Local delivery of VEGF adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep.
Impaired materno-placental perfusion causes two important obstetric complications, fetal growth restriction and preeclampsia. This study investigated whether adenoviral vector-mediated overexpression of vascular endothelial growth factor (VEGF) in the uterine arteries (UtAs) increases uterine artery blood flow (UBF). First-generation adenovirus vectors (5 x 10(11) particles) containing the VEGF gene (Ad.VEGF-A or -D) or the beta-galactosidase reporter gene (Ad.lacZ) were injected into the UtAs of pregnant sheep (n=6) at 88-102 days of gestation (term=145 days). UBF was measured using Doppler sonography before, and 4-7 days after injection. Mean UBF increased significantly from 233+/-156 (s.d.) ml min(-1) to 753+/-415 ml min(-1) following Ad.VEGF-A injection (P=0.005, n=5); Ad.lacZ infection had no significant effect. Organ bath experiments on uterine arterial sections 4-7 days after injection showed that, compared with Ad.lacZ vessels, Ad.VEGF-A-transduced vessels had a reduced contractile response to phenylephrine (E max 148+/-10.9 vs E max 228.2+/-27.5, P<0.05) but increased relaxation with bradykinin (pD2 (-log EC50) values 9.11+/-0.01 vs 8.65+/-0.11, P<0.05). Injection of Ad.VEGF-A into the UtAs increases UBF by enhancing vasodilatation. This may provide the basis for therapy in pregnancies complicated by uteroplacental insufficiency.
Prenatal Gene Therapy Group, Institute for Women's Health, Royal Free and University College London Medical School, London, UK. a.david@ucl.ac.uk
A L
AL
David
B
B
Torondel
I
I
Zachary
V
V
Wigley
K
K
Abi-Nader
K A
KA
Nader
V
V
Mehta
S M K
SM
Buckley
T
T
Cook
M
M
Boyd
C H
CH
Rodeck
J
J
Martin
D M
DM
Peebles
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001158:Arteries; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005317:Fetal Growth Retardation / Q000503:physiopathology / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D007275:Injections, Intravenous; D023421:Models, Animal; D021041:Placental Circulation; D011247:Pregnancy; D012039:Regional Blood Flow; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D014161:Transduction, Genetic / Q000379:methods*; D014463:Ultrasonography; D014599:Uterus / Q000000981:diagnostic imaging; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics*; D014664:Vasodilation / Q000235:genetics
D042461:Vascular Endothelial Growth Factor A