Vascular Endothelial Growth Factor Governs Endothelial Nitric-oxide Synthase Expression via a KDR/Flk-1 Receptor and a Protein Kinase C Signaling Pathway*

The mechanism by which vascular endothelial growth factor (VEGF) regulates endothelial nitric-oxide synthase (eNOS) expression is presently unclear. Here we report that VEGF treatment of bovine adrenal cortex endothelial cells resulted in a 5-fold increase in both eNOS protein and activity. Endothelial NOS expression was maximal following 2 days of constant VEGF exposure (500 pm) and declined to base-line levels by day 5. The elevated eNOS protein level was sustained over the time course if VEGF was co-incubated withl-N G-nitroarginine methyl ester, a competitive eNOS inhibitor. Addition ofS-nitroso-N-acetylpenicillamine, a nitric oxide donor, prevented VEGF-induced eNOS up-regulation. These data suggest that nitric oxide participates in a negative feedback mechanism regulating eNOS expression. Various approaches were used to investigate the role of the two high affinity VEGF receptors in eNOS up-regulation. A KDR receptor-selective mutant increased eNOS expression, whereas an Flt-1 receptor-selective mutant did not. Furthermore, VEGF treatment increased eNOS expression in a KDR but not in an Flt-1 receptor-transfected porcine aorta endothelial cell line. SU1498, a selective inhibitor of the KDR receptor tyrosine kinase, blocked eNOS up-regulation, thus providing further evidence that the KDR receptor signals for eNOS up-regulation. Finally, treatment of adrenal cortex endothelial cells with VEGF or phorbol ester resulted in protein kinase C activation and elevated eNOS expression, whereas inhibition of protein kinase C with isoform-specific inhibitors abolished VEGF-induced eNOS up-regulation. Taken together, these data demonstrate that VEGF increases eNOS expression via activation of the KDR receptor tyrosine kinase and a downstream protein kinase C signaling pathway.

• Publication year

  1999

• Venue

  Journal of Biological Chemistry

• Publication date

  1999-11-12

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.274.46.33057PMID 10551875
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• KDR activation is crucial for VEGF165-mediated Ca2+ mobilization in human umbilical vein endothelial cells.

  1999cited by this paper
• Role of protein kinase C isoforms in phorbol ester-induced vascular endothelial growth factor expression in human glioblastoma cells.

  1999cited by this paper
• Role of Protein Kinase C Isoforms in Phorbol Ester-induced Vascular Endothelial Growth Factor Expression in Human Glioblastoma Cells*

  1999cited by this paper
• The proliferative effect of vascular endothelial growth factor requires protein kinase C-alpha and protein kinase C-zeta.

  1999cited by this paper
• Role of phospholipase C, protein kinase C, and calcium in VEGF-induced venular hyperpermeability.

  1999cited by this paper
• Vascular endothelial growth factor (VEGF) and its receptors

  1999cited by this paper
• Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells.

  1999cited by this paper
• The Proliferative Effect of Vascular Endothelial Growth Factor Requires Protein Kinase C-α and Protein Kinase C-ζ

  1999cited by this paper
• Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis.

  1998cited by this paper
• Nitric oxide synthase modulates angiogenesis in response to tissue ischemia.

  1998cited by this paper
• Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor.

  1998cited by this paper
• Vascular endothelial growth factor inhibits apoptotic death in hematopoietic cells after exposure to chemotherapeutic drugs by inducing MCL1 acting as an antiapoptotic factor.

  1998cited by this paper
• VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells.

  1998cited by this paper
• Nitric oxide synthase expression in endothelial cells exposed to mechanical forces.

  1998cited by this paper
• Neuropilin-1 Is a Placenta Growth Factor-2 Receptor*

  1998cited by this paper
• eNOS-overexpressing mice: too much NO makes the blood pressure low.

  1998cited by this paper
• Regression of vessels in the tunica vasculosa lentis is initiated by coordinated endothelial apoptosis: A role for vascular endothelial growth factor as a survival factor for endothelium

  1998cited by this paper
• Homologous Up-regulation of KDR/Flk-1 Receptor Expression by Vascular Endothelial Growth Factor in Vitro *

  1998cited by this paper
• Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase.

  1998cited by this paper
• VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR).

