Background: Obesity in pregnancy is associated with increased risk of miscarriage, preeclampsia, gestational diabetes, stillbirth, and abnormal fetal growth. Altered maternal glucose, lipid, and inflammatory profiles are evident from early gestation and may disrupt placental development/function. This work aimed to understand how obesity influences placental endothelial metabolism and activation, and relate this to abnormal fetal growth.
Methods: A metabolic flow cytometry panel was developed combining markers for trophoblast, stromal, endothelial and haematopoietic populations with markers of glucose and lipid transport, glycolysis, mitochondrial metabolism, fatty acid metabolism, and proliferation (CD36, GLUT1, PKM, LDH, ATP5A, ACAC, CPT1A, and Ki67). This was applied to; 1) digested first-trimester placental villous tissue (obese BMI >30kg/m2, n=7; lean BMI <25kg/m2, n=4), and 2) HUVEC endothelial cells (n=4) exposed to fetal serum collected at birth from lean-AGA infants (n=14), or obese-SGA (<10th centile, n=7), obese-AGA (20th–80th centile, n=11), or obese-LGA (>90th centile, n=10) infants.
Results: Distinct metabolic signatures were observed across first-trimester placental cell populations, with cytotrophoblasts and endothelial cells being predominantly glycolytic, while haematopoietic cells exhibited greater mitochondrial metabolism. Obesity associated with increased GLUT1 expression in endothelial cells and cytotrophoblasts (p<0.05), and trends towards increased endothelial fatty acid synthesