Adenovirus-mediated gene transfer of placental growth factor to perivascular tissue induces angiogenesis via upregulation of the expression of endogenous vascular endothelial growth factor-A.
Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family that binds specifically to VEGF receptor (VEGFR)-1. However, the mechanism of PlGF- and VEGFR-1-mediated angiogenesis has remained unclear and some in vitro studies suggest that VEGF-A/VEGFR-2 signaling may also play a role in PlGF-mediated angiogenesis. To clarify these issues we evaluated angiogenic responses in a well-characterized periadventitial angiogenesis model using adenovirus-mediated PlGF-2 (AdvPlGF-2) gene transfer. We also investigated the roles of VEGFR-1 and VEGFR-2 in PlGF-2-mediated angiogenesis. Using a periadventitial collar technique, AdvPlGF-2 (1 x 10(9) plaque-forming units/ml) was transferred to the adventitia of New Zealand White rabbits alone or together with adenoviruses encoding soluble VEGFR-1 (sVEGFR-1) or soluble VEGFR-2 (sVEGFR-2). Adenoviruses encoding LacZ were used as controls. All animals were killed 7 days after gene transfer. Increased neo-vessel formation, upregulation of endogenous VEGF-A expression, and a significant inflammatory response were seen in AdvPlGF-2-transduced arteries. The neo-vessels were large and well perfused. sVEGFR-1 and sVEGFR-2 suppressed the angiogenic response of PlGF-2 by 80 and 71.7%, respectively. We conclude that adenovirus-mediated PlGF-2 gene transfer to vascular tissue increases endogenous VEGF-A expression and produces significant angiogenesis. Both sVEGFR-1 and sVEGFR-2 can inhibit PlGF-2-mediated angiogenesis. PlGF-2 is a potentially useful candidate for the induction of therapeutic angiogenesis in vivo.
Roy
Himadri
H
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio 70211, Finland.
Bhardwaj
Shalini
S
Babu
Mohan
M
Jauhiainen
Suvi
S
Herzig
Karl-Heinz
KH
Bellu
Anna R
AR
Haisma
Hidde J
HJ
Carmeliet
Peter
P
Alitalo
Kari
K
Ylä-Herttuala
Seppo
S
D000256:Adenoviridae / Q000235:genetics; D043925:Angiogenesis Inducing Agents; D000818:Animals; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007763:Lac Operon; D008297:Male; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D015398:Signal Transduction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2