  1998cited by this paper
• Nitric Oxide Is an Upstream Signal of Vascular Endothelial Growth Factor-induced Extracellular Signal-regulated Kinase½ Activation in Postcapillary Endothelium*

  1998cited by this paper
• Vascular endothelial growth factor stimulates proliferation but not migration or invasiveness in human extravillous trophoblast.

  1998cited by this paper
• Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling.

  1998cited by this paper
• Vascular Endothelial Growth Factor Induces Expression of the Antiapoptotic Proteins Bcl-2 and A1 in Vascular Endothelial Cells*

  1998cited by this paper
• Reciprocal relation between VEGF and NO in the regulation of endothelial integrity

  1997cited by this paper
• Vascular endothelial growth factor and vascular permeability changes in human diabetic retinopathy.

  1997cited by this paper
• VEGF145, a Secreted Vascular Endothelial Growth Factor Isoform That Binds to Extracellular Matrix*

  1997cited by this paper
• Vascular endothelial growth factor inhibits endothelial cell apoptosis induced by tumor necrosis factor-alpha: balance between growth and death signals.

  1997cited by this paper
• Expression and regulation of endothelial nitric oxide synthase.

  1997cited by this paper
• Hepatocyte growth factor stimulates the differentiation of human tracheal epithelia in vitro.

  1997cited by this paper
• Vascular endothelial growth factor/vascular permeability factor augments nitric oxide release from quiescent rabbit and human vascular endothelium.

  1997cited by this paper
• Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis.

  1997cited by this paper
• The Vascular Endothelial Growth Factor Receptor KDR Activates Multiple Signal Transduction Pathways in Porcine Aortic Endothelial Cells*

  1997cited by this paper
• Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells.

  1997cited by this paper
• The biology of vascular endothelial growth factor.

  1997cited by this paper
• Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in normal and atherosclerotic human arteries.

  1997cited by this paper
• Shear stress induction of the endothelial nitric oxide synthase gene is calcium‐dependent but not calcium‐activated

  1997cited by this paper
• Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth.

  1996cited by this paper
• The angiogenesis induced by HIV–1 Tat protein is mediated by the Flk–1/KDR receptor on vascular endothelial cells

  1996cited by this paper
• Nitric oxide and cardiac function.

  1996cited by this paper
• VEGF improves myocardial blood flow but produces EDRF-mediated hypotension in porcine hearts.

  1996cited by this paper
• The Carboxyl-terminal Domain(111165) of Vascular Endothelial Growth Factor Is Critical for Its Mitogenic Potency (*)

  1996cited by this paper
• Outward K+ current in epithelial cells isolated from intermediate portion of endolymphatic sac of guinea pigs.

  1996cited by this paper
• Transforming Growth Factor 1 Down-regulates Vascular Endothelial Growth Factor Receptor 2/flk-1 Expression in Vascular Endothelial Cells (*)

  1996cited by this paper
• Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium.

  1996cited by this paper
• Identification of Vascular Endothelial Growth Factor Determinants for Binding KDR and FLT-1 Receptors

  1996cited by this paper
• Chronic hypoxia upregulates endothelial and inducible NO synthase gene and protein expression in rat lung.

  1996cited by this paper
• Effects of vascular endothelial growth factor on hemodynamics and cardiac performance.

  1996cited by this paper
• Parvalbumin relaxes frog skeletal muscle when sarcoplasmic reticulum Ca(2+)-ATPase is inhibited.

  1996cited by this paper
• VEGF induces NO-dependent hyperpermeability in coronary venules.

  1996cited by this paper
• Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide.

  1995cited by this paper
• Vascular Endothelial Cell Growth Factor Promotes Tyrosine Phosphorylation of Mediators of Signal Transduction That Contain SH2 Domains

  1995cited by this paper
• Role of Sp1 in transcriptional activation of human nitric oxide synthase type III gene.

  1995cited by this paper
• Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress.

  1995cited by this paper
• Isolation and chromosomal localization of the human endothelial nitric oxide synthase (NOS3) gene.

  1994cited by this paper
• Nitric oxide: physiology, pathophysiology, and pharmacology.

  1991cited by this paper
• Identification of a new endothelial cell growth factor receptor tyrosine kinase.

  1991cited by this paper
• The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA.

  1991cited by this paper
• Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells.

