Inhibition of VEGF or TGF- Signaling Activates Endothelium and Increases Leukocyte Rolling

Abstract

Objective Motivated by the central roles that VEGF and 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 VCAM-1 and E-selectin were increased in sEng-expressing mice, indicating higher levels of these adhesion receptors. Conclusions VEGF or TGF-β neutralization results in 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 non-activated state and have implications for therapeutic approaches that neutralize VEGF or TGF-β.