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      Differential Effects of Vascular Endothelial Growth Factor-C and Placental Growth Factor-1 on the Hydraulic Conductivity of Frog Mesenteric Capillaries

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          Abstract

          Vascular endothelial growth factors (VEGFs) are known to increase vascular permeability. VEGF-A acts on two receptor tyrosine kinases, VEGF receptor-1 (VEGF-R1 or flt-1) and VEGF receptor-2 (VEGF-R2, flk-1 or KDR). VEGF-C acts only on VEGF-R2 on vascular endothelial cells, whereas placental growth factor-1 (PlGF-1) acts only on VEGF-R1. The effects of perfusion of these receptor-specific proteins on hydraulic conductivity (L<sub>p</sub>) was measured in frog mesenteric capillaries. The effect of PlGF on L<sub>p</sub> was not conclusive, and overall fluid flux did not increase during that time. VEGF-C acutely and transiently increased L<sub>p</sub> (4.5 ± 0.9-fold), which was more obvious in a subset of vessels, in a similar manner to that reported for VEGF-A. In the subset of vessels in which VEGF-C significantly increased L<sub>p</sub> acutely, there was a sustained 12-fold increase in L<sub>p</sub> 20 min after perfusion, but this was not seen in those vessels which did not respond acutely to VEGF-C, or in vessels exposed to PlGF-1. L<sub>p</sub> was also increased 24 h after perfusion with VEGF-C, but not with PlGF-1. Western blot analysis showed that VEGF-R1 and VEGF-R2 are both present in frog tissue. These data show that the VEGFs that stimulate VEGF-R2 chronically increase L<sub>p</sub>, but not those that stimulate VEGF-R1 only. This supports the hypothesis that chronic increases in microvascular permeability induced by VEGF are mediated via activation of VEGF-R2 rather than VEGF-R1.

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          Most cited references 3

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          Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation.

           L W Wu,  L D Mayo,  J Dunbar (2000)
          This study was initiated to identify signaling proteins used by the receptors for vascular endothelial cell growth factor KDR/Flk1, and Flt1. Two-hybrid cloning and immunoprecipitation from human umbilical vein endothelial cells (HUVEC) showed that KDR binds to and promotes the tyrosine phosphorylation of phospholipase Cgamma (PLCgamma). Neither placental growth factor, which activates Flt1, epidermal growth factor (EGF), or fibroblast growth factor (FGF) induced tyrosine phosphorylation of PLCgamma, indicating that KDR is uniquely important to PLCgamma activation in HUVEC. By signaling through KDR, VEGF promoted the tyrosine phosphorylation of focal adhesion kinase, induced activation of Akt, protein kinase Cepsilon (PKCepsilon), mitogen-activated protein kinase (MAPK), and promoted thymidine incorporation into DNA. VEGF activates PLCgamma, PKCepsilon, and phosphatidylinositol 3-kinase independently of one another. MEK, PLCgamma, and to a lesser extent PKC, are in the pathway through which KDR activates MAPK. PLCgamma or PKC inhibitors did not affect FGF- or EGF-mediated MAPK activation. MAPK/ERK kinase inhibition diminished VEGF-, FGF-, and EGF-promoted thymidine incorporation into DNA. However, blockade of PKC diminished thymidine incorporation into DNA induced by VEGF but not FGF or EGF. Signaling through KDR/Flk1 activates signaling pathways not utilized by other mitogens to induce proliferation of HUVEC.
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            Heterodimers of Placenta Growth Factor/Vascular Endothelial Growth Factor

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              Two functional forms of vascular endothelial growth factor receptor-2/Flk-1 mRNA are expressed in normal rat retina.

              Vascular endothelial growth factor (VEGF) is an important mediator of ocular neovascularization by exerting its endothelial specific mitogenic effects through high affinity tyrosine kinase receptors. By screening a rat retina cDNA library, we have isolated a clone encoding the full-length prototypic form of the rat VEGF receptor-2/Flk-1, as well as a short form of the mRNA that encodes the complete seven N-terminal immunoglobulin-like extracellular ligand-binding domains, transmembrane region, NH2-terminal half of the intracellular kinase domain, and kinase insert domain but does not encode the COOH-terminal half of the intracellular kinase domain and carboxyl-terminal region. Both forms of mRNA are detected in rat retina, although the short form is expressed at a lower level. VEGF induced a biphasic increase of cytoplasmic calcium with both forms in HK 293 transfected cells, indicating that both forms of the VEGF receptor-2/Flk-1 are functional and that the COOH-terminal half of the intracellular kinase domain and carboxyl region of VEGF receptor-2/Flk-1 are not strictly necessary for either ligand binding or this biological activity.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2001
                April 2001
                13 April 2001
                : 38
                : 2
                : 176-186
                Affiliations
                aCardiovascular Research Institute, University of Leicester, Leicester, bDepartment of Physiology, University of Bristol, Bristol, UK
                Article
                51044 J Vasc Res 2001;38:176–186
                10.1159/000051044
                11316953
                © 2001 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 8, References: 32, Pages: 11
                Categories
                Research Paper

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