Inhibition of VEGF or TGF-β signaling activates endothelium and increases leukocyte rolling

OBJECTIVE-: Motivated by the central roles that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β play in the assembly and maintenance of the vasculature, we examined the impact of systemic VEGF or TGF-β signal inhibition on endothelial activation as detected by leukocyte-endothelial interactions. METHODS AND RESULTS-: VEGF or TGF-β 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-β resulted in endothelial surface expression of P-selectin and impaired peripheral vasodilatation. Neither inhibition of VEGF nor TGF-β was associated with platelet or leukocyte activation, as detected by the activation markers platelet P-selectin and the active integrin αIIbβIII, 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-β 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-β in maintaining the endothelium in a nonactivated state and have implications for therapeutic approaches that neutralize VEGF or TGF-β.