Abstract 565: LPA-PKD-1-HDAC7/NCoR1-FoxO1 Signaling Axis Regulates Endothelial Cell CD36 Transcription and Stimulates Arteriogenic Responses

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Bin Ren ◽  
Devi P Ramakrishnan ◽  
Brian Walcott ◽  
Yiliang Chen ◽  
Brad Best ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Malignant Tumors ◽  
Three Dimensional ◽  
Boyden Chamber ◽  
Dependent Manner ◽  
Novel Approach ◽  
Signaling Axis

Lysophosphatidic acid (LPA), a bioactive signaling phospholipid, down-regulates CD36 expression in microvascular endothelial cells (MVECs) via protein kinase PKD-1 signaling, thereby abolishing endothelial cell responses to its antiangiogenic ligand thrombospondin-1. However, little is known regarding mechanisms by which MVEC-specific CD36 transcription is regulated. We describe that in MVECs LPA represses CD36 transcription by activating a PKD-1 signaling that induces formation of a HDAC7/NCoR1/FoxO1 complex in the nucleus. Promoter analysis first identified FoxO1 as a transcription factor responsible for the CD36 transcription, which was confirmed by a chromatin-immunoprecipitation assay. Using a combination of PKD-1 gene transduction with co-immmunoprecipitation assay, we showed an increased interaction of HDAC7/NCoR1 with FoxO1 in response to LPA. However, HDAC7 and FoxO1 interaction was attenuated with PKD-1 silencing. Furthermore, based on results from an angiogenesis profiling with real time qPCR, doxycycline inducible constitutively active PKD-1 plasmids were transduced into tumor associated endothelial cells using a Lentiviral system to induce the PKD-1 expression. The results showed that turning off CD36 transcription reprograms by PKD-1 signaling was accompanied by an induced expression of ephrin B2 and activation of MAPK/ERK1/2 signaling, which are two critical “molecular signatures” involved in arteriogenesis. Moreover, three dimensional spheroid assay, a modified Boyden Chamber assay and in vivo Matrigel assay revealed that turning off CD36 transcription promoted angiogenesis in vitro and in vivo in a PKD-1-dependent manner. Immunofluorescence microscopy also showed the presence of this signaling pathway in the vasculature of Lewis lung carcinomas grown in cd36 deficient mice. In summary, our data suggest that a LPA-PKD-1-HDAC7/NCoR1-FoxO1 signaling axis is critical for transcriptional regulation of CD36 and mediates silencing of this antiangiogenic switch. This subsequently results in MVEC reprogramming for proangiogenic and arteriogenic responses. Therefore, targeting this signaling cascade could be a novel approach for malignant tumors, cardiovascular ischemia and other thrombotic diseases.

The Tyrophostin Adaphostin (NSC680410) Inhibits Multiple Myeloma Bone Marrow Angiogenesis In Vitro and In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2507-2507 ◽  
Author(s):  
Klaus Podar ◽  
Jing Zhang ◽  
Marc S. Raab ◽  
Sonia Vallet ◽  
Mariateresa Fulciniti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Dependent Manner ◽  
Antiangiogenic Effect ◽  
Myelocytic Leukemia ◽  
Endothelial Cell Growth

Abstract Our own and other previous studies demonstrate marked anti-proliferative activity of the tyrophostin adaphostin (NSC680410) in a variety of hematologic malignancies including chronic myelocytic leukemia (CML), chronic lymphcytic leukemia (CLL), acute myelocytic leukemia (AML), and Multiple Myeloma. Here we show that adaphostin (NSC680410), similar to bortezomib, additionally inhibits tumor angiogenesis within the MM bone marrow (BM) microenvironment. This effect is elicited both indirectly by inhibition of VEGF production and secretion in MM cells, as well as directly by abrogation of endothelial cell growth. Specifically, adaphostin triggers marked downregulation of nuclear c-Myc expression in MM cells. Both adaphostin, as well as specific downregulation of c-Myc using siRNA, lead to a decrease in cobalt chloride- induced Hif-1alpha- expression and Hif-1alpha activity, as evidenced by western blot analysis and expression of Hif-1alpha- driven luciferase, respectively. Indeed secretion of the Hif-1alpha target gene VEGF is markedly inhibited in a dose- and time- dependent manner. Importantly, neither knockdown of c-Abl expression nor exogenous overexpression of caspase- cleavage- induced c-Abl fragment abrogates drug- induced Hif-1alpha downregulation or inhibition of its activity. Taken together, these results indicate the existence of a c-Myc/ Hif-1alpha- dependent, but c-Abl- independent, pathway modulating MM cell production and secretion of VEGF. In contrast, we demonstrate a direct antiangiogenic effect of adaphostin on endothelial cells, similar to H2O2, is mediated via c-Jun upregulation, inhibition of cell proliferation, and the induction of cell apoptosis. Moreover, our data further demonstrate activity of adaphostin within the BM microenvironment. Adaphostin, similar to bortezomib, significantly inhibits VEGF secretion triggered by adhesion of MM cells to BMSCs and endothelial cells. Consequently, conditioned medium derived from adaphostin- treated co-cultures markedly inhibits endothelial cell growth and tubule formation in a dose- dependent manner. Finally, we confirmed these in vitro results using an in vivo xenograft mouse model of human MM. Specifically, western blot analysis, as well as immunohistochemistry, demonstrate marked downregulation of both Hif-1alpha and CD31 in tumors isolated from adaphostin- treated animals versus control animals, confirming the in vivo antiangiogenic effect of adaphostin. Similar effects were obtained using a SCIDhu mouse model as well as a significant decrease of MM- related bone disease, due to anti- VEGF activity of adaphostin. Taken together, these data provide the rationale for the clinical evaluation of adaphostin to target both MM cells and the BM milieu to improve patient outcome in Multiple Myeloma.

ADAMTS13 Promotes Angiogenesis and Modulates VEGF-Mediated Angiogenic Activities

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1145-1145
Author(s):  
Manfai Lee ◽  
Jonathan Baza ◽  
George M. Rodgers
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Endothelial Cell Migration ◽  
Molar Ratio ◽  
Assay Method ◽  
Boyden Chamber ◽  
Dependent Manner

Abstract Abstract 1145 Severe plasma ADAMTS13 deficiency results in the clinical disorder thrombotic thrombocytopenic purpura. However, other potential pathophysiological roles of ADAMTS13 in endothelial cell biology remain unexplored. To assess the possible role of ADAMTS13 in angiogenesis, cell proliferation and migration of human umbilical vein endothelial cells (HUVEC) were studied in vitro. ADAMTS13 was found to be a highly potent chemoattractant, and additionally was capable of neutralizing VEGF activity in two angiogenesis assays-cell proliferation and cell migration. In the Boyden chamber cell migration assay, treatment of endothelial cells with exogenous recombinant ADAMTS13 promoted cell migration in a dose-dependent manner, with 1 ng/mL increasing cell migration across a gelatinized polycarbonate membrane by 14-fold. In the same model, 5 ng/mL VEGF165 (molar ratio of ADAMTS13:VEGF165 = 1/19) only increased cell migration by 7 fold. A steady decrease in endothelial cell migration was observed when the concentration of ADAMTS13 exceeded 1 ng/mL (Figure 1). Coincubation of 30 ng/mL ADAMTS13 with 6.16 ng/mL VEGF165 (molar ratio of ADAMTS13/VEGF165 = 1.3/1) inhibited endothelial cell migration by 45% compared to VEGF alone (Figure 2). A second model using an in vitro scratch-wound assay confirmed the Boyden chamber data. Substitution of ADAMTS13 with ADAM17, an analog of ADAMTS13 without the thrombospondin domain reversed the inhibition of VEGF-mediated cell migration, suggesting that the thrombospondin domain of ADAMTS13 is responsible for the inhibitory interaction with VEGF165. This finding was in agreement with our previously published co-immunoprecipitation assay data (Blood 2010, 116, 4307). Similar patterns of inhibition were observed with VEGF121 and VEGF189, indicating that other isoforms of VEGF may interact with the TSP domain of ADAMTS13. Using a manual proliferation assay method, HUVEC treated with 30 ng/mL ADAMTS13 and 6.16 ng/mL VEGF165 proliferated 40% slower than the control treated with VEGF alone. Combined with our findings on the inhibition of endothelial cell-tube formation in a Matrigel assay with ADAMTS13 and VEGF165 previously reported, our cumulative data suggest that 1) ADAMTS13 promotes angiogenesis by increasing cell migration and 2) ADAMTS13 can modulate VEGF-mediated angiogenic activities. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Lysophosphatidic acid suppresses endothelial cell CD36 expression and promotes angiogenesis via a PKD-1–dependent signaling pathway

