Rho family GTPases regulate VEGF-stimulated endothelial cell motility.
Migration of endothelial cells induced by vascular endothelial growth factor (VEGF) is a critical step in angiogenesis. Stimulation of motility by growth factors such as VEGF requires interaction with the signal transduction pathways activated by the extracellular matrix (ECM). Here we demonstrate that the Rac GTPase is the critical intersection activated by type 1 collagen ECM and VEGF during stimulation of endothelial cell motility. To analyze the role of the Rho family GTPases in VEGF-stimulated endothelial cell chemotaxis and ECM-stimulated haptotaxis, we transduced the respective fusion proteins in human foreskin dermal endothelial cells using a Tat peptide from the human immunodeficiency virus Tat protein. VEGF signaling required Rac activation during chemotaxis, and Rac and Cdc42 were activated during haptotaxis on type I collagen. Similar to VEGF, Rac activation induced an increase in endothelial cell stress fiber and focal adhesion. Surprisingly, Rho activation was not present in collagen-induced haptotaxis or stimulation of chemotaxis by VEGF, although Rho induced stress fibers and focal adhesions similar to Rac activation. The result of constitutive Rho activation was an inhibition of haptotaxis. Thus, Rac is required and sufficient for the activation of endothelial cell haptotaxis and VEGF-stimulated chemotaxis.
Soga
N
N
Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Namba
N
N
McAllister
S
S
Cornelius
L
L
Teitelbaum
S L
SL
Dowdy
S F
SF
Kawamura
J
J
Hruska
K A
KA
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000962:Antimalarials / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D002738:Chloroquine / Q000494:pharmacology; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015696:Gene Products, tat / Q000235:genetics; D006801:Humans; D008222:Lymphokines / Q000378:metabolism* / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016596:Vinculin / Q000187:drug effects / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*
D000199:Actins; D000962:Antimalarials; D016228:Endothelial Growth Factors; D015696:Gene Products, tat; D008222:Lymphokines; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016596:Vinculin; D002738:Chloroquine; D003094:Collagen; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins