothelial Cells
Three independent measures indicated that the population ofcirculating endothelial cells included viable cells. First,preparations of circulating endothelial cells responded to histamineby shifting the distribution of P-selectin from the cytosol(Figure 1G) to the surface in 19±16 percent of the cells(Figure 1H). This shift is typical of activated endothelialcells. Second, circulating endothelial cells from four patientswith sickle cell anemia remained alive when cultured with primaryisolates of MVEC (Figure 1D). These two qualitative tests gaveno information about the actual proportion of viable circulatingendothelial cells. However, fluorescent staining for live anddead cells (Figure 1C) revealed that 66±30 percent ofcirculating endothelial cells in patients with sickle cell anemiawere alive. The percentages varied among patients; the individualvalues for the 15 patients we tested were 29, 31, 38, 38, 40,43, 47, 62, 67, 95, 100, 100, 100, 100, and 100 percent viablecirculating endothelial cells. There was no correspondence betweenthe proportion of live cells and clinical status (68±33percent viability for eight patients in a steady state and 64±28percent viability for seven patients with acute painful crisis).
Preliminary studies established that our enrichment and analysisprotocols did not themselves adversely affect the viabilityof cultured endothelial cells, indicating that the dead cellsfound in the blood from our study subjects were not an artifactof the in vitro manipulations.
Phenotype of Circulating Endothelial Cells
Among the various types of endothelial cells, only microvascularendothelial cells express CD36. We used this marker to identifythe vascular origin of circulating endothelial cells (Figure 1Eand Figure 1F). About half (53±4 percent) of the circulatingendothelial cells in samples of normal blood were positive forCD36 (Table 2). The proportion of circulating endothelial cellsthat were positive for CD36 was somewhat higher (78±15percent) in samples from patients with sickle cell anemia (Table 2),and the absolute number of microvascular circulating endothelialcells in these patients was, on average, nine times normal.We found no difference in the proportion of CD36-positive circulatingendothelial cells among patients at the onset of a painful crisisor in a steady state (76±16 vs. 80±16 percent).The increase in circulating endothelial cells during an acutepainful crisis is due predominantly to microvascular endothelialcells.
Table 2. Phenotype of Circulating Endothelial Cells in Patients with Sickle Cell Anemia and Normal Subjects.
We also examined circulating endothelial cells for dual expressionof P1H12 and adhesion molecules that appear on activated endothelialcells. The percentage of circulating endothelial cells withsurface expression of ICAM-1, VCAM-1, E-selectin, or P-selectinwas markedly greater among patients with sickle cell anemiathan among the normal controls (Table 2). The percentage ofcirculating endothelial cells that were positive for these activationmarkers was similar for samples obtained from patients in asteady state and patients at the onset of acute painful crises.In individual patients, the proportion of viable and dead circulatingendothelial cells with these markers was exactly the same. Theexpression of the endothelial activation markers on circulatingendothelial cells from the four control patients with hemolyticanemias other than sickle cell disease was in the normal range.
Discussion
Evidence that perturbation of vascular-wall endothelium contributesto the vascular abnormalities of sickle cell anemia includesfindings of histopathological changes in splenic and cerebralvasculatures21,22,23,24; the development of thromboses at sitesof underlying intimal hyperplasia22,23,24; the abnormal presenceof endothelial-cell adhesion molecules such as ICAM-1, VCAM-1,and E-selectin in the blood25; and increased numbers of circulatingendothelial cells.8,9 Several other abnormalities in the diseaseare probably related to the vascular endothelium. These includeactivation of the coagulation system, abnormal adhesion of redcells and white cells to endothelium, and disturbances of vasoregulation.Moreover, hypoxia and increased levels of interleukin-1, endotoxin,tumor necrosis factor, C-reactive protein, and thrombin tendto be present in the blood of patients with sickle cell anemia.26All these factors modulate the endothelial phenotype and maycontribute to the development of vascular disease in sicklecell anemia by modulating the expression of various hemostaticand adhesion molecules on endothelial cells.5
Our data show that the increased number of circulating endothelialcells in patients with sickle cell anemia is not simply dueto hyposplenia, high reticulocyte counts (i.e., hematopoieticstress), or both, because control patients with these abnormalitieshad normal numbers of circulating endothelial cells. We foundthat the number of circulating endothelial cells tends to increaseat the onset of acute painful episodes, but the mechanism ofthis phenomenon is not known. It might reflect actual physicaldislodgment of cells from vessels due to endothelial injuryat the time of vaso-occlusion or it might be due to moleculessuch as thrombin that can cause the release of endothelial cellsfrom underlying matrix proteins in vessels or bone marrow. Ourdata show that in patients with sickle cell anemia circulatingendothelial cells tend to be viable. These cells tend to bemicrovascular in origin, as defined by the marker CD36.27,28The increased numbers of circulating endothelial cells at theonset of an acute painful crisis consist mostly of CD36-positivecells. We cannot say with certainty that CD36-negative circulatingendothelial cells are not microvascular in origin, since CD36-negativeendothelial cells have been identified in dermal microvessels.29
