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• W2120691494 abstract "PECAM-1 is a 130-kd member of the Ig superfamily present on endothelial cells, platelets, polymorphonuclear leukocytes, monocytes, and lymphocytes. Its expression begins early in development and persists through adulthood. PECAM-1 functions as an adhesion and signaling molecule between adjacent endothelial cells and between endothelial cells and circulating blood elements. Antibodies directed against PECAM-1 have been shown to affect angiogenesis, endothelial cell migration, and polymorphonuclear leukocyte transmigration. Furthermore, its dimerization is associated with the modulation of integrin affinity. Antibody inhibition studies suggest that PECAM-1 plays a role in modulating thrombosis; however, recent in vitro aggregation studies performed on platelets harvested from PECAM-1-deficient mice revealed no abnormalities. In this report we demonstrate prolonged in vivo bleeding times in PECAM-1-deficient mice. This abnormality was not corrected when wild-type hematopoietic precursors were engrafted into marrow-ablated PECAM-1-deficient mice. Furthermore, normal bleeding times were observed when marrow-ablated wild-type mice were engrafted with hematopoietic precursors harvested from PECAM-1-deficient mice. These studies are consistent with a role for PECAM-1 in modulating thrombosis in the vasculature, which is potentially mediated by endothelial cell PECAM-1 expression. PECAM-1 is a 130-kd member of the Ig superfamily present on endothelial cells, platelets, polymorphonuclear leukocytes, monocytes, and lymphocytes. Its expression begins early in development and persists through adulthood. PECAM-1 functions as an adhesion and signaling molecule between adjacent endothelial cells and between endothelial cells and circulating blood elements. Antibodies directed against PECAM-1 have been shown to affect angiogenesis, endothelial cell migration, and polymorphonuclear leukocyte transmigration. Furthermore, its dimerization is associated with the modulation of integrin affinity. Antibody inhibition studies suggest that PECAM-1 plays a role in modulating thrombosis; however, recent in vitro aggregation studies performed on platelets harvested from PECAM-1-deficient mice revealed no abnormalities. In this report we demonstrate prolonged in vivo bleeding times in PECAM-1-deficient mice. This abnormality was not corrected when wild-type hematopoietic precursors were engrafted into marrow-ablated PECAM-1-deficient mice. Furthermore, normal bleeding times were observed when marrow-ablated wild-type mice were engrafted with hematopoietic precursors harvested from PECAM-1-deficient mice. These studies are consistent with a role for PECAM-1 in modulating thrombosis in the vasculature, which is potentially mediated by endothelial cell PECAM-1 expression. The expression of PECAM-1 (CD31), a 130-kd member of the Ig superfamily, begins early in development at the stage of hemangioblast formation and persists through adulthood.1Newman PJ The role of PECAM-1 in vascular cell biology.Ann NY Acad Sci. 1994; 714: 165-174Crossref PubMed Scopus (137) Google Scholar, 2Newman PJ The biology of PECAM-1.J Clin Invest. 1997; 100: S25-S29Crossref PubMed Scopus (134) Google Scholar, 3Newman PJ Switched at birth: a new family for PECAM-1.J Clin Invest. 1999; 103: 5-9Crossref PubMed Scopus (238) Google Scholar It is expressed on endothelial cells, platelets, polymorphonuclear leukocytes, monocytes, and T and B lymphocytes and is thought to serve several functions, including that of an adhesion molecule mediating cell-cell adhesion between adjacent endothelial cells and between endothelial cells and polymorphonuclear leukocytes, platelets, monocytes, and lymphocytes.1Newman PJ The role of PECAM-1 in vascular cell biology.Ann NY Acad Sci. 1994; 714: 165-174Crossref PubMed Scopus (137) Google Scholar, 2Newman PJ The biology of PECAM-1.J Clin Invest. 1997; 100: S25-S29Crossref PubMed Scopus (134) Google Scholar, 3Newman PJ Switched at birth: a new family for PECAM-1.J Clin Invest. 1999; 103: 5-9Crossref PubMed Scopus (238) Google Scholar, 4Chosay JG Fisher MA Farhood A Ready KA Dunn CJ Jaeschke H Role of PECAM-1 (CD31) in neutrophil transmigration in murine models of liver and peritoneal inflammation.Am J Physiol. 1998; 37: G776-G782Google Scholar, 5Vaporciyan AA DeLisser HM Yan HC Mendiguren II Thom SR Jones ML Ward PA Albelda SM Involvement of platelet-endothelial cell adhesion molecule-1 in neutrophil recruitment in vivo.Science. 1993; 262: 1580-1582Crossref PubMed Scopus (433) Google Scholar It has been shown to be a modulator of in vitro and in vivo angiogenesis, endothelial cell migration, and polymorphonuclear leukocyte transmigration. PECAM-1 localization and phosphorylation state are known to be affected by integrin engagement, hypoxia, hyperglycemia, and osmolarity.4Chosay JG Fisher MA Farhood A Ready KA Dunn CJ Jaeschke H Role of PECAM-1 (CD31) in neutrophil transmigration in murine models of liver and peritoneal inflammation.Am J Physiol. 1998; 37: G776-G782Google Scholar, 5Vaporciyan AA DeLisser HM Yan HC Mendiguren II Thom SR Jones ML Ward PA Albelda SM Involvement of platelet-endothelial cell adhesion molecule-1 in neutrophil recruitment in vivo.Science. 1993; 262: 1580-1582Crossref PubMed Scopus (433) Google Scholar, 6Bogen S Pak J Garifallou M Deng X Muller WA Monoclonal antibody to murine PECAM-1 (CD31) blocks acute inflammation in vivo.J Exp Med. 1994; 179: 1059-1064Crossref PubMed Scopus (283) Google Scholar, 7Elias CG Spellberg JP Karantamir B Lin CH Wang YJ McKenna PJ Muller WA Zukowski MM Andrew DP Ligation of Cd31/Pecam-1 modulates the function of lymphocytes, monocytes and neutrophils.Eur J Immunol. 1998; 28: 1948-1958Crossref PubMed Scopus (42) Google Scholar, 8Pinter EM Barreuther M Lu T Imhof BA Madri JA Platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) tyrosine phosphorylation state changes during vasculogenesis in the murine conceptus.Am J Pathol. 1997; 150: 1523-1530PubMed Google Scholar, 9Pinter E Mahooti S Wang Y Imhof BA Madri JA Hyperglycemia-induced vasculopathy in the murine vitelline vasculature: correlation with PECAM-1/CD31 tyrosine phosphorylation state.Am J Pathol. 1999; 154: 1367-1379Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 10Kalra VK Shen Y Sultana C Rattan V Hypoxia induces PECAM-1 phosphorylation and transendothelial migration of monocytes.Am J Physiol. 1996; 271: H2025-H2034PubMed Google Scholar, 11Lu TT Yan LG Madri JA Integrin engagement mediates tyrosine dephosphorylation on platelet-endothelial cell adhesion molecule 1.Proc Natl Acad Sci USA. 1996; 93: 11808-11813Crossref PubMed Scopus (98) Google Scholar, 12Lu TT Barreuther M Davis S Madri JA Platelet endothelial cell adhesion molecule-1 is phosphorylatable by c-Src, binds Src-Src homology 2 domain, and exhibits immunoreceptor tyrosine-based activation motif-like properties.J Biol Chem. 1997; 272: 14442-14446Crossref PubMed Scopus (92) Google Scholar, 13DeLisser HM Christofidou-Solomidou M Strieter RM Burdick MD Robinson CS Wexler RS Kerr JS Garlanda C Merwin JR Madri JA Albelda SM Involvement of endothelial PECAM-1/CD31 in angiogenesis.Am J Pathol. 1997; 151: 671-677PubMed Google Scholar In addition to its adhesive functions, PECAM-1 has been shown to be a participant in signaling pathways.3Newman PJ Switched at birth: a new family for PECAM-1.J Clin Invest. 1999; 103: 5-9Crossref PubMed Scopus (238) Google Scholar, 8Pinter EM Barreuther M Lu T Imhof BA Madri JA Platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) tyrosine phosphorylation state changes during vasculogenesis in the murine conceptus.Am J Pathol. 1997; 150: 1523-1530PubMed Google Scholar, 11Lu TT Yan LG Madri JA Integrin engagement mediates tyrosine dephosphorylation on platelet-endothelial cell adhesion molecule 1.Proc Natl Acad Sci USA. 1996; 93: 11808-11813Crossref PubMed Scopus (98) Google Scholar, 14Kim CS Wang T Madri JA Platelet endothelial cell adhesion molecule-1 expression modulates endothelial cell migration in vitro.Lab Invest. 1998; 78: 583-590PubMed Google Scholar After engagement of PECAM-1, integrin affinity changes have been noted on platelets and lymphocytes,15Bogen SA, Baldwin HS, Watkins SC, Albelda SM, Abbas AK: Association of murine CD31 with transmigrating lymphocytes following antigenic stimulation. Am J Pathol 141:843–854Google Scholar, 16Varon D Jackson DE Shenkman B Dardik R Tamarin I Savion N Newman PJ Platelet/endothelial cell adhesion molecule-1 serves as a costimulatory agonist receptor that modulates integrin-dependent adhesion and aggregation of human platelets.Blood. 1998; 91: 500-507Crossref PubMed Google Scholar, 17Rainger GE Buckley C Simmons DL Nash GB Cross-talk between cell adhesion molecules regulates the migration velocity of neutrophils.Curr Biol. 1977; 7: 316-325Abstract Full Text Full Text PDF Scopus (83) Google Scholar, 18Pellegatta F Chierchia SL Zocchi MR Functional association of platelet endothelial cell adhesion molecule-1 and phosphoinositide 3-kinase in human neutrophils.J Biol Chem. 1998; 273: 27768-27771Crossref PubMed Scopus (78) Google Scholar, 19Sagawa K Kimura T Swieter M Siraganian RP The protein-tyrosine phosphatase Shp-2 associates with tyrosine-phosphorylated adhesion molecule PECAM-1 (CD31).J Biol Chem. 1977; 272: 31086-31091Crossref Scopus (94) Google Scholar and changes in intracellular calcium localization have been documented.20Gurubhagavatula I Amrani Y Pratico D Ruberg FL Albelda SM Panettieri RA Engagement of human PECAM-1 (CD31) on human endothelial cells increases intracellular calcium ion concentration and stimulates prostacyclin release.J Clin Invest. 1998; 101: 212-222Crossref PubMed Scopus (76) Google Scholar PECAM-1-mediated signaling is thought to occur, in part, via its cytoplasmic ITIM (immunoregulatory tyrosine inhibitory motif) domain. This domain is known to mediate binding of signaling and adapter molecules having one or tandem SH2 domains, when the tyrosine residues residing in the PECAM-1 ITIM domain are phosphorylated.3Newman PJ Switched at birth: a new family for PECAM-1.J Clin Invest. 1999; 103: 5-9Crossref PubMed Scopus (238) Google Scholar, 11Lu TT Yan LG Madri JA Integrin engagement mediates tyrosine dephosphorylation on platelet-endothelial cell adhesion molecule 1.Proc Natl Acad Sci USA. 1996; 93: 11808-11813Crossref PubMed Scopus (98) Google Scholar, 12Lu TT Barreuther M Davis S Madri JA Platelet endothelial cell adhesion molecule-1 is phosphorylatable by c-Src, binds Src-Src homology 2 domain, and exhibits immunoreceptor tyrosine-based activation motif-like properties.J Biol Chem. 1997; 272: 14442-14446Crossref PubMed Scopus (92) Google Scholar Specifically, the phosphatase SHP-2 has been shown to bind to tyrosine-phosphorylated PECAM-1.19Sagawa K Kimura T Swieter M Siraganian RP The protein-tyrosine phosphatase Shp-2 associates with tyrosine-phosphorylated adhesion molecule PECAM-1 (CD31).J Biol Chem. 1977; 272: 31086-31091Crossref Scopus (94) Google Scholar, 21Jackson DE Ward CM Wang R Newman PJ The protein-tyrosine phosphatase SHP-2 binds platelet/endothelial cell adhesion molecule-1 (PECAM-1) and forms a distinct signaling complex during platelet aggregation: evidence for a mechanistic link between PECAM-1- and integrin-mediated cellular signaling.J Biol Chem. 1977; 272: 6986-6993Google Scholar Recently we have found that in addition to its interactions with SHP-2, PECAM-1 can serve as a reservoir for and a modulator of β-catenin, binding tyrosine-phosphorylated β-catenin, and, if PECAM-1 is tyrosine phosphorylated, bringing β-catenin into close proximity to SHP-2, facilitating dephosphorylation of the bound β-catenin.22Ilan N Mahooti S Rimm DL Madri JA PECAM-1 (CD31) functions as a reservoir for and a modulator of tyrosine phosphorylated beta catenin.J Cell Sci. 1999; 112: 3005-3014Crossref PubMed Google Scholar These observations prompted the generation of PECAM-1-deficient mice. The animals were found to be viable and exhibited an abnormal transit of polymorphonuclear leukocytes across vascular basement membranes as their only demonstrable phenotype.23Duncan GS Andrew DP Takimoto H Kaufman SA Yoshida H Spellberg J Luis de la Pompa J Elia A Wakeham A Karan-Tamir B Muller WA Senaldi G Zukowski MM Mak TW Genetic evidence for functional redundancy of platelet/endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions.J Immunol. 1999; 162: 3022-3030PubMed Google Scholar Other recent investigations using vital microscopy techniques have revealed delays in leukocyte transmigration in PECAM-1-deficient mice.24Thompson RD Larbi KY Harrison V Duncan GS Mak TW Nourshargh S IL-1B-induced leukocyte responses in cremasteric venules of mice deficient in PECAM-1.FASEB J. 1999; 13: A670Google Scholar In this manuscript we report further analyses of the PECAM-1-deficient mice. Specifically, we have demonstrated a prolongation in bleeding time in PECAM-1-deficient mice. Furthermore, we have shown that this phenotype persists when the PECAM-1-deficient mice are engrafted with wild-type hematopoietic precursors. PECAM-1-deficient mice were generated as described.23Duncan GS Andrew DP Takimoto H Kaufman SA Yoshida H Spellberg J Luis de la Pompa J Elia A Wakeham A Karan-Tamir B Muller WA Senaldi G Zukowski MM Mak TW Genetic evidence for functional redundancy of platelet/endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions.J Immunol. 1999; 162: 3022-3030PubMed Google Scholar The colony was bred at the Yale University Animal Care Facility (New Haven, CT) and the Blood Research Institute (Milwaukee, WI), in accordance with established protocols. Phenotype was assessed by flow cytometric analysis (FACS) of peripheral blood elements as described.23Duncan GS Andrew DP Takimoto H Kaufman SA Yoshida H Spellberg J Luis de la Pompa J Elia A Wakeham A Karan-Tamir B Muller WA Senaldi G Zukowski MM Mak TW Genetic evidence for functional redundancy of platelet/endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions.J Immunol. 1999; 162: 3022-3030PubMed Google Scholar Platelet, RBC, and WBC counts were performed on blood collected by retroorbital bleeding with a heparinized capillary tube. Two hundred microliters of blood was immediately transferred to Eppendorf tubes containing K3 EDTA (2.0 mg/ml). Samples were diluted in saline and counted on a Baker System 9110+CP Hematology Analyzer (Biochem Immunosystems, Allentown, PA) or sent to a commercial laboratory (ANTECH Diagnostics, Farmingdale, NY) for analysis. Bleeding times were assessed using an adaptation of the method used by Kung et al.25Kung SH Hagstrom JN Cass D Tai SJ Lin HF Stafford DW High KA Human factor IX corrects the bleeding diathesis of mice with hemophilia B.Blood. 1998; 91: 784-790PubMed Google Scholar Deep anesthesia was induced with metofane gas. The mice were then secured into a tabletop holder, with their tails taped downward and perpendicular to their bodies. After being pulled through a 1.5-mm-diameter template, the tails were transected with a scalpel blade and bled onto a Whatman filter paper. The filter was dabbed to the wound every 30 seconds without disrupting the forming clot. Any blood dripping during the 30-second intervals was allowed to drop freely onto the filter. The experiment was continued until bleeding stopped completely (wild type and heterozygous). The bleeding of PECAM-1-deficient animals was stopped by cauterization at 20 minutes to prevent hypovolemic shock. Hematopoietic precursor engraftment of PECAM-1-deficient and wild-type mice was performed as described.26Becker PS Nilsson SK Li Z Berrios VM Dooner MS Cooper CL Hsieh CC Quesenberry PJ Adhesion receptor expression by hematopoietic cell lines and murine progenitors: modulation by cytokines and cell cycle status.Exp Hematol. 1999; 27: 533-541Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Recipient mice were irradiated (500 Rads twice, separated by 2 hours) using a cesium 127 irradiator. Donor animals were euthanized by cervical dislocation. Femur, tibia, and iliac crest were aseptically removed and cleaned free of muscle, and the ends were cut off with a scalpel blade. The marrow was flushed into a 50-ml tube, using a 22-gauge needle attached to a 5-ml syringe containing 10% fetal bovine serum in 1× phosphate-buffered saline. Cells from multiple animals were pooled, filtered through a 40-μm cell strainer (Beckton Dickinson, Franklin New Jersey), washed, and counted. Marrow precursor cells were diluted to 2.5 × 106/200 μl and injected retroorbitally into each irradiated recipient deficient or wild-type mouse. After 30 days recipients were tested for platelet number and bleeding time. Statistics (averages, standard deviations, Student’st-test) were performed on a Power Macintosh 9600/300 computer using Excel 4.0. Statistical differences were assessed by one-way analysis of variance and the Student-Newman-Keuls method forpost hoc analysis, with SigmaStat software (Jandel Corporation, San Rafael, CA). As previously described,19Sagawa K Kimura T Swieter M Siraganian RP The protein-tyrosine phosphatase Shp-2 associates with tyrosine-phosphorylated adhesion molecule PECAM-1 (CD31).J Biol Chem. 1977; 272: 31086-31091Crossref Scopus (94) Google Scholar PECAM-1 expression in circulating blood elements is not detectable in PECAM-1 homozygous null mice (−/−, KO), whereas it is present in reduced amounts in heterozygotes (+/−, Het) compared to wild-type (+/+, WT) littermates. The presence or absence of PECAM-1 expression was confirmed by immunofluorescence of tissue sections (data not shown). During our harvests of blood for FACS analysis of phenotype we noticed a difference (prolongation) in bleeding times of some of the mice. When the FACS data were correlated with this observation we determined that the animals exhibiting prolonged bleeding times were the PECAM-1-deficient (−/−) mice. This finding prompted us to perform standardized bleeding times on all of our litters. Bleeding times were performed in a blinded fashion at two sites by separate investigators over a 2-year period. At the Yale University School of Medicine the mice wre bled at 3 weeks of age. In all of the mice studied to date (60 mice of varying ages spanning a 2-year period), all of the homozygous null (−/−, KO) mice exhibited a prolonged bleeding time of more than 20 minutes (the test was arbitrarily stopped at this time point to avoid possible death due to hypovolemic shock). The heterozygous animals(+/−, Het) exhibited bleeding times similar to those of wild-type (+/+, WT) littermates (11 ± 1.5 