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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1185.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

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

Tony E. Walshe; Vandana S. Dole; Arindel S.R. Maharaj; Ian S. Patten; Denisa D. Wagner; Patricia A. D'Amore

From the Schepens Eye Research Institute and Harvard Medical School (T.E.W., A.S.R.M., P.A.D.), the Immune Disease Institute (V.S.D., I.S.P., D.D.W.), and the Department of Pathology, Harvard Medical School (V.S.D., D.D.W., P.A.D.), Boston, Mass.

Correspondence to Patricia A. D'Amore, Schepens Eye Research Institute and Harvard Medical School, 20 Staniford Street, Boston, MA 02114. E-mail patricia.damore{at}schepens.harvard.edu and Denisa D. Wagner, E-mail: wagner@idi.harvard.edu

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 IIbβIII, 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.

VEGF or TGF-β neutralization resulted in increased leukocyte rolling along the mesenteric venules. VEGF and TGF-β signaling limits the expression of endothelial adhesion factors, such as P-selectin, and modulates the vasoactive response. Taken together, these findings indicate an essential role for VEGF and TGF-β in maintaining the endothelium in a noninflammatory state.

Key Words: VEGF • TGF-β • P-selectin • nitric oxide • inflammation