The circulating endothelial cells in patients with sickle cellanemia tend to have an activated phenotype, as evidenced bythe expression of four adhesion molecules: ICAM-1, VCAM-1, E-selectin,and P-selectin. ICAM-1 is constitutively expressed in smallamounts but increases after the activation of endothelial cells;the other three markers are expressed only on activated endothelium.Preliminary studies indicate that circulating endothelial cellsin patients with sickle cell anemia express tissue factor abnormally,30suggesting that the endothelium has a procoagulant phenotypein addition to the proadhesive phenotype identified here. Theproportion of circulating endothelial cells with activationmarkers was the same for live and dead cells, indicating thatthe activated phenotype is not an artifact due to cell death;indeed, it suggests that the circulating endothelial cells diedafter activation. If circulating endothelial cells truly representin situ endothelial cells, our data imply that the vessel-wallendothelium is activated in patients with sickle cell anemia,whether they are in a steady state or an acute painful crisis.We do not know why circulating endothelial cells are increasedand activated in patients in a steady state, but recent dataindicate that markers of inflammation, such as C-reactive protein,are elevated variably or even chronically in sickle cell anemia.26,31,32Chronic activation of endothelial cells could be a risk factorfor vaso-occlusion, and fluctuations in the activation of thesecells (in response to biologic modifiers) might account forthe apparently random attacks of vaso-occlusive crises.
It is likely that endothelial-cell activation increases therisk of vaso-occlusion.26 In addition to (or instead of) thesickling process, vaso-occlusion may involve disturbances ofendothelial function that influence hemostasis, or the adhesionof red cells and white cells to endothelium may promote vaso-occlusion.26The four adhesion molecules that we tested are involved in white-celladhesion, and VCAM mediates the adhesion of sickle red cells.Whether endothelial-cell injury or dysfunction (as opposed toactivation) also contributes to the vascular pathobiology ofsickle cell disease is unknown.
Supported by a grant (HL 55174) from the National Institutesof Health.
We are indebted to Barrie Miller for assisting with monoclonal-antibodyproduction and to Dr. Steve Nelson for providing samples fromchildren with sickle disease.
Source Information
From the Department of Medicine, University of Minnesota Medical School, Minneapolis (A.S., Y.L., P.B., S.C., R.P.H.), and the Fred Hutchinson Cancer Research Center, Seattle (E.W.).
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Wu, X., Lensch, M. W., Wylie-Sears, J., Daley, G. Q., Bischoff, J.
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Su, E. J, Cheng, Y.-H., Chatterton, R. T, Lin, Z.-H., Yin, P., Reierstad, S., Innes, J., Bulun, S. E
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(2007). Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Protein Kinase C {beta}-Inhibitor Enzastaurin in Combination with Gemcitabine and Cisplatin in Patients with Advanced Cancer. Clin. Cancer Res.
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Norden-Zfoni, A., Desai, J., Manola, J., Beaudry, P., Force, J., Maki, R., Folkman, J., Bello, C., Baum, C., DePrimo, S. E., Shalinsky, D. R., Demetri, G. D., Heymach, J. V.
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Buckstein, R., Kerbel, R. S., Shaked, Y., Nayar, R., Foden, C., Turner, R., Lee, C. R., Taylor, D., Zhang, L., Man, S., Baruchel, S., Stempak, D., Bertolini, F., Crump, M.
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Mehra, N., Penning, M., Maas, J., Beerepoot, L. V., van Daal, N., van Gils, C. H., Giles, R. H., Voest, E. E.
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Skrabal, C. A., Choi, Y. H., Kaminski, A., Steiner, M., Kundt, G., Steinhoff, G., Liebold, A.
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Rucci, N., Recchia, I., Angelucci, A., Alamanou, M., Del Fattore, A., Fortunati, D., Susa, M., Fabbro, D., Bologna, M., Teti, A.
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Beerepoot, L. V., Radema, S. A., Witteveen, E. O., Thomas, T., Wheeler, C., Kempin, S., Voest, E. E.
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(2006). Differential CD146 Expression on Circulating Versus Tissue Endothelial Cells in Rectal Cancer Patients: Implications for Circulating Endothelial and Progenitor Cells As Biomarkers for Antiangiogenic Therapy. JCO
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(2006). Blood Monocytes Mimic Endothelial Progenitor Cells. Stem Cells
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Stachelek, S. J., Alferiev, I., Connolly, J. M., Sacks, M., Hebbel, R. P., Bianco, R., Levy, R. J.