Blood ◽  
2011 ◽  
Vol 117 (22) ◽  
pp. 6036-6045 ◽  
Author(s):  
Bin Ren ◽  
James Hale ◽  
Sowmya Srikanthan ◽  
Roy L. Silverstein
Keyword(s):  
Endothelial Cell ◽  
Signaling Pathway ◽  
Lysophosphatidic Acid ◽  
Malignant Tumors ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Down Regulation ◽  
Thrombospondin 1

Abstract In pathologic settings including retinal ischemia and malignant tumors, robust angiogenesis occurs despite the presence in the microenvironment of antiangiogenic proteins containing thrombospondin structural homology (TSR) domains. We hypothesized that antiangiogenesis mediated by TSR-containing proteins could be blunted by localized down-regulation of their cognate receptor on microvascular endothelial cells (MVECs), CD36. Through screening a panel of endothelial cell agonists, we found that lysophosphatidic acid (LPA) dramatically down-regulated CD36 surface expression on primary MVECs. LPA is a lipid-signaling mediator known to have proangiogenic activity, but the mechanisms are largely unknown. We observed that LPA caused CD36 down-regulation in a dose- and time-dependent manner and was long lasting. Down-regulation occurred at the transcriptional level via a signaling pathway involving specific LPA receptors and protein kinase D. LPA-induced MVEC CD36 repression significantly attenuated in vitro antiangiogenic responses to thrombospondin-1, including blockade of migration, tube formation, and VEGFR-2 signaling in response to fibroblast growth factor-2. In vivo relevance was demonstrated by showing that LPA abrogated thrombospondin-1–mediated inhibition of neovascularization of Matrigel plugs implanted in mice. Our data thus indicate that the proangiogenic mechanism of LPA may in part be via switching off the antiangiogenic switch mediated by TSR proteins and CD36.

Intracellular diaphragmed fenestrae in cultured capillary endothelial cells

1988 ◽  
Vol 89 (3) ◽  
pp. 441-447 ◽  
Author(s):  
R. Montesano ◽  
L. Orci
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Three Dimensional ◽  
Collagen Matrix ◽  
Cell Cytoplasm ◽  
Experimental Conditions ◽  
Intracellular Location ◽  
Capillary Endothelial Cells

The endothelium of visceral capillaries is characterized by the occurrence of numerous fenestrae, which are usually bridged by a thin, single-layered diaphragm. Both in vivo and in vitro, diaphragmed fenestrae perforate the endothelial cell cytoplasm in the most attenuated regions of the cell. We report here that in capillary endothelial cells grown under experimental conditions promoting the development of intracellular lumina (for example, suspension within a three-dimensional collagen matrix), diaphragmed fenestrae can form in a unique, previously undescribed intracellular location - that is, within thin cytoplasmic septa separating contiguous luminal compartments.

scholarly journals Perfusion Flow Enhances Osteogenic Gene Expression and the Infiltration of Osteoblasts and Endothelial Cells into Three-Dimensional Calcium Phosphate Scaffolds

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Matthew J. Barron ◽  
Jeremy Goldman ◽  
Chung-Jui Tsai ◽  
Seth W. Donahue
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Three Dimensional ◽  
Mrna Levels ◽  
Cellular Viability ◽  
Vegf Mrna ◽  
Perfusion Flow

