scholarly journals Recapitulating the Angiogenic Switch in a Hydrogel-Based 3D In Vitro Tumor-Stroma Model

2021 ◽  
Vol 8 (11) ◽  
pp. 186
Author(s):  
Claudia Kuehlbach ◽  
Sabine Hensler ◽  
Margareta M. Mueller
Keyword(s):  
Endothelial Cells ◽  
High Throughput Screening ◽  
Vascular System ◽  
Tumor Stroma ◽  
Tubular Structures ◽  
Continuous Increase ◽  
Angiogenic Switch ◽  
Cultivation Period

To ensure nutrient and oxygen supply, tumors beyond a size of 1–2 mm3 need a connection to the vascular system. Thus, tumor cells modify physiological tissue homeostasis by secreting inflammatory and angiogenic cytokines. This leads to the activation of the tumor microenvironment and the turning of the angiogenic switch, resulting in tumor vascularization and growth. To inhibit tumor growth by developing efficient anti-angiogenic therapies, an in depth understanding of the molecular mechanism initiating angiogenesis is essential. Yet so far, predominantly 2D cell cultures or animal models have been used to clarify the interactions within the tumor stroma, resulting in poor transferability of the data obtained to the in vivo situation. Consequently, there is an abundant need for complex, humanized, 3D models in vitro. We established a dextran-hydrogel-based 3D organotypic in vitro model containing microtumor spheroids, macrophages, neutrophils, fibroblasts and endothelial cells, allowing for the analysis of tumor–stroma interactions in a controlled and modifiable environment. During the cultivation period of 21 days, the microtumor spheroids in the model grew in size and endothelial cells formed elongated tubular structures resembling capillary vessels, that appeared to extend towards the tumor spheroids. The tubular structures exhibited complex bifurcations and expanded without adding external angiogenic factors such as VEGF to the culture. To allow high-throughput screening of therapeutic candidates, the 3D cell culture model was successfully miniaturized to a 96-well format, while still maintaining the same level of tumor spheroid growth and vascular sprouting. The quantification of VEGF in the conditioned medium of these cultures showed a continuous increase during the cultivation period, suggesting the contribution of endogenous VEGF to the induction of the angiogenic switch and vascular sprouting. Thus, this model is highly suitable as a testing platform for novel anticancer therapeutics targeting the tumor as well as the vascular compartment.

PPARs and angiogenesis

2011 ◽  
Vol 39 (6) ◽  
pp. 1601-1605 ◽  
Author(s):  
David Bishop-Bailey
Keyword(s):  
Endothelial Cells ◽  
Critical Role ◽  
Molecular Target ◽  
Experimental Models ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Angiogenic Switch ◽  
Receptor Family

The PPAR (peroxisome-proliferator-activated receptor) family consists of three ligand-activated nuclear receptors: PPARα, PPARβ/δ and PPARγ. These PPARs have important roles in the regulation of glucose and fatty acid metabolism, cell differentiation and immune function, but were also found to be expressed in endothelial cells in the late 1990s. The early endothelial focus of PPARs was PPARγ, the molecular target for the insulin-sensitizing thiazolidinedione/glitazone class of drugs. Activation of PPARγ was shown to inhibit angiogenesis in vitro and in models of retinopathy and cancer, whereas more recent data point to a critical role in the development of the vasculature in the placenta. Similarly, PPARα, the molecular target for the fibrate class of drugs, also has anti-angiogenic properties in experimental models. In contrast, unlike PPARα or PPARγ, activation of PPARβ/δ induces angiogenesis, in vitro and in vivo, and has been suggested to be a critical component of the angiogenic switch in pancreatic cancer. Moreover, PPARβ/δ is an exercise mimetic and appears to contribute to the angiogenic remodelling of cardiac and skeletal muscle induced by exercise. This evidence and the emerging mechanisms by which PPARs act in endothelial cells are discussed in more detail.

Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 1810-1817 ◽  
Author(s):  
Annemie Collen ◽  
Roeland Hanemaaijer ◽  
Florea Lupu ◽  
Paul H. A. Quax ◽  
Natascha van Lent ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Collagen Matrix ◽  
Tubular Structures ◽  
Tubule Formation ◽  
Tnf Α ◽  
Membrane Type

Adult angiogenesis, associated with pathologic conditions, is often accompanied by the formation of a fibrinous exudate. This temporary matrix consists mainly of fibrin but is intermingled with plasma proteins and collagen fibers. The formation of capillary structures in a fibrinous matrix in vivo was mimicked by an in vitro model, in which human microvascular endothelial cells (hMVECs) seeded on top of a fibrin-10% collagen matrix form capillarylike tubular structures after stimulation with basic fibroblast growth factor/tumor necrosis factor α (bFGF/TNF-α) or vascular endothelial growth factor (VEGF)/TNF-α. In the fibrin-collagen matrix the metalloproteinase inhibitor BB94 inhibited tubule formation by 70% to 80%. Simultaneous inhibition of plasmin and metalloproteinases by aprotinin and BB94 caused a nearly complete inhibition of tubule formation. Adenoviral transduction of tissue inhibitor of metalloproteinases 1 (TIMP-1) and TIMP-3 into endothelial cells revealed that TIMP-3 markedly inhibited angiogenesis, whereas TIMP-1 had only a minor effect. Immunohistochemical analysis showed the presence of matrix metalloproteinase 1 (MMP-1), MMP-2, and membrane-type 1 (MT1)–MMP, whereas MMP-9 was absent. The endothelial production of these MMPs was confirmed by antigen assays and real-time polymerase chain reaction (PCR). MT1-MMP mRNA was markedly increased in endothelial cells under conditions that induced tubular structures. The presence of MMP-1, MMP-2, and MT1-MMP was also demonstrated in vivo in the newly formed vessels of a recanalized arterial mural thrombus. These data suggest that MMPs, in particular MT-MMPs, play a pivotal role in the formation of capillarylike tubular structures in a collagen-containing fibrin matrix in vitro and may be involved in angiogenesis in a fibrinous exudate in vivo.

Oncogenic Transcription Factor Evi1 Regulates Hematopoietic Stem Cell Proliferation through GATA-2 Expression.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 228-228 ◽  
Author(s):  
Hiromi Yuasa ◽  
Yuichi Oike ◽  
Atsushi Iwama ◽  
Daisuke Sugiyama ◽  
Ichiro Nishikata ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Network Formation ◽  
Vascular System ◽  
Upstream Region ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Adult Bone

Abstract Chromosomal abnormalities, such as translocation, mutation or deletion, are central to the pathogenesis of human cancers. Recently, several transcription factors have been isolated as genes responsible for leukemia from the region surrounding chromosomal breakpoints, which are implicated in the regulation of normal hematopoiesis. Among on them, ecotropic viral integration site-1 (Evi1) is a transcription factor activated by retroviral integration in murine leukemias and chromosomal rearrangements in human leukemias. Evi1 is a zinc finger transcription factor and contains two separated DNA-binding domains. It was reported that Evi1−/− embryos die at approximately E10.5, exhibiting widespread hypocellularity and hemorrhaging. However, the role in normal hematopoiesis or authentic target genes of Evi1 has not been elucidated. Here, we show that Evi1 is predominantly expressed in hematopoietic stem cells (HSCs) in embryos and adult bone marrows, and Evi1−/− embryos are markedly decreased in numbers of HSC. One embryo-equivalent cells from E9.5 P-Sp of Evi1+/+, Evi1+/− and Evi1−/− embryos (Ly5.2) were transplanted into a busulfan-conditioned newborn recipient (Ly5.1). At 2 months posttransplant, donor-derived Ly5.2(+) cells could be detected in the peripheral blood of the recipients that received P-Sp cells from the Evi1+/+ and Evi1+/− but not from the Evi1−/− embryos. Thus, Evi1 is critical for the generation of HSCs in the P-Sp. Both Evi1−/− embryos and yolk sac showed marked retardation in the organization of the vascular system, particularly in vascular remodeling, compared with controls. Using an in vitro P-Sp culture analysis, we found normal in vitro differentiation of endothelial cells in Evi1−/− P-Sp cultures but defects in their in vitro network formation, which is normally promoted by Ang-1 secreted from developing HSCs in P-Sp cultures. HSCs from adult bone marrow or HSCs from E9.5 wild type embryos rescued defective angiogenesis in Evi1−/− embryos. The fine vascular network coincided with the region where HSCs formed a colony. Their round morphology confirmed that exogenous adult HSCs did not differentiate into elongated endothelial cells. We showed that recombinant Ang-1 alone restored the defective angiogenesis in Evi1−/− embryos to a wild type level. It is suggested that the defect in hematopoietic cells induced defective angiogenesis in Evi1−/− embryos mediated by Ang-1. Notably, mRNA expression of GATA-2, which is essential for proliferation of definitive HSCs, was profoundly reduced in Evi1−/− embryos. Analysis of the GATA-2 promotor revealed that Evi1 directly binds to the 5′ upstream region of the GATA−2 exon and positively regulates its promoter activity in vitro and in vivo. Restoration of GATA-2 expression dramatically rescued the defective expansion of Evi1−/− embryos HSCs in vitro. Our results reveal that GATA-2 is a critical in vivo target for Evi1 and indicate hierarchical regulation of the HSC pool by transcriptional regulators.