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Morris, C. R., Kato, G. J., Poljakovic, M., Wang, X., Blackwelder, W. C., Sachdev, V., Hazen, S. L., Vichinsky, E. P., Morris, S. M. Jr, Gladwin, M. T.
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Zhang, H., Vakil, V., Braunstein, M., Smith, E. L. P., Maroney, J., Chen, L., Dai, K., Berenson, J. R., Hussain, M. M., Klueppelberg, U., Norin, A. J., Akman, H. O., Ozcelik, T., Batuman, O. A.
(2005). Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood
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(2005). The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood
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Gaugler, M-H
(2005). A unifying system: does the vascular endothelium have a role to play in multi-organ failure following radiation exposure?. Br. J. Radiol.
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(2004). Overexpression of human heme oxygenase-1 attenuates endothelial cell sloughing in experimental diabetes. Am. J. Physiol. Heart Circ. Physiol.
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Embury, S. H., Matsui, N. M., Ramanujam, S., Mayadas, T. N., Noguchi, C. T., Diwan, B. A., Mohandas, N., Cheung, A. T. W.
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Quilici, J., Banzet, N., Paule, P., Meynard, J.-B., Mutin, M., Bonnet, J.-L., Ambrosi, P., Sampol, J., Dignat-George, F.
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Kaul, D. K., Liu, X.-d., Choong, S., Belcher, J. D., Vercellotti, G. M., Hebbel, R. P.
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Turhan, A., Jenab, P., Bruhns, P., Ravetch, J. V., Coller, B. S., Frenette, P. S.
(2004). Intravenous immune globulin prevents venular vaso-occlusion in sickle cell mice by inhibiting leukocyte adhesion and the interactions between sickle erythrocytes and adherent leukocytes. Blood
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Makin, A. J, Blann, A. D, Chung, N. A.Y, Silverman, S. H, Lip, G. Y.H
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(2004). Increased levels of viable circulating endothelial cells are an indicator of progressive disease in cancer patients. Ann Oncol
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West, D. C., Romano, P. S., Azari, R., Rudominer, A., Holman, M., Sandhu, S.
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Keller, T. T, Mairuhu, A. T.A, de Kruif, M. D, Klein, S. K, Gerdes, V. E.A, ten Cate, H., Brandjes, D. P.M, Levi, M., van Gorp, E. C.M
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Matsumura, G., Miyagawa-Tomita, S., Shin'oka, T., Ikada, Y., Kurosawa, H.
(2003). First Evidence That Bone Marrow Cells Contribute to the Construction of Tissue-Engineered Vascular Autografts In Vivo. Circulation
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Shet, A. S., Aras, O., Gupta, K., Hass, M. J., Rausch, D. J., Saba, N., Koopmeiners, L., Key, N. S., Hebbel, R. P.
(2003). Sickle blood contains tissue factor-positive microparticles derived from endothelial cells and monocytes. Blood
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Varghese, A., Weir, E. K.
(2003). T-Type Calcium Current in Sickle Cell Disease: A Channel to Therapy?. Circ. Res.
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Wu, S., Haynes, J. Jr, Taylor, J. T., Obiako, B. O., Stubbs, J. R., Li, M., Stevens, T.
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Perelman, N., Selvaraj, S. K., Batra, S., Luck, L. R., Erdreich-Epstein, A., Coates, T. D., Kalra, V. K., Malik, P.
(2003). Placenta growth factor activates monocytes and correlates with sickle cell disease severity. Blood
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Siddiqui, A K, Ahmed, S
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Yan, X., Lin, Y., Yang, D., Shen, Y., Yuan, M., Zhang, Z., Li, P., Xia, H., Li, L., Luo, D., Liu, Q., Mann, K., Bader, B. L.
(2003). A novel anti-CD146 monoclonal antibody, AA98, inhibits angiogenesis and tumor growth. Blood
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Belcher, J. D., Bryant, C. J., Nguyen, J., Bowlin, P. R., Kielbik, M. C., Bischof, J. C., Hebbel, R. P., Vercellotti, G. M.
(2003). Transgenic sickle mice have vascular inflammation. Blood
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Hines, P. C., Zen, Q., Burney, S. N., Shea, D. A., Ataga, K. I., Orringer, E. P., Telen, M. J., Parise, L. V.
(2003). Novel epinephrine and cyclic AMP-mediated activation of BCAM/Lu-dependent sickle (SS) RBC adhesion. Blood
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Chong, A.-Y., Blann, A.D., Lip, G.Y.H.
(2003). Assessment of endothelial damage and dysfunction: observations in relation to heart failure. QJM
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Driscoll, M. C., Hurlet, A., Styles, L., McKie, V., Files, B., Olivieri, N., Pegelow, C., Berman, B., Drachtman, R., Patel, K., Brambilla, D.