Maintaining cellular viabilityin vivoandin vitrois a critical issue in three-dimensional bone tissue engineering. While the use of osteoblast/endothelial cell cocultures on three-dimensional constructs has shown promise for increasingin vivovascularization,in vitromaintenance of cellular viability remains problematic. This study used perfusion flow to increase osteogenic and angiogenic gene expression, decrease hypoxic gene expression, and increase cell and matrix coverage in osteoblast/endothelial cell co-cultures. Mouse osteoblast-like cells (MC3T3-E1) were cultured alone and in co-culture with mouse microvascular endothelial cells (EOMA) on three-dimensional scaffolds for 1, 2, 7, and 14 days with or without perfusion flow. mRNA levels were determined for several osteogenic, angiogenic, and hypoxia-related genes, and histological analysis was performed. Perfusion flow downregulated hypoxia-related genes (HIF-1α, VEGF, and OPN) at early timepoints, upregulated osteogenic genes (ALP and OCN) at 7 days, and downregulated RUNX-2 and VEGF mRNA at 14 days in osteoblast monocultures. Perfusion flow increased cell number, coverage of the scaffold perimeter, and matrix area in the center of scaffolds at 14 days. Additionally, perfusion flow increased the length of endothelial cell aggregations within co-cultures. These suggest perfusion stimulated co-cultures provide a means of increasing osteogenic and angiogenic activity.

scholarly journals Structure and Function of a Vimentin-associated Matrix Adhesion in Endothelial Cells

2001 ◽  
Vol 12 (1) ◽  
pp. 85-100 ◽  
Author(s):  
Meredith Gonzales ◽  
Babette Weksler ◽  
Daisuke Tsuruta ◽  
Robert D. Goldman ◽  
Kristine J. Yoon ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factors ◽  
Endothelial Cell ◽  
Branching Morphogenesis ◽  
Basement Membranes ◽  
Αvβ3 Integrin ◽  
Dependent Manner ◽  
Matrix Adhesion ◽  
Focal Contacts

The α4 laminin subunit is a component of endothelial cell basement membranes. An antibody (2A3) against the α4 laminin G domain stains focal contact-like structures in transformed and primary microvascular endothelial cells (TrHBMECs and HMVECs, respectively), provided the latter cells are activated with growth factors. The 2A3 antibody staining colocalizes with that generated by αv and β3 integrin antibodies and, consistent with this localization, TrHBMECs and HMVECs adhere to the α4 laminin subunit G domain in an αvβ3-integrin–dependent manner. The αvβ3 integrin/2A3 antibody positively stained focal contacts are recognized by vinculin antibodies as well as by antibodies against plectin. Unusually, vimentin intermediate filaments, in addition to microfilament bundles, interact with many of the αvβ3 integrin-positive focal contacts. We have investigated the function of α4-laminin and αvβ3-integrin, which are at the core of these focal contacts, in cultured endothelial cells. Antibodies against these proteins inhibit branching morphogenesis of TrHBMECs and HMVECs in vitro, as well as their ability to repopulate in vitro wounds. Thus, we have characterized an endothelial cell matrix adhesion, which shows complex cytoskeletal interactions and whose assembly is regulated by growth factors. Our data indicate that this adhesion structure may play a role in angiogenesis.

Abstract 116: Arterial Endothelial Cell Has Stronger Angiogenic Potential Compared To Venous Endothelial Cell Through Up-regulation Of Endogenous FGF2 And FGF5 Expression In 3D Microfluidic System

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Ha-Rim Seo ◽  
Hyo Eun Jeong ◽  
Hyung Joon Joo ◽  
Seung-Cheol Choi ◽  
Jong-Ho Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Molecular Mechanisms ◽  
Umbilical Vein ◽  
Assay System ◽  
Vascular Density ◽  
Angiogenic Potential ◽  
Angiogenesis Assay

