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Inhibition of VEGF or TGF-{beta} signaling activates endothelium and increases leukocyte rolling.

ABSTRACT: 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.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.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.

SUBMITTER: Walshe TE

PROVIDER: S-EPMC2775449 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Inhibition of VEGF or TGF-{beta} signaling activates endothelium and increases leukocyte rolling.

Walshe Tony E TE Dole Vandana S VS Maharaj Arindel S R AS Patten Ian S IS Wagner Denisa D DD D'Amore Patricia A PA

Arteriosclerosis, thrombosis, and vascular biology 20090521 8

<h4>Objective</h4>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.<h4>Methods and results</h4>VEGF or TGF-beta inhibition, accomplished using adenovirus expression of soluble Flt1 (Ad-sFlt1) or soluble endoglin (Ad-sEng), res ...[more]

PMID: 19461051

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Inhibition of VEGF or TGF-{beta} signaling activates endothelium and increases leukocyte rolling.

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Inhibition of VEGF or TGF-{beta} signaling activates endothelium and increases leukocyte rolling.

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