Dasatinib Inhibits Multiple Myeloma Growth by Blocking PDGF-Rb and c-Src Activity in Patient-Derived Tumor and Endothelial Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 550-550
Author(s):  
Addolorata M.L. Coluccia ◽  
Teresa Cirulli ◽  
Paola Neri ◽  
Franco Dammacco ◽  
Pierfrancesco Tassone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Plasma Cells ◽  
High Dose ◽  
Tumor Vessel ◽  
Angiogenic Switch ◽  
Synergistic Cytotoxicity

Abstract Multiple myeloma (MM) is characterized by a clonal proliferation of immunoglobulin-secreting plasma cells in the bone-marrow (BM) and remains an incurable disease, despite the use of high-dose chemotherapies. Since a marked (BM)-angiogenesis is the hallmark of MM, but not of monoclonal gammopathies of undetermined significance (MGUS), validation of novel agents targeting MM tumor cells and their permissive BM-stroma is crucial to improve patient outcome. Patients fulfilling the International Myeloma Working Group diagnostic criteria for MM (n = 21) and MGUS (n = 14) were studied. Healthy donors or patients with benign anemia (due to vitamin B12 deficiency) were also incuded as controls. In plasma cells and endothelial cells (ECs) isolated from BM-aspirates by anti-CD138 and Ulex Europaeus agglutinin-1 (UEA-1) coated-beads, we dissected the contribution of activity against individual targets such as platelet-derived growth factor (PDGF)-receptor beta (PDGF-Rb) and c-Src tyrosine kinases (TKs), to the anti-tumor/vessel efficacy of dasatinib (BMS-354825), a novel orally bioavailable TK inhibitor. The PDGF-BB/PDGF-Rb kinase-axis was found constitutively activated in plasma cells from patients with MM but not with MGUS or benign anemias, thus supporting its pathophysiological role in MM. PDGF-Rb activated, independently of vascular endothelial growth factor (VEGF)-receptors (VEGF-R1 and VEGF-R2), the mitogen-activated protein kinases (ERK1/2) and the phosphatidylinositol 3-kinase (PI3-K)/AKT-dependent cascade, thereby increasing MM plasma cell growth. Expression of PDGF-Rb, at both mRNA and protein levels, was also increased in MMECs compared to MGECs, correlating with AKT phosphorylation. Exposure to recombinant PDGF-BB or conditioned media from MM plasma cells triggered PDGF-Rb phosphorylation and MMEC migration and spontaneous sprouting in vitro (both being mandatory for angiogenesis). Dasatinib abrogated PDGF-elicited tumor/vessel growth and impaired VEGF-signaling via c-Src TK-inhibition (IC50=25–100nM) in both MM-patient tumor and ECs. The use of small-interfering (si)-RNAs validated c-Src as a key VEGF-downstream effector of MMEC proliferation, migration and capillarogenesis in vitro. Nevertheless, the inhibitory effect elicited by siSrc was partially rescued by recombinant PDGF-BB which sustained the expression of pro-angiogenic factors such as VEGF, interleukin (IL)-8, basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) in MMECs. Dasatinib reversed all these transcriptional effects, thereby abrogating MMEC angiogenesis in the CAM assay as well as the neovascularization and tumor growth of MM-xenografts in vivo. More importantly, low-dose dasatinib showed synergistic cytotoxicity in vitro when tested in combination with conventional MM drugs (i.e. bortezomib and thalidomide), thereby increasing therapeutic efficacy and overcoming drug resistance. These findings indicate that: the PDGF-BB/PDGF-Rb kinase-axis elicits direct effects on MM plasma cells and could promote the MM “angiogenic switch”, hence disease progression; the inhibition of this pathway could provide the rationale for clinical trials with dasatinib which interferes with shared growth-signaling cascades in MM-patient isolated plasma cells and ECs, involving PDGF-Rb and cytosolic c-Src TKs.

