Abstract 032: Soluble fms-like Tyrosine Kinase-1 (sFlt-1)/Placental Growth Factor (PlGF) Imbalance Disrupts Vascular and Uteroplacental Gelatinolytic Matrix Metalloproteinase MMP-2 and -9 and Collagenolytic MMP-1 and -7 Balance in Hypertensive Pregnancy

Abstract

Preeclampsia is a complication of pregnancy manifested as hypertension-in-pregnancy (HTN-Preg) and fetal growth restriction. Placental ischemia could be an initiating event, but the linking mechanisms and tissue targets are unclear. Placental ischemia is associated with increased sFlt-1/PlGF ratio, and we have shown changes in MMPs in pregnant rat model of reduced uterine perfusion pressure (RUPP). To test the hypothesis that sFlt-1/PlGF imbalance could target vascular and uteroplacental MMPs, we tested if raising sFlt-1/PlGF ratio by infusing sFlt-1 (10 μg/kg/day) in Preg rats would increase BP and alter MMPs, and if correcting sFlt-1/PlGF ratio by infusing PlGF (20 μg/kg/day) in RUPP rats improves BP and reverses the changes in MMPs. On day 19, BP was recorded and the aorta, placenta, uterus and uterine artery were isolated for measuring MMP activity using gelatin and casein zymography and protein levels of MMPs and collagen I and IV using Western blots. BP was in Preg+sFlt 121±3 > Preg 93±7 and in RUPP+PlGF 97±4 < RUPP 118±4 mmHg. Litter size and pup weight were in Preg+sFlt < Preg and in RUPP+PlGF > RUPP. MMP-2 levels were in aorta of Preg+sFlt 3.30±0.05 < Preg 7.75±0.13, and in RUPP+PlGF 6.70±0.19 > RUPP 2.62±0.12. Similarly, MMP-2 in placenta, uterus and uterine artery and MMP-9 in all tissues were in Preg+sFlt < Preg and in RUPP+PlGF > RUPP. In contrast, MMP-1 levels were in aorta of Preg+sFlt 1.73±0.33 > Preg 0.55±0.49, and in RUPP+PlGF 0.53±0.18 < RUPP 4.04±0.30. Also, MMP-1 in placenta, uterus and uterine artery and MMP-7 in all tissues were in Preg+sFlt > Preg and in RUPP+PlGF < RUPP. The MMP-2 and -9 substrate collagen IV was in aorta of Preg+sFlt 0.16±0.00 > Preg 0.06±0.01, and in RUPP+PlGF 0.01±0.00 < RUPP 0.18±0.01. Similarly, collagen IV in placenta, uterus and uterine artery and the MMP-1 and -7 substrate collagen I in all tissues were in Preg+sFlt > Preg and in RUPP+PlGF < RUPP. Thus, sFlt-1/PlGF imbalance is a likely mechanism linking placental ischemia to decreased gelatinases, increased collagenases and improper vascular and uteroplacental remodeling. Correcting sFlt-1/PlGF balance by infusing PlGF could rectify the balance between gelatinolytic and collagenolytic MMPs and thereby restore proper vascular and uteroplacental remodeling in HTN-Preg.