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.
David
A L
AL
Prenatal Gene Therapy Group, Institute for Women's Health, Royal Free and University College London Medical School, London, UK. a.david@ucl.ac.uk
Torondel
B
B
Zachary
I
I
Wigley
V
V
Abi-Nader
K
K
Nader
K A
KA
Mehta
V
V
Buckley
S M K
SM
Cook
T
T
Boyd
M
M
Rodeck
C H
CH
Martin
J
J
Peebles
D M
DM
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