minutesversus 12 ± 1.4 minutes) (Figure 1). Repeat bleedings of the same mice yielded similar results. At the Blood Research Institute at the Blood Center of Southeastern Wisconsin, mice were bled at 8–9 weeks of age. Similar to the findings noted at Yale University, the homozygous null (−/−, KO) mice exhibited prolonged bleeding times (16.6 ± 3.2 minutes) compared to wild-type littermates (12.1 ± 6.9 minutes) (n = 15, P = 0.03). In addition, when the area of blood deposited on the filter paper was analyzed, a significant increase in area was noted for the homozygous null (−/−, KO) mice (1097.2 ± 390.7 mm2) compared to wild-type littermates (689.1 ± 382.3 mm2) (n = 15, P = 0.01). Differences in the bleeding times obtained at Yale University and the Blood Research Center are most likely the result of subtle differences in technique of particular individuals. It should be noted, however, that at both sites the knockout animals exhibited prolonged bleeding times compared to wild-type mice. Platelet counts performed on blood from wild-type (+/+), heterozygotes (+/−), and homozygotes (−/−) revealed similar platelet numbers (1.03 × 106 ± 1.21 × 105, 1.01 × 106 ± 3.53 × 104, and 9.93 × 105 ± 4.72 × 104, respectively) in all of the mice tested (see Figure 2, Figure 4). Transmission electron microscopy of circulating platelets harvested from wild type (+/+), heterozygotes (+/−), and homozygotes (−/−) revealed no detectable morphological differences (data not shown). Similarly, RBC and WBC counts performed on wild-type and homozygous null mice revealed similar cell numbers. RBC counts were 8.1 × 106 ± 1.3 × 105 for WT (+/+) miceversus 6.9 × 106 ± 1.8 × 105 for KO (−/−) mice (Figure 2B), and WBC counts were 3.25 × 103 ± 3.5 × 102 for WT mice versus 4.0 × 103 ± 1.0 × 102 for KO mice (Figure 2C). Further analysis of the WBC fraction revealed no statistically significant differences in polymorphonuclear leukocyte or lymphocyte fractions (Figure 2, D and E).Figure 4Bleeding times correlate with the recipient after marrow ablation and subsequent engraftment. Groups of WT and KO mice underwent marrow ablation and engraftment with donor bone marrow. Thirty days after engraftment bleeding times and platelet numbers were assessed. A: WT (n = 12) and KO (n = 17) mice exhibited the expected bleeding times (see Figure 2). KO mice engrafted with WT bone marrow (WT ≫ KO, n = 7) exhibited prolonged bleeding times (>20 minutes), whereas WT mice engrafted with either KO (KO ≫ WT, n = 6) or WT (WT ≫ WT, n = 5) bone marrow exhibited bleeding times indistinguishable from WT mice. The vertical lines denote standard deviations. When compared, bleeding times of WT, KO ≫ WT, and WT ≫ WT mice were not statistically different from each other but were statistically different (P < 0.05) from KO and WT ≫ KO mice. Bleeding times for KO and WT ≫ KO mice were not statistically different from each other. B: Platelet counts in the same groups of WT, KO, WT ≫ KO, KO ≫ WT, and WT ≫ WT mice. All mice had appreciable levels of platelets, and there was no correlation between the modest differences in platelet numbers and bleeding times.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In light of recent findings suggesting that modulation of platelet PECAM-1 interactions can influence platelet function,16Varon D Jackson DE Shenkman B Dardik R Tamarin I Savion N Newman PJ Platelet/endothelial cell adhesion molecule-1 serves as a costimulatory agonist receptor that modulates integrin-dependent adhesion and aggregation of human platelets.Blood. 1998; 91: 500-507Crossref PubMed Google Scholar, 27Schimmenti LA Yan HC Madri JA Albelda SM Platelet endothelial cell adhesion molecule, PECAM-1, modulates cell migration.J Cell Physiol. 