Transcriptomal comparison of human dermal lymphatic endothelial cells ex vivo and in vitro

2007 ◽  
Vol 28 (2) ◽  
pp. 179-192 ◽  
Author(s):  
Nikolaus Wick ◽  
Pipsa Saharinen ◽  
Juha Saharinen ◽  
Elisabeth Gurnhofer ◽  
Carl W. Steiner ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular System ◽  
Vascular Endothelial Cells ◽  
Ex Vivo ◽  
Lymphatic Endothelial Cell ◽  
Marker Genes ◽  
Lymphatic Endothelial Cells ◽  
Extracellular Matrix Components

The in vivo functions of lymphatic endothelial cells depend on their microenvironment, which cannot be fully reproduced in vitro. Because of technical limitations, gene expression in uncultured, “ex vivo” lymphatic endothelial cells has not been characterized at the molecular level. We combined tissue micropreparation and direct cell isolation with DNA chip experiments to identify 159 genes differentiating human lymphatic endothelial cells from blood vascular endothelial cells ex vivo. The same analysis performed with cultured primary cells revealed that only 19 genes characteristic for lymphatic endothelium ex vivo retained this property upon culture, while 27 marker genes were newly induced. In addition, a set of panendothelial genes could be recognized. The propagation of lymphatic endothelial cells in culture stimulated transcription of genes associated with cell turnover, basic metabolism, and the cytoskeleton. On the other hand, there was downregulation of genes encoding extracellular matrix components, signaling via transmembrane tyrosine kinase pathways and the chemokine (C-C) ligand 21. Direct ex vivo analysis of the lymphatic endothelial cell transcriptome is helpful for the understanding of the physiology of the lymphatic vascular system and of the pathogenesis of its diseases.

scholarly journals miR-31 Functions as a Negative Regulator of Lymphatic Vascular Lineage-Specific Differentiation In Vitro and Vascular Development In Vivo

2010 ◽  
Vol 30 (14) ◽  
pp. 3620-3634 ◽  
Author(s):  
Deena M. Leslie Pedrioli ◽  
Terhi Karpanen ◽  
Vasilios Dabouras ◽  
Giorgia Jurisic ◽  
Glenn van de Hoek ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular System ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Vascular Development ◽  
Negative Regulator ◽  
Tissue Fluid ◽  
Specific Differentiation

ABSTRACT The lymphatic vascular system maintains tissue fluid homeostasis, helps mediate afferent immune responses, and promotes cancer metastasis. To address the role microRNAs (miRNAs) play in the development and function of the lymphatic vascular system, we defined the in vitro miRNA expression profiles of primary human lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BVECs) and identified four BVEC signature and two LEC signature miRNAs. Their vascular lineage-specific expression patterns were confirmed in vivo by quantitative real-time PCR and in situ hybridization. Functional characterization of the BVEC signature miRNA miR-31 identified a novel BVEC-specific posttranscriptional regulatory mechanism that inhibits the expression of lymphatic lineage-specific transcripts in vitro. We demonstrate that suppression of lymphatic differentiation is partially mediated via direct repression of PROX1, a transcription factor that functions as a master regulator of lymphatic lineage-specific differentiation. Finally, in vivo studies of Xenopus and zebrafish demonstrated that gain of miR-31 function impaired venous sprouting and lymphatic vascular development, thus highlighting the importance of miR-31 as a negative regulator of lymphatic development. Collectively, our findings identify miR-31 is a potent regulator of vascular lineage-specific differentiation and development in vertebrates.

