Blood flow remodels growing vasculature during vascular endothelial growth factor gene therapy and determines between capillary arterialization and sprouting angiogenesis.
BACKGROUND
For clinically relevant proangiogenic therapy, it would be essential that the growth of the whole vascular tree is promoted. Vascular endothelial growth factor (VEGF) is well known to induce angiogenesis, but its capability to promote growth of larger vessels is controversial. We hypothesized that blood flow remodels vascular growth during VEGF gene therapy and may contribute to the growth of large vessels.


RESULTS
Adenoviral (Ad) VEGF or LacZ control gene transfer was performed in rabbit hindlimb semimembranous muscles with or without ligation of the profound femoral artery (PFA). Contrast-enhanced ultrasound and dynamic susceptibility contrast MRI demonstrated dramatic 23- to 27-fold increases in perfusion index and a strong decrease in peripheral resistance 6 days after AdVEGF gene transfer in normal muscles. Enlargement by 20-fold, increased pericyte coverage, and decreased alkaline phosphatase and dipeptidyl peptidase IV activities suggested the transformation of capillaries toward an arterial phenotype. Increase in muscle perfusion was attenuated, and blood vessel growth was more variable, showing more sprouting angiogenesis and formation of blood lacunae after AdVEGF gene transfer in muscles with ligated PFA than in normal muscles. Three-dimensional ultrasound reconstructions and histology showed that the whole vascular tree, including large arteries and veins, was enlarged manifold by AdVEGF. Blood flow was normalized and enlarged collaterals persisted in operated limbs 14 days after AdVEGF treatment.


CONCLUSIONS
This study shows that (1) blood flow modulates vessel growth during VEGF gene therapy and (2) VEGF overexpression promotes growth of arteries and veins and induces capillary arterialization leading to supraphysiological blood flow in target muscles.
Rissanen
Tuomas T
TT
Department of Biotechnology, A.I. Virtanen Institute, Kuopio University, Kuopio, Finland.
Korpisalo
Petra
P
Markkanen
Johanna E
JE
Liimatainen
Timo
T
Ordén
Maija-Riitta
MR
Kholová
Ivana
I
de Goede
Anna
A
Heikura
Tommi
T
Gröhn
Olli H
OH
Ylä-Herttuala
Seppo
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000254:growth & development; D001808:Blood Vessels / Q000187:drug effects / Q000254:growth & development*; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D003952:Diagnostic Imaging; D015316:Genetic Therapy; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D012039:Regional Blood Flow / Q000502:physiology*; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology
D042461:Vascular Endothelial Growth Factor A