TY - JOUR
T1 - Effects of protein and gene transfer of the angiopoietin-1 fibrinogen-like receptor-binding domain on endothelial and vessel organization
AU - Weber, Cornelia C.
AU - Cai, Hao
AU - Ehrbar, Martin
AU - Kubota, Hisashi
AU - Martiny-Baron, Georg
AU - Weber, Wilfried
AU - Djonov, Valentin
AU - Weber, Ernst
AU - Mallik, Ajit S.
AU - Fussenegger, Martin
AU - Frei, Karl
AU - Hubbell, Jeffrey A.
AU - Zisch, Andreas H.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/6/10
Y1 - 2005/6/10
N2 - The vessel-stabilizing effect of angiopoietin-1 (Ang1)/ Tie2 receptor signaling is a potential target for pro-angiogenic therapies as well as anti-angiogenic inhibition of tumor growth. We explored the endothelial and vascular specific activities of the Ang1 monomer, i.e. dissociated from its state as an oligomer. A truncated monomeric Ang1 variant (i.e. ΔAng1) containing the isolated fibrinogen-like receptor-binding domain of Ang1 was created and recombinantly produced in insect cells. ΔAng1 ligated the Tie2 receptor without triggering its phosphorylation. Moreover, monomeric ΔAng1 was observed to bind α5β1 integrin with similar affinity compared with Tie2. Unexpectedly, in vitro treatment of endothelial cells with ΔAng1 showed some of the known effects of full-length Ang1, including inhibition of basal endothelial cell permeability and stimulation of cell adhesion as well as activation of MAPKs. Local treatment of the microvasculature of the developing chicken chorioallantoic membrane with the ΔAng1 protein led to profound reduction of the mean vascular length density, thinning of vessels, and reduction of the number of vessel branching points. Similar effects were observed in side-by-side experiments with the recombinant full-length Ang1 protein. These effects of simplification of the vessel branching pattern were confirmed through local gene transfer with lentiviral particles encoding ΔAng1 or full-length Ang1. Together, our findings suggest a potential use for exogenous Ang1 in reducing rather than increasing vascular density. Furthermore, we show that the isolated receptor-binding domain of Ang1 is capable of mediating some effects of full-length Ang1 independently of Tie2 phosphorylation, possibly through integrin ligation.
AB - The vessel-stabilizing effect of angiopoietin-1 (Ang1)/ Tie2 receptor signaling is a potential target for pro-angiogenic therapies as well as anti-angiogenic inhibition of tumor growth. We explored the endothelial and vascular specific activities of the Ang1 monomer, i.e. dissociated from its state as an oligomer. A truncated monomeric Ang1 variant (i.e. ΔAng1) containing the isolated fibrinogen-like receptor-binding domain of Ang1 was created and recombinantly produced in insect cells. ΔAng1 ligated the Tie2 receptor without triggering its phosphorylation. Moreover, monomeric ΔAng1 was observed to bind α5β1 integrin with similar affinity compared with Tie2. Unexpectedly, in vitro treatment of endothelial cells with ΔAng1 showed some of the known effects of full-length Ang1, including inhibition of basal endothelial cell permeability and stimulation of cell adhesion as well as activation of MAPKs. Local treatment of the microvasculature of the developing chicken chorioallantoic membrane with the ΔAng1 protein led to profound reduction of the mean vascular length density, thinning of vessels, and reduction of the number of vessel branching points. Similar effects were observed in side-by-side experiments with the recombinant full-length Ang1 protein. These effects of simplification of the vessel branching pattern were confirmed through local gene transfer with lentiviral particles encoding ΔAng1 or full-length Ang1. Together, our findings suggest a potential use for exogenous Ang1 in reducing rather than increasing vascular density. Furthermore, we show that the isolated receptor-binding domain of Ang1 is capable of mediating some effects of full-length Ang1 independently of Tie2 phosphorylation, possibly through integrin ligation.
UR - http://www.scopus.com/inward/record.url?scp=20444446335&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20444446335&partnerID=8YFLogxK
U2 - 10.1074/jbc.M410367200
DO - 10.1074/jbc.M410367200
M3 - Article
C2 - 15781448
AN - SCOPUS:20444446335
VL - 280
SP - 22445
EP - 22453
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 23
ER -