  1989cited by this paper

• Aberrant Uteroplacental and Vascular Signaling and Remodeling by Matrix Metalloproteinases in Pregnancy-Related Hypertension and Preeclampsia

  2026cites this paper
• Investigating Causal Associations Between Circulating Cytokines and Vestibular Disorders Using Mendelian Randomization: Insights from Large-Scale Genome-Wide Association Studies Data in European Populations

  2025cites this paper
• Constructing sodium alginate/carboxymethyl chitosan coating capable of catalytically releasing NO or CO for improving the hemocompatibility and endothelialization of magnesium alloys.

  2024cites this paper
• Fisiopatología de la preeclampsia materna

  2024cites this paper
• Risk factors for thromboembolism during first-line treatment of patients with unresectable advanced or recurrent colorectal cancer: a retrospective short study

  2023cites this paper
• Role of Dickkopf-3 in Blood Pressure Regulation in Mice and Hypertensive Rats

  2023cites this paper
• Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice

  2022cites this paper
• A study of diabetes‐induced erectile dysfunction treated with human umbilical cord mesenchymal stem cells

  2022cites this paper
• H2O2-responsive VEGF/NGF gene co-delivery nano-system achieves stable vascularization in ischemic hindlimbs

  2021cites this paper
• Pharmacological HIF‐PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation

  2021cites this paper
• Neonatal Extracellular Superoxide Dismutase Knockout Mice Increase Total Superoxide Dismutase Activity and VEGF Expression after Chronic Hyperoxia

  2021cites this paper
• Neuroprotective Effect of Vascular Endothelial Growth Factor on Motoneurons of the Oculomotor System

  2021cites this paper
• Pharmacologic HIF-PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation

  2021cites this paper
• Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis

  2020cites this paper
• Vascular toxicity associated with anti-angiogenic drugs.

  2020cites this paper
• Transcutaneous CO2 application accelerates fracture repair in streptozotocin-induced type I diabetic rats

  2020cites this paper
• Spotlight on ROS and β3-Adrenoreceptors Fighting in Cancer Cells

  2019cites this paper
• Roles of pharmacogenomics in non-anthracycline antineoplastic-induced cardiovascular toxicities: A systematic review and meta-analysis of genotypes effect.

  2019cites this paper
• Microvesicles Secreted by Nitric Oxide‐Primed Mesenchymal Stromal Cells Boost the Engraftment Potential of Hematopoietic Stem Cells

  2018cites this paper
• Reciprocal regulation of eNOS and caveolin-1 functions in endothelial cells

  2018cites this paper
• Molecular determinants of microvascular dysfunction in hypertensive pregnancy and preeclampsia

  2018cites this paper
• Gremlin 1 blocks vascular endothelial growth factor signaling in the pulmonary microvascular endothelium

  2018influential citation
• Management of VEGF-Targeted Therapy-Induced Hypertension

  2018cites this paper
• Cell-type-specific methylome-wide association studies implicate neurodegenerative processes and neuroimmune communication in major depressive disorder

  2018cites this paper
• Increased risk of adverse drug events secondary to bevacizumab treatment in patients with advanced or metastatic breast cancer: a meta-analysis of randomized controlled trials

  2018cites this paper
• Dihydroartemisinin enhances VEGFR1 expression through up-regulation of ETS-1 transcription factor

  2018cites this paper
• TOWARDS A TREATMENT FOR DIABETIC RETINOPATHY: Intravitreal Toxicity and Preclinical Safety Evaluation of Inducible Nitric Oxide Synthase Inhibitors

  2017cites this paper
• HIV gp 120 induces endothelial dysfunction in tumour necrosis factor-a-activated porcine and human endothelial cells

  2017cites this paper
• Nitric oxide elevation in polytrauma is driven by oxygen radicals.

  2017cites this paper
• VEGF released from a fibrin biomatrix increases VEGFR‐2 expression and improves early outcome after ischaemia–reperfusion injury

  2017cites this paper
• Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia.

  2017cites this paper
• Implication of VEGF and aquaporin 4 mediating Müller cell swelling to diabetic retinal edema

  2017cites this paper
• Effects of previous physical training on adriamycin nephropathy and its relationship with endothelial lesions and angiogenesis in the renal cortex

  2017cites this paper
• The Role of Statins in Prevention of Preeclampsia: A Promise for the Future?

