Hemodynamic, vascular and reproductive impact of FMS-Like Tyrosine Kinase 1 (FLT1) blockade on the uteroplacental circulation during normal mouse pregnancy

To investigate the role of FMS-like tyrosine kinase 1 (FLT1, previously known as VEGFR1) signaling during pregnancy, mice were injected with anti-FLT1 neutralizing antibody beginning on Gestational Day 8 or 12, and every other day thereafter until Day 18; vehicle-only injected mice served as controls. Uterine artery blood flow was measured with ultrasound on Days 13 and 18, and morphometric measurements of the uterine arcade were carried out on Day 19 to provide a measure of gestational vascular remodeling; reproductive performance was evaluated by determining litter size, resorption rates, and pup and placental weights. Antibody injections beginning on Day 8 or Day 12 resulted in significant reductions of uterine artery peak systolic and diastolic flows at gestational age 13 and 18. In addition, normal reproductive function was compromised as evidenced by a significant reduction in average number of viable pups along with enhanced resorption rates. Reproductive performance was also significantly compromised in this group, although less severely. There was no evidence of a reduction in main uterine artery diameters, although arterial distensibility was reduced, and the diameter of the main uterine vein was significantly smaller in the antibody injected mice. Significant reductions in main uterine artery and segmental artery length were also noted. Placental and pup weights were similar in all the groups. FLT1 inhibition during murine pregnancy impaired blood flow to the fetal-placental unit, compromised several indices of vascular remodeling, reduced fecundity and increased fetal reabsorptions. The effects of FLT1 inhibition are most pronounced when targeted during early pregnancy.