Expression of vascular endothelial growth factor receptor-2 or Tie-2 on peripheral blood cells defines functionally competent cell populations capable of reendothelialization.
BACKGROUND
Receptor tyrosine kinases that include vascular endothelial growth factor (VEGFR)-1, VEGFR-2, and Tie-2 regulate cardiovascular development and physiological and pathological angiogenesis. We were interested in the phenotypic and functional characterization of peripheral blood cells expressing these receptors and their therapeutic potential in vascular injury.


RESULTS
VEGFR-1+, VEGFR-2+, and Tie-2+ cells constituted approximately 3.0+/-0.2%, 0.8+/-0.5%, and 2.0+/-0.3%, respectively, of the total population of mononuclear cells in blood. Phenotypic analysis demonstrated that all 3 cell populations mainly expressed markers of monocytic/macrophage lineage. Only VEGFR-2+ and Tie-2+ cells phenotypically, morphologically, and functionally differentiated to endothelial cells after culture, whereas VEGFR-1+ cells did not. None of the cell types proliferated in vitro. Only freshly isolated VEGFR-2+ or Tie-2+ cells but not VEGFR-2- or Tie-2- cell populations significantly contributed to efficient endothelialization of balloon-injured femoral arteries of nude mice. Furthermore, these cells also differentiated into -actin-positive smooth muscle cells. Administration of bromodeoxyuridine to animals transplanted with human endothelial progenitor cells showed that VEGFR-2+ and Tie-2+ cells proliferated in vivo.


CONCLUSIONS
These data demonstrate that expression of VEGFR-2 and/or Tie-2 on peripheral blood cells defines functionally competent cell populations that proliferate in vivo and that contribute to reendothelialization. These findings may have implications for a cell-based approach in vascular diseases.
Nowak
Grzegorz
G
Division of Transplantation Surgery, Karolinska University Hospital-Huddinge, Karolinska Institute, Stockholm. Sweden.
Karrar
Azza
A
Holmén
Carolina
C
Nava
Silvia
S
Uzunel
Mehmet
M
Hultenby
Kjell
K
Sumitran-Holgersson
Suchitra
S
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D049109:Cell Proliferation; D002634:Chemotaxis, Leukocyte; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D004730:Endothelium, Vascular / Q000166:cytology*; D005263:Femoral Artery / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D042787:Receptor, TIE-2 / Q000096:biosynthesis* / Q000097:blood; D033581:Stem Cell Transplantation; D017539:Tunica Intima / Q000166:cytology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis* / Q000097:blood
D015415:Biomarkers; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042787:Receptor, TIE-2; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2