Placental Ischemia Influences Developmental Programming in Growth Restricted Offspring
Authors: Coats Laura E. , Davis Gwendolyn K. , Bamrick Daniel R. , Bakrania Bhavisha R. , Alexander Barbara T. 
Published: June 2021

The initiating event in preeclampsia (PE) involves placental ischemia and results in hypertension in the mother with intrauterine growth restriction (IUGR) in the offspring. Currently, there are no treatment options for PE beyond early delivery of the fetus which also results in preterm birth and IUGR. It is well established that IUGR programs increased risk for chronic disease in the offspring. Thus, identification of therapeutics to provide benefit to the mother while also improving fetal growth and long‐term health in the offspring are warranted. Soluble guanylate cyclase (sGC) inducers are therapeutic agents that mediate the synthesis of cyclic guanosine monophosphate monophosphate (cGMP). cGMP activates cGMP dependent protein kinase and leads to vascular smooth muscle cell relaxation, causing vasodilation which improves blood flow and reduces blood pressure. Preclinical use of sGC inducers show benefit in an experimental model of PE induced by reduced uterine perfusion pressure (RUPP). We hypothesize that RUPP in the pregnant rat induces IUGR via a reduction in placental perfusion coupled with impaired placental transport of nutrients; an effect mitigated by activation of sGCs. RUPP or a sham was performed at day 14 of gestation followed by administration of vehicle or a sGC inducer (riociguat, 10mg/kg/day) by subcutaneous osmotic pump from day 14 of gestation to day 20 gestation (Group 1) or to birth (Group 2). In group 1, fetal weight, placental weight and placental efficiency did not differ; however, placental weight tended to decrease in IUGR offspring from untreated RUPPs compared to untreated Shams. In group 2, birth weight and pup length did not significantly differ. However, birth weight tended to decrease and pup length tended to increase in treated control offspring. To evaluate nutrient delivery to the offspring, nutrient transporters were quantitated in the placenta of untreated RUPP and sham dams. Placental transporters are necessary for appropriate nutrient delivery to the offspring for normal growth and development. In group 1, placental GLUT‐1 and heart fatty acid binding protein (hFABP) protein expression did not differ in RUPP relative to control. Additional studies will examine protein expression of other transporters such as cholesterol transporter (ABCA1), glucose transporter glucose diffusion channel connexin (Cx26), and sodium‐coupled neutral amino acid transporters 1 and 2 (SNAT1 and SNAT2). Placental morphometics and the effect of maternal interventions on increased blood pressure in IUGR offspring will also be assessed.

Support or Funding Information

NIH: R56HL143459, P20GM121334, P20GM104357, P01‐HL51971, T32HL105324, F30DK112718 AHA: GRNT19900004, PRE34060010

Group 1 (Gestational Day 20)

Placental Weight (g)

Control
0.75 ± 0.03

RUPP
0.66 ± 00.10

Group 2 (Postnatal Day 1)

Birthweight (g)

Vehicle
Treated

Control
5.95 ± 0.24
5.12 ±0.23

IUGR
5.77 ± 0.24
5.71 ± 0.24

Length (cm)

Vehicle
Treated

Control
4.97 ± 0.53
5.61 ±0.61

IUGR
5.03 ± 0.34
5.17 ±0.14

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.