1992; 153: 417-428Crossref PubMed Scopus (112) Google Scholar, 28Rosenblum WI Murata S Nelson GH Werner PK Ranken R Harmon RC Anti-CD31 delays platelet adhesion/aggregation at sites of endothelial injury in mouse cerebral arterioles.Am J Pathol. 1994; 145: 33-36PubMed Google Scholar, 29Rosenblum WI Nelson GH Wormley B Werner P Wang J Shih CC Role of platelet-endothelial cell adhesion molecule (PECAM) in platelet adhesion/aggregation over injured but not denuded endothelium in vivo and ex vivo.Stroke. 1996; 27: 709-711Crossref PubMed Scopus (69) Google Scholar, 30Rosenblum WI Platelet adhesion and aggregation without endothelial denudation or exposure of basal lamina and/or collagen.J Vasc Res. 1997; 34: 409-417Crossref PubMed Scopus (45) Google Scholar we embarked on a stem cell therapy approach to attempt a correction of the prolonged bleeding time and to gain a better understanding of the role of PECAM-1 roles in thrombosis. As illustrated in Figure 3, A and B, engraftment of wild-type bone marrow stem cells in marrow-ablated PECAM-1-deficient mice resulted in reconstitution of the bone marrow with PECAM-1-positive hematopoietic precursors and circulating blood elements. Platelet counts obtained from these engrafted mice were essentially indistinguishable from those of wild-type mice (1.03 × 106 ± 1.21 × 105versus 8.2 × 105 ± 2.25 × 105, respectively) (Figure 4B). Surprisingly, bleeding times in these mice remained prolonged (more than 20 minutes) (Figure 4A), despite the presence of PECAM-1-positive platelets (Figure 3B). As illustrated in Figure 3, C and D, engraftment of PECAM-1-deficient bone marrow stem cells in marrow-ablated wild-type mice resulted in reconstitution of the bone marrow with PECAM-1-negative hematopoietic precursors and circulating blood elements. Platelet counts obtained from these engrafted mice were also similar to those of wild-type mice (1.03 × 106 ± 1.21 × 105 versus 8.31 × 105 ± 1.77 × 104, respectively) (Figure 4B). Bleeding times in these animals remained normal (11 ± 1.6 minutes) (Figure 4A), despite the presence of PECAM-1-negative platelets (Figure 3D). Figure 3, E and F, illustrates engraftment of WT bone marrow stem cells in marrow-ablated wild-type mice, which resulted in reconstitution of the bone marrow with PECAM-1-positive hematopoietic precursors and circulating blood elements. Taken together, these data suggest that the prolonged bleeding in PECAM-1-deficient animals is due to a vascular rather than a platelet defect. PECAM-1 (CD31) has been implicated as a modulator of a variety of vascular endothelial, polymorphonuclear leukocyte, monocyte, lymphocyte, and platelet functions.2Newman PJ The biology of PECAM-1.J Clin Invest. 1997; 100: S25-S29Crossref PubMed Scopus (134) Google Scholar, 3Newman PJ Switched at birth: a new family for PECAM-1.J Clin Invest. 1999; 103: 5-9Crossref PubMed Scopus (238) Google Scholar, 8Pinter EM Barreuther M Lu T Imhof BA Madri JA Platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) tyrosine phosphorylation state changes during vasculogenesis in the murine conceptus.Am J Pathol. 1997; 150: 1523-1530PubMed Google Scholar, 11Lu TT Yan LG Madri JA Integrin engagement mediates tyrosine dephosphorylation on platelet-endothelial cell adhesion molecule 1.Proc Natl Acad Sci USA. 1996; 93: 11808-11813Crossref PubMed Scopus (98) Google Scholar, 14Kim CS Wang T Madri JA Platelet endothelial cell adhesion molecule-1 expression modulates endothelial cell migration in vitro.Lab Invest. 1998; 78: 583-590PubMed Google Scholar, 27Schimmenti LA Yan HC Madri JA Albelda SM Platelet endothelial cell adhesion molecule, PECAM-1, modulates cell migration.J Cell Physiol. 