  2017cites this paper
• Novel Pathophysiological Mechanisms in Hypertension.

  2017cites this paper
• Vascular Endothelial Growth Factor Augments Arginine Transport and Nitric Oxide Generation via a KDR Receptor Signaling Pathway

  2017cites this paper
• Cavin-1 regulates caveolae-mediated LDL transcytosis: crosstalk in an AMPK/eNOS/ NF-κB/Sp1 loop

  2017cites this paper
• Abnormal lipid metabolism is associated with angiogenic and anti angiogenic factor imbalance in PIH women

  2017influential citation
• Aberrant Pulmonary Vascular Growth and Remodeling in Bronchopulmonary Dysplasia

  2016cites this paper
• The safety of monoclonal antibodies for treatment of colorectal cancer

  2016cites this paper
• Disorders of Vascular Permeability.

  2016cites this paper
• Restoring placental growth factor-soluble fms-like tyrosine kinase-1 balance reverses vascular hyper-reactivity and hypertension in pregnancy.

  2016cites this paper
• Mechanisms of Hypertension and Renal Injury During Vascular Endothelial Growth Factor Signaling Inhibition

  2016cites this paper
• Spectrum of Factors Triggering Endothelial Dysfunction in PIH.

  2016cites this paper
• Hypertension and renal toxicity during angiogenesis inhibition : Salt dependency and treatment options

  2016cites this paper
• The Potential Role of Nitric Oxide in Halting Cancer Progression Through Chemoprevention

  2016cites this paper
• Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia.

  2016cites this paper
• Chapter 10 – Cardiovascular Complications from Cancer Therapy: Hypertension–Focus on Vascular Endothelial Growth Factor Inhibitors

  2016cites this paper
• Fetal endocrine and metabolic adaptations to hypoxia: the role of the hypothalamic-pituitary-adrenal axis.

  2015cites this paper
• Etiology of angiogenesis inhibition-related hypertension.

  2015cites this paper
• Electrospun nitric oxide releasing bandage with enhanced wound healing.

  2015cites this paper
• Hypertension and Vascular Endothelial Growth Factors

  2015cites this paper
• Nitric oxide-releasing polymer incorporated ointment for cutaneous wound healing.

  2015cites this paper
• Antihypertensive therapy in preeclampsia is not modulated by VEGF polymorphisms

  2015cites this paper
• The utility of cardiac biomarkers and echocardiography for the early detection of bevacizumab- and sunitinib-mediated cardiotoxicity.

  2015cites this paper
• for Vascular Integrity in Infant Mice (BRM) Are Dispensable in Multiple Models of Postnatal Angiogenesis But Are Required

  2015cites this paper
• High Intraocular Pressure Following Anti-Vascular Endothelial Growth Factor Therapy: Proposed Pathophysiology due to Altered Nitric Oxide Metabolism

  2015cites this paper
• Hypoxia, Arterial Blood Pressure, and Microcirculation

  2014cites this paper
• Inducible nitric oxide synthase inhibits oxygen consumption in collateral-dependent myocardium.

  2014cites this paper
• Mesenchymal stem cell pre-treatment with cytokines and hydrogen peroxide modifies their adhesion to cardiac endothelium and murine heart sections AND A preliminary study of the molecular regulation of placental growth factor and vascular endothelial growth factor in murine preadipocytes

  2014cites this paper
• Pharmacogenetics of erectile dysfunction: navigating into uncharted waters.

  2014cites this paper
• VEGF and eNOS Expression in Umbilical Cord from Pregnancy Complicated by Hypertensive Disorder with Different Severity

  2014cites this paper
• Hypertension During Vascular Endothelial Growth Factor Inhibition: Focus on Nitric Oxide, Endothelin-1, and Oxidative Stress

  2014cites this paper
• The Nebivolol action on vascular tone is dependent on actin cytoskeleton polymerization and Rho-A activity into ECs and SMCs

  2014cites this paper
• A Transient Proteinuria: An Unusual Complication of Hypothyroidism

  2014cites this paper
• Vascular Endothelial Growth Factors Enhance the Permeability of the Mouse Blood-brain Barrier

  2014cites this paper
• Immunohistochemical Localisation of PDE 5 in Rat Lung during Pre-and Postnatal Development

  2014cites this paper
• Mechanism of hypertension and proteinuria during angiogenesis inhibition: evolving role of endothelin-1

  2013cites this paper
• Post-translational regulation of endothelial nitric oxide synthase in vascular endothelium

  2013cites this paper
• The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1.