(2003). Stroke risk in siblings with sickle cell anemia. Blood
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Weiner, D. L., Hibberd, P. L., Betit, P., Cooper, A. B., Botelho, C. A., Brugnara, C.
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Burger, P. E., Coetzee, S., McKeehan, W. L., Kan, M., Cook, P., Fan, Y., Suda, T., Hebbel, R. P., Novitzky, N., Muller, W. A., Wilson, E. L.
(2002). Fibroblast growth factor receptor-1 is expressed by endothelial progenitor cells. Blood
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Woywodt, A., Bahlmann, F. H., de Groot, K., Haller, H., Haubitz, M.
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Segal, M. S., Bihorac, A., Koc, M.
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Benkerrou, M., Delarche, C., Brahimi, L., Fay, M., Vilmer, E., Elion, J., Gougerot-Pocidalo, M.-A., Elbim, C.
(2002). Hydroxyurea corrects the dysregulated L-selectin expression and increased H2O2 production of polymorphonuclear neutrophils from patients with sickle cell anemia. Blood
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Eldor, A., Rachmilewitz, E. A.
(2002). The hypercoagulable state in thalassemia. Blood
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Setty, B. N. Y., Rao, A. K., Stuart, M. J.
(2001). Thrombophilia in sickle cell disease: the red cell connection. Blood
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Stevens, T., Rosenberg, R., Aird, W., Quertermous, T., Johnson, F. L., Garcia, J. G. N., Hebbel, R. P., Tuder, R. M., Garfinkel, S.
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de Bont, E. S. J. M., Guikema, J. E. J., Scherpen, F., Meeuwsen, T., Kamps, W. A., Vellenga, E., Bos, N. A.
(2001). Mobilized Human CD34+ Hematopoietic Stem Cells Enhance Tumor Growth in a Nonobese Diabetic/Severe Combined Immunodeficient Mouse Model of Human Non-Hodgkin's Lymphoma. Cancer Res.
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Wandersee, N. J., Lee, J. C., Deveau, S. A., Barker, J. E.
(2001). Reduced incidence of thrombosis in mice with hereditary spherocytosis following neonatal treatment with normal hematopoietic cells. Blood
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Mancuso, P., Burlini, A., Pruneri, G., Goldhirsch, A., Martinelli, G., Bertolini, F.
(2001). Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood
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Solovey, A. A., Solovey, A. N., Harkness, J., Hebbel, R. P.
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Brittain, J. E., Mlinar, K. J., Anderson, C. S., Orringer, E. P., Parise, L. V.
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Nath, K. A., Grande, J. P., Haggard, J. J., Croatt, A. J., Katusic, Z. S., Solovey, A., Hebbel, R. P.
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MUTUNGA, M., FULTON, B., BULLOCK, R., BATCHELOR, A., GASCOIGNE, A., GILLESPIE, J. I., BAUDOUIN, S. V.
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Kalka, C., Tehrani, H., Laudenberg, B., Vale, P. R., Isner, J. M., Asahara, T., Symes, J. F.
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Styles, L. A., Hoppe, C., Klitz, W., Vichinsky, E., Lubin, B., Trachtenberg, E.
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Gehling, U. M., Ergun, S., Schumacher, U., Wagener, C., Pantel, K., Otte, M., Schuch, G., Schafhausen, P., Mende, T., Kilic, N., Kluge, K., Schafer, B., Hossfeld, D. K., Fiedler, W.
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Shiu, Y.-T., Udden, M. M., McIntire, L. V.
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Bernaudin, F., Verlhac, S., Freard, F., Roudot-Thoraval, F., Benkerrou, M., Thuret, I., Mardini, R., Vannier, J.P., Ploix, E., Romero, M., Casse-Perrot, C., Helly, M., Gillard, E., Sebag, G., Kchouk, H., Pracros, J.P., Finck, B., Dacher, J.N., Ickowicz, V., Raybaud, C., Poncet, M., Lesprit, E., Reinert, P.H., Brugieres, P.
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Bosch, I., Melichar, H., Pardee, A. B.
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Manodori, A. B., Barabino, G. A., Lubin, B. H., Kuypers, F. A.
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Peichev, M., Naiyer, A. J., Pereira, D., Zhu, Z., Lane, W. J., Williams, M., Oz, M. C., Hicklin, D. J., Witte, L., Moore, M. A. S., Rafii, S.
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Harlan, J. M.
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Bhattacharya, V., McSweeney, P. A., Shi, Q., Bruno, B., Ishida, A., Nash, R., Storb, R. F., Sauvage, L. R., Hammond, W. P., Wu, M. H.-D.
(2000). Enhanced endothelialization and microvessel formation in polyester grafts seeded with CD34+ bone marrow cells. Blood
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Dignat-George, F., Blann, A., Sampol, J.
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Cashman, J.D., Clark-Lewis, I., Eaves, A.C., Eaves, C.J.
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