1992; 153: 417-428Crossref PubMed Scopus (112) Google Scholar Until recently the conclusions drawn regarding the role of PECAM-1 in many of these diverse processes were based on overexpression of dominant negative and dominant positive constructs and antibody blocking and activation studies.28Rosenblum WI Murata S Nelson GH Werner PK Ranken R Harmon RC Anti-CD31 delays platelet adhesion/aggregation at sites of endothelial injury in mouse cerebral arterioles.Am J Pathol. 1994; 145: 33-36PubMed Google Scholar, 29Rosenblum WI Nelson GH Wormley B Werner P Wang J Shih CC Role of platelet-endothelial cell adhesion molecule (PECAM) in platelet adhesion/aggregation over injured but not denuded endothelium in vivo and ex vivo.Stroke. 1996; 27: 709-711Crossref PubMed Scopus (69) Google Scholar, 30Rosenblum WI Platelet adhesion and aggregation without endothelial denudation or exposure of basal lamina and/or collagen.J Vasc Res. 1997; 34: 409-417Crossref PubMed Scopus (45) Google Scholar, 31Wu XW Lian EC Binding properties and inhibition of platelet aggregation by a monoclonal antibody to CD31 (PECAM-1).Arterioscler Thromb Vasc Biol. 1997; 17: 3154-3158Crossref PubMed Scopus (23) Google Scholar The generation of PECAM-1-deficient mice now provides the means to study the a priori significance of the molecule and its physiological relevance from implantation through adulthood. It was expected that knocking out PECAM-1 would produce obvious and catastrophic changes affecting the developing animal. However, likely because of redundancy, PECAM-1-deficient mice are viable, with seemingly subtle functional irregularities. To date the most obvious of these has been a delay at the basal lamina after polymorphonuclear leukocytes migrate through the endothelium, after an inflammatory stimulus.23Duncan GS Andrew DP Takimoto H Kaufman SA Yoshida H Spellberg J Luis de la Pompa J Elia A Wakeham A Karan-Tamir B Muller WA Senaldi G Zukowski MM Mak TW Genetic evidence for functional redundancy of platelet/endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions.J Immunol. 1999; 162: 3022-3030PubMed Google Scholar Our observation of prolonged bleeding times in PECAM-1-deficient mice and data implicating PECAM-1 as a participant in platelet/platelet and platelet/endothelial associations16Varon D Jackson DE Shenkman B Dardik R Tamarin I Savion N Newman PJ Platelet/endothelial cell adhesion molecule-1 serves as a costimulatory agonist receptor that modulates integrin-dependent adhesion and aggregation of human platelets.Blood. 1998; 91: 500-507Crossref PubMed Google Scholar, 28Rosenblum WI Murata S Nelson GH Werner PK Ranken R Harmon RC Anti-CD31 delays platelet adhesion/aggregation at sites of endothelial injury in mouse cerebral arterioles.Am J Pathol. 1994; 145: 33-36PubMed Google Scholar, 29Rosenblum WI Nelson GH Wormley B Werner P Wang J Shih CC Role of platelet-endothelial cell adhesion molecule (PECAM) in platelet adhesion/aggregation over injured but not denuded endothelium in vivo and ex vivo.Stroke. 1996; 27: 709-711Crossref PubMed Scopus (69) Google Scholar, 30Rosenblum WI Platelet adhesion and aggregation without endothelial denudation or exposure of basal lamina and/or collagen.J Vasc Res. 1997; 34: 409-417Crossref PubMed Scopus (45) Google Scholar, 31Wu XW Lian EC Binding properties and inhibition of platelet aggregation by a monoclonal antibody to CD31 (PECAM-1).Arterioscler Thromb Vas" @default.
• W2120691494 created "2016-06-24" @default.
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• W2120691494 date "2000-07-01" @default.
• W2120691494 modified "2023-10-15" @default.
• W2120691494 title "PECAM-1 (CD31) Expression Modulates Bleeding Time in Vivo" @default.
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