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Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase
- Source :
- Circulation research. 93(4)
- Publication Year :
- 2003
-
Abstract
- Fluid shear stress generated by blood flowing over the endothelium is a major determinant of arterial tone, vascular remodeling, and atherogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an essential role in regulation of vascular function and structure by blood flow, but the molecular mechanisms that transduce mechanical force to eNOS activation are not well understood. In this study, we found that laminar flow (shear stress=12 dyne/cm 2 ) rapidly activates vascular endothelial growth factor receptor 2 (VEGFR2) in a ligand-independent manner and leads to eNOS activation in cultured endothelial cells. Flow-stimulated VEGFR2 recruits phosphoinositide 3-kinase and mediates activation of Akt and eNOS. Inhibiting VEGFR2 kinase with selective inhibitors blocks flow-induced activation of Akt and eNOS and production of NO. Decreasing VEGFR2 expression with antisense VEGFR2 oligonucleotides significantly attenuates activation of Akt and eNOS. Furthermore, Src kinases are involved in flow-stimulated VEGFR2 because inhibiting Src kinases by PP2, a selective inhibitor for Src kinases, abolishes flow-induced VEGFR2 tyrosine phosphorylation and downstream signaling. Finally, we show that inhibiting VEGFR2 kinase significantly reduces flow-mediated NO-dependent arteriolar dilation in vivo. These data identify VEGFR2 as a key mechanotransducer that activates eNOS in response to blood flow.
- Subjects :
- Physiology
Ligands
chemistry.chemical_compound
Phosphatidylinositol 3-Kinases
Enos
Cricetinae
Benzoquinones
Enzyme Inhibitors
Phosphorylation
Quinones
Antibodies, Monoclonal
respiratory system
Genistein
Cell biology
Nitric oxide synthase
Vasodilation
medicine.anatomical_structure
src-Family Kinases
cardiovascular system
Cardiology and Cardiovascular Medicine
circulatory and respiratory physiology
Proto-oncogene tyrosine-protein kinase Src
Signal Transduction
medicine.medical_specialty
Endothelium
Lactams, Macrocyclic
Biology
Protein Serine-Threonine Kinases
Nitric Oxide
Cell Line
Growth factor receptor
Internal medicine
Proto-Oncogene Proteins
medicine
Animals
Protein kinase B
Tyrosine phosphorylation
Kinase insert domain receptor
biology.organism_classification
Integrin alphaVbeta3
Vascular Endothelial Growth Factor Receptor-2
Enzyme Activation
Endocrinology
Cheek
chemistry
Rifabutin
biology.protein
Blood Vessels
Endothelium, Vascular
Stress, Mechanical
Nitric Oxide Synthase
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 15244571
- Volume :
- 93
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Circulation research
- Accession number :
- edsair.doi.dedup.....783477113c49512279af7bd5351fccaa