S. M. Deeney1, K. N. Powers1, B. Dodson1, K. W. Liechty1, A. Marwan1, T. M. Crombleholme1 1Laboratory For Fetal And Regenerative Biology,Department Of Surgery, School Of Medicine, University Of Colorado Denver – Anschutz Medical Campus; Division Of Pediatric General Thoracic And Fetal Surgery, Colorado Children’s Hospital,Aurora, CO, USA
Introduction:
Intrauterine growth restriction (IUGR) is characterized by decreased serum bioavailability of IGF-1 both clinically and across a wide range of animal models. Our laboratory recently described a novel surgical mouse model of intrauterine growth restriction (IUGR) and rescued the IUGR phenotype using intraplacental adenovirus mediated gene transfer of human insulin-like growth factor-1 (Ad-IGF-1). Mouse birthweight, growth trajectory, glucose tolerance and blood pressure correct to control levels. The mechanism by which fetal reprogramming occurs has yet to be fully elucidated. We hypothesize that Ad-IGF-1 intraplacental gene transfer restores the bioavailability of serum levels of IGF-1 in IUGR pups.
Methods:
In time-mated e18 C57/BL6J dams, one of two naturally occurring mesenteric uterine artery branches were ligated in one pup (excluding the pups at the uterine ends), inducing IUGR (n=3). Control pups were those with dual arteries on the opposite uterine horn as well as sham-operated pups (n=5). A subset of IUGR pups (n=3) received 5 ul intraplacental injections of 1×10^8 pfu adenovirus expressing human IGF-1 after artery ligation. Serum samples were obtained by decapitation of the pups following delivery via hysterotomy at e20. Serum and placenta homogenate levels of mouse IGF-1 and IGFBP-3 were measured in duplicate by ELISA. Bioavailability of IGF-1 was defined as the molar ratio of IGF-1 to IGFBP-3. Statistical analysis was by Student’s T-test.
Results:
Serum levels of bioavailable IGF-1 were significantly reduced in IUGR pups compared to controls (P=0.01) and were restored with Ad-IGF-1 gene transfer (p>0.05). Placental levels of bioavailable IGF-1 were not different in all groups (p>0.05).
Conclusion:
Intraplacental Ad-IGF-1 gene transfer restores the serum levels of bioavailable IGF-1, while not changing these levels in the placenta itself. This is the first demonstration of how Ad-IGF-1 gene transfer restores pup serum bioavailable IGF-1 levels in IUGR mice, suggesting a possible mechanism by which IGF-1 induces fetal reprogramming of IUGR mice.