  2013cites this paper
• Hydrogen Sulfide Attenuates Cardiac Dysfunction After Heart Failure Via Induction of Angiogenesis

  2013cites this paper
• Autologous Bone-Marrow Mesenchymal Stem Cell Implantation and Endothelial Function in a Rabbit Ischemic Limb Model

  2013cites this paper
• Membrane Protein Complexes Involved in Thrombospondin-1 Regulation of Nitric Oxide Signaling

  2013cites this paper
• MECHANISMS OF ANGIOGENESISAND LYMPHANGIOGENESIS

  2013cites this paper
• International SportMed Journal Original research article The VEGFR2 gene His472Gln polymorphism in Polish endurance athletes

  2013cites this paper
• Mechanisms of angiogenesis and lymphangiogenesis in calcific aortic valve stenosis

  2013cites this paper
• Immune cells control skin lymphatic electrolyte homeostasis and blood pressure.

  2013cites this paper
• Evaluation of Hypertension and Proteinuria as Markers of Efficacy in Antiangiogenic Therapy for Metastatic Colorectal Cancer

  2013cites this paper
• MECHANISMS OF ANGIOGENESISAND LYMPHANGIOGENESIS IN CALCIFIC AORTIC VALVE STENOSIS

  2013cites this paper
• Risk of treatment-related mortality with sorafenib in patients with cancer.

  2013cites this paper
• First-in-Human Phase I Study of PRS-050 (Angiocal), an Anticalin Targeting and Antagonizing VEGF-A, in Patients with Advanced Solid Tumors

  2013cites this paper
• human internal mammary artery Vascular endothelial growth factor-mediated, endothelium-dependent relaxation in

  2013cites this paper
• Activation of VEGFR-2 signaling in response to moderate dose of ultraviolet B promotes survival of normal human keratinocytes.

  2012cites this paper
• The Current State of Targeted Agents in Rectal Cancer

  2012cites this paper
• Hypoxic preconditioning induces an AT2-R/VEGFR-2(Flk-1) interaction in the neonatal brain microvasculature for neuroprotection.

  2012cites this paper
• VEGF genetic polymorphisms affect the responsiveness to sildenafil in clinical and postoperative erectile dysfunction

  2012cites this paper
• Novel Adverse Events of Bevacizumab in the US FDA Adverse Event Reporting System Database

  2012cites this paper
• Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials.

  2012cites this paper
• Physical and molecular characteristics of day 75 nuclear transfer cloned bovine conceptuses

  2012cites this paper
• Vasorelaxation effect and mechanism of action of vascular endothelial growth factor-165 in isolated perfused human skin flaps.

  2012cites this paper
• Sunitinib‐induced changes in circulating endothelial cell‐related proteins in patients with metastatic renal cell cancer

  2012cites this paper
• Antiangiogenic Therapy for Metastatic Breast Cancer

  2012cites this paper
• A Review of the Treatment Options in Recurrent Glioblastoma: Focus on Bevacizumab

  2011cites this paper
• Immunohistochemical Study of the Angiogenetic Network of VEGF, HIF1α, VEGFR-2 and Endothelial Nitric Oxide Synthase (eNOS) in Human Breast Cancer

  2011cites this paper
• A Novel Peptide Derived from Human Apolipoprotein E Is an Inhibitor of Tumor Growth and Ocular Angiogenesis

  2011cites this paper
• Effects of aging on time course of neovascularization-related gene expression following acute hindlimb ischemia in mice.

  2011cites this paper
• RETRACTED ARTICLE: Gold nanoparticles inhibit vascular endothelial growth factor-induced angiogenesis and vascular permeability via Src dependent pathway in retinal endothelial cells

  2011cites this paper
• Bevacizumab-Induced Hypertension

  2011cites this paper
• Mechanisms of Antiangiogenic-Induced Arterial Hypertension

  2011cites this paper
• The P2Y2 Nucleotide Receptor in Vascular Inflammation and Angiogenesis

  2010cites this paper