Multistep nature of microvascular recruitment of ex vivo-expanded embryonic endothelial progenitor cells during tumor angiogenesis.
Tissue neovascularization involves recruitment of circulating endothelial progenitor cells that originate in the bone marrow. Here, we show that a class of embryonic endothelial progenitor cells (Tie-2+, c-Kit+, Sca-1+, and Flk-1-/low), which were isolated at E7.5 of mouse development at the onset of vasculogenesis, retain their ability to contribute to tumor angiogenesis in the adult. Using intravital fluorescence videomicroscopy, we further defined the multistep process of embryonic endothelial progenitor cell (eEPC) homing and incorporation. Circulating eEPCs are specifically arrested in "hot spots" within the tumor microvasculature, extravasate into the interstitium, form multicellular clusters, and incorporate into functional vascular networks. Expression analysis and in vivo blocking experiments provide evidence that the initial cell arrest of eEPC homing is mediated by E- and P-selectin and P-selectin glycoprotein ligand 1. This paper provides the first in vivo insights into the mechanisms of endothelial progenitor cell recruitment and, thus, indicates novel ways to interfere with pathological neovascularization.
Vajkoczy
Peter
P
Department of Neurosurgery, Klinikum Mannheim, University of Heidelberg, Mannheim, Germany.
Blum
Sabine
S
Lamparter
Mathias
M
Mailhammer
Reinhard
R
Erber
Ralph
R
Engelhardt
Britta
B
Vestweber
Dietmar
D
Hatzopoulos
Antonis K
AK
D000818:Animals; D015415:Biomarkers; D001808:Blood Vessels / Q000166:cytology / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D004622:Embryo, Mammalian; D004730:Endothelium, Vascular / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D005910:Glioma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D006439:Hemodynamics; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D019087:Selectins / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*
D015415:Biomarkers; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019087:Selectins