scholarly journals Fibrin and Collagen Differentially but Synergistically Regulate Sprout Angiogenesis of Human Dermal Microvascular Endothelial Cells in 3-Dimensional Matrix

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Xiaodong Feng ◽  
Marcia G. Tonnesen ◽  
Shaker A. Mousa ◽  
Richard A. F. Clark
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Type I Collagen ◽  
Three Dimensional ◽  
Tumor Stroma ◽  
Microvascular Endothelial Cells ◽  
Type I ◽  
Microvascular Endothelial

Angiogenesis is a highly regulated event involving complex, dynamic interactions between microvascular endothelial cells and extracellular matrix (ECM) proteins. Alteration of ECM composition and architecture is a hallmark feature of wound clot and tumor stroma. We previously reported that during angiogenesis, endothelial cell responses to growth factors are modulated by the compositional and mechanical properties of a surrounding three-dimensional (3D) extracellular matrix (ECM) that is dominated by either cross-linked fibrin or type I collagen. However, the role of 3D ECM in the regulation of angiogenesis associated with wound healing and tumor growth is not well defined. This study investigates the correlation of sprout angiogenesis and ECM microenvironment using in vivo and in vitro 3D angiogenesis models. It demonstrates that fibrin and type I collagen 3D matrices differentially but synergistically regulate sprout angiogenesis. Thus blocking both integrin alpha v beta 3 and integrin alpha 2 beta 1 might be a novel strategy to synergistically block sprout angiogenesis in solid tumors.

scholarly journals The anti-angiogenic compound dimethyl fumarate inhibits the serine synthesis pathway and increases glycolysis in endothelial cells

2021 ◽  
Author(s):  
Maria Carmen Ocana ◽  
Chendong Yang ◽  
Manuel Bernal ◽  
Beatriz Martinez-Poveda ◽  
Hieu S. Vu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Essential Feature ◽  
Cell Metabolism ◽  
Krebs Cycle ◽  
Dimethyl Fumarate ◽  
Angiogenic Switch ◽  
Glycine Synthesis

A pathological and persistent angiogenesis is observed in several diseases like retinopathies, diabetes, psoriasis and cancer. Dimethyl fumarate, an ester from the Krebs cycle intermediate fumarate, is approved as a drug for the treatment of psoriasis and multiple sclerosis, and its anti-angiogenic activity has been reported in vitro and in vivo. However, it is not known whether dimethyl fumarate is able to modulate endothelial cell metabolism, considered an essential feature for the angiogenic switch. By means of different experimental approximations, including proteomics, isotope tracing and metabolomics experimental approaches, in this work we studied the possible role of dimethyl fumarate in endothelial cell energetic metabolism. We demonstrate for the first time that dimethyl fumarate promotes glycolysis and diminishes cell respiration, which could be a consequence of a down-regulation of serine and glycine synthesis through inhibition of PHGDH activity in endothelial cells. This new target can open a new field of study regarding the mechanism of action of dimethyl fumarate.

Desmopressin (DDAVP) Enhances Platelet Adhesion to the Extracellular Matrix of Cultured Human Endothelial Cells through Increased Expression of Tissue Factor

1997 ◽  
Vol 77 (05) ◽  
pp. 0975-0980 ◽  
Author(s):  
Angel Gálvez ◽  
Goretti Gómez-Ortiz ◽  
Maribel Díaz-Ricart ◽  
Ginés Escolar ◽  
Rogelio González-Sarmiento ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Tissue Factor ◽  
Platelet Adhesion ◽  
Umbilical Vein ◽  
Procoagulant Activity ◽  
Experimental Conditions ◽  
Chromogenic Assay

SummaryThe effect of desmopressin (DDAVP) on thrombogenicity, expression of tissue factor and procoagulant activity (PCA) of extracellular matrix (ECM) generated by human umbilical vein endothelial cells cultures (HUVEC), was studied under different experimental conditions. HUVEC were incubated with DDAVP (1, 5 and 30 ng/ml) and then detached from their ECM. The reactivity towards platelets of this ECM was tested in a perfusion system. Coverslips covered with DD A VP-treated ECMs were inserted in a parallel-plate chamber and exposed to normal blood anticoagulated with low molecular weight heparin (Fragmin®, 20 U/ml). Perfusions were run for 5 min at a shear rate of 800 s1. Deposition of platelets on ECMs was significantly increased with respect to control ECMs when DDAVP was used at 5 and 30 ng/ml (p <0.05 and p <0.01 respectively). The increase in platelet deposition was prevented by incubation of ECMs with an antibody against human tissue factor prior to perfusion. Immunofluorescence studies positively detected tissue factor antigen on DDAVP derived ECMs. A chromogenic assay performed under standardized conditions revealed a statistically significant increase in the procoagulant activity of the ECMs produced by ECs incubated with 30 ng/ml DDAVP (p <0.01 vs. control samples). Northern blot analysis revealed increased levels of tissue factor mRNA in extracts from ECs exposed to DDAVP. Our data indicate that DDAVP in vitro enhances platelet adhesion to the ECMs through increased expression of tissue factor. A similar increase in the expression of tissue factor might contribute to the in vivo hemostatic effect of DDAVP.

Epinephrine Induces von Willebrand Factor Release from Cultured Endothelial Cells: Involvement of Cyclic AMP-dependent Signalling in Exocytosis

1997 ◽  
Vol 77 (06) ◽  
pp. 1182-1188 ◽  
Author(s):  
Ulrich M Vischer ◽  
Claes B Wollheinn
Keyword(s):  
Endothelial Cells ◽  
Adenylate Cyclase ◽  
Von Willebrand Factor ◽  
Umbilical Vein ◽  
Free Calcium ◽  
Camp Content ◽  
Von Willebrand ◽  
Willebrand Factor

Summaryvon Willebrand factor (vWf) is released from endothelial cell storage granules after stimulation with thrombin, histamine and several other agents that induce an increase in cytosolic free calcium ([Ca2+]i). In vivo, epinephrine and the vasopressin analog DDAVP increase vWf plasma levels, although they are thought not to induce vWf release from endothelial cells in vitro. Since these agents act via a cAMP-dependent pathway in responsive cells, we examined the role of cAMP in vWf secretion from cultured human umbilical vein endothelial cells. vWf release increased by 50% in response to forskolin, which activates adenylate cyclase. The response to forskolin was much stronger when cAMP degradation was blocked with IBMX, an inhibitor of phosphodiesterases (+200%), whereas IBMX alone had no effect. vWf release could also be induced by the cAMP analogs dibutyryl-cAMP (+40%) and 8-bromo-cAMP (+25%); although their effect was weak, they clearly potentiated the response to thrombin. Epinephrine (together with IBMX) caused a small, dose-dependent increase in vWf release, maximal at 10-6 M (+50%), and also potentiated the response to thrombin. This effect is mediated by adenylate cyclase-coupled β-adrenergic receptors, since it is inhibited by propranolol and mimicked by isoproterenol. In contrast to thrombin, neither forskolin nor epinephrine caused an increase in [Ca2+]j as measured by fura-2 fluorescence. In addition, the effects of forskolin and thrombin were additive, suggesting that they act through distinct signaling pathways. We found a close correlation between cellular cAMP content and vWf release after stimulation with epinephrine and forskolin. These results demonstrate that cAMP-dependent signaling events are involved in the control of exocytosis from endothelial cells (an effect not mediated by an increase in [Ca2+]i) and provide an explanation for epinephrine-induced vWf release.

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