Background: Human body contains many kinds of different type of endothelial cells (EC). However, cellular difference of their angiogenic potential has been hardly understood. We compared in vitro angiogenic potential between arterial EC and venous EC and investigated its underlying molecular mechanisms. Method: Used human aortic endothelial cells (HAEC) which was indicated from arterial EC and human umbilical vein endothelial cells (HUVEC) indicated from venous EC. To explore angiogenic potential in detail, we adopted a novel 3D microfluidic angiogenesis assay system, which closely mimic in vivo angiogenesis. Results: In 3D microfluidic angiogenesis assay system, HAEC demonstrated stronger angiogenic potential compared to HUVEC. HAEC maintained its profound angiogenic property under different biophysical conditions. In mRNA microarray sorted on up- regulated or down-regulated genes, HAEC demonstrated significantly higher expression of gastrulation brain homeobox 2 (GBX2), fibroblast grow factor 2 (FGF2), FGF5 and collagen 8a1. Angiogenesis-related protein assay revealed that HAEC has higher secretion of endogenous FGF2 than HUVEC. HAEC has only up-regulated FGF2 and FGF5 in this part of FGF family. Furthermore, FGF5 expression under vascular endothelial growth factor-A (VEGF-A) stimulation was higher in HAEC compared to HUVEC although VEGF-A augmented FGF5 expression in both HAEC and HUVEC. Those data suggested that FGF5 expression in both HAEC and HUVEC is partially dependent to VEGF-A stimulate. HUVEC and HAEC reduced vascular density after FGF2 and FGF5 siRNA treat. Conclusion: HAEC has stronger angiogenic potential than HUVEC through up-regulation of endogenous FGF2 and FGF5 expression

Abstract 531: Tie-2/Cre--Mediated Conditional Deletion of Lipid Phosphate Phosphatase-3 Reveals Its Role in Endothelial Cell Apoptosis

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Ishita Chatterjee ◽  
Kishore K Wary
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Genome Wide Association Study ◽  
Vascular Endothelial Cell ◽  
Protein Levels ◽  
Conditional Deletion ◽  
Transmission Electron ◽  
Increased Risk

Rationale: A recent genome-wide association study (GWAS) has linked a frequently occurring variation in the LPP3 (also known as PPAP2b) loci to increased risk of coronary heart disease (CAD). However, the in vivo function of LPP3 in vascular endothelial cell is incompletely understood. Goal: To address the endothelial cell (EC) specific function of Lpp3 in mice. Results: Tie-2/Cre mediated Lpp3 deletion did not affect normal vasculogenesis in early embryonic development, in contrast, in late embryonic stages it led to impaired angiogenesis associated with hemorrhage, edema and late embryonic lethal phenotype. Immunohistochemical staining followed by microscopic analyses of mutant embryos revealed reduced fibronectin and VE-cadherin expression throughout different vascular bed, and increased apoptosis in CD31+ vascular structures. Transmission electron microscopy (TEM) showed the presence of apoptotic endothelial cells and disruption of adherens junctions in mutant embryos. LPP3-knockdown in vitro showed an increase in p53 and p21 protein levels, with concomitant decrease in cell proliferation. LPP3-knockdown also decreased transendothelial electrical resistance (TER), interestingly re-expression of ß-catenin cDNA into LPP3-depleted endothelial cells partially restored the effect of loss of LPP3. Conclusion: These results suggest the ability of LPP3 to regulate survival and apoptotic activities of endothelial cells during patho/physiological angiogenesis.

Shear Stress Modulates the Expression of Thrombospondin-1 and CD36 in Endothelial Cells in vitro and during Shear Stress-Induced Angiogenesis in vivo

2006 ◽  
Vol 19 (1) ◽  
pp. 205873920601900 ◽  
Author(s):  
M. Bongrazio ◽  
L. DA Silva-Azevedo ◽  
E.C. Bergmann ◽  
O. Baum ◽  
B. Hinz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Western Blot ◽  
Dependent Manner ◽  
Vascular Networks ◽  
Thrombospondin 1 ◽  
Matrix Bound ◽  
Stress Dependent

Binding of thrombospondin-1 (TSP-1) to the CD36 receptor inhibits angiogenesis and induces apoptosis in endothelial cells (EC). Conversely, matrix-bound TSP-1 supports vessel formation. In this study we analyzed the shear stress-dependent expression of TSP-1 and CD36 in endothelial cells in vitro and in vivo to reveal its putative role in the blood flow-induced remodelling of vascular networks. Shear stress was applied to EC using a cone-and-plate apparatus and gene expression was analyzed by RT-PCR, Northern and Western blot. Angiogenesis in skeletal muscles of prazosin-fed (50 mg/1 drinking water; 4 d) mice was assessed by measuring capillary-to-fiber (C/F) ratios. Protein expression in whole muscle homogenates (WMH) or BS-1 lectin-enriched EC fractions (ECF) was analyzed by Western blot. Shear stress down-regulated TSP-1 and CD36 expression in vitro in a force- and time-dependent manner sustained for at least 72 h and reversible by restoration of no-flow conditions. In vivo, shear stress-driven increase of C/F in prazosin-fed mice was associated with reduced expression of TSP-1 and CD36 in ECF, while TSP-1 expression in WMH was increased. Down-regulation of endothelial TSP-1/CD36 by shear stress suggests a mechanism for inhibition of apoptosis in perfused vessels and pruning in the absence of flow. The increase of extra-endothelial (e.g. matrix-bound) TSP-1 could support a splitting type of vessel growth.

Vascular endothelial growth factor (VEGF) in cartilage neovascularization and chondrocyte differentiation: auto-paracrine role during endochondral bone formation

2000 ◽  
Vol 113 (1) ◽  
pp. 59-69 ◽  
Author(s):  
M.F. Carlevaro ◽  
S. Cermelli ◽  
R. Cancedda ◽  
F. Descalzi Cancedda
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Hypertrophic Chondrocytes ◽  
Endothelial Cell Migration ◽  
Vegf Receptor ◽  
Hypertrophic Cartilage ◽  
Endothelial Growth Factor

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) induces endothelial cell migration and proliferation in culture and is strongly angiogenic in vivo. VEGF synthesis has been shown to occur in both normal and transformed cells. The receptors for the factor have been shown to be localized mainly in endothelial cells, however, the presence of VEGF synthesis and the VEGF receptor in cells other than endothelial cells has been demonstrated. Neoangiogenesis in cartilage growth plate plays a fundamental role in endochondral ossification. We have shown that, in an avian in vitro system for chondrocyte differentiation, VEGF was produced and localized in cell clusters totally resembling in vivo cartilage. The factor was synthesized by hypertrophic chondrocytes and was released into their conditioned medium, which is highly chemotactic for endothelial cells. Antibodies against VEGF inhibited endothelial cell migration induced by chondrocyte conditioned media. Similarly, endothelial cell migration was inhibited also by antibodies directed against the VEGF receptor 2/Flk1 (VEGFR2). In avian and mammalian embryo long bones, immediately before vascular invasion, VEGF was distinctly localized in growth plate hypertrophic chondrocytes. In contrast, VEGF was not observed in quiescent and proliferating chondrocytes earlier in development. VEGF receptor 2 colocalized with the factor both in hypertrophic cartilage in vivo and hypertrophic cartilage engineered in vitro, suggesting an autocrine loop in chondrocytes at the time of their maturation to hypertrophic cells and of cartilage erosion. Regardless of cell exposure to exogenous VEGF, VEGFR-2 phosphorylation was recognized in cultured hypertrophic chondrocytes, supporting the idea of an autocrine functional activation of signal transduction in this non-endothelial cell type as a consequence of the endogenous VEGF production. In summary we propose that VEGF is actively responsible for hypertrophic cartilage neovascularization through a paracrine release by chondrocytes, with invading endothelial cells as a target. Furthermore, VEGF receptor localization and signal transduction in chondrocytes strongly support the hypothesis of a VEGF autocrine activity also in morphogenesis and differentiation of a mesoderm derived cell.

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