Inhibition of VEGF or TGF-{beta} signaling activates endothelium and increases leukocyte rolling.
OBJECTIVE
Motivated by the central roles that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta play in the assembly and maintenance of the vasculature, we examined the impact of systemic VEGF or TGF-beta signal inhibition on endothelial activation as detected by leukocyte-endothelial interactions.


RESULTS
VEGF or TGF-beta inhibition, accomplished using adenovirus expression of soluble Flt1 (Ad-sFlt1) or soluble endoglin (Ad-sEng), resulted in a significant increase in the number of leukocytes rolling along the mesenteric venous endothelium and a significant decrease in rolling velocity in Ad-sEng mice. Neutralization of VEGF or TGF-beta resulted in endothelial surface expression of P-selectin and impaired peripheral vasodilatation. Neither inhibition of VEGF nor TGF-beta was associated with platelet or leukocyte activation, as detected by the activation markers platelet P-selectin and the active integrin alphaIIbbetaIII, or by leukocyte expression of L-selectin. Soluble vascular cell adhesion molecule (VCAM)-1 and E-selectin were increased in sEng-expressing mice, indicating higher levels of these adhesion receptors.


CONCLUSIONS
VEGF or TGF-beta neutralization leads to impaired endothelium-mediated vasodilatation and elevated expression of surface adhesion molecules, resulting in increased leukocyte adhesion. These results indicate an essential role for both VEGF and TGF-beta in maintaining the endothelium in a nonactivated state and have implications for therapeutic approaches that neutralize VEGF or TGF-beta.
Walshe
Tony E
TE
Schepens Eye Research Institute and Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA.
Dole
Vandana S
VS
Maharaj
Arindel S R
AS
Patten
Ian S
IS
Wagner
Denisa D
DD
D'Amore
Patricia A
PA
D000818:Animals; D002448:Cell Adhesion; D019040:E-Selectin / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D008642:Mesenteric Veins / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019007:P-Selectin / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology*
D019040:E-Selectin; D019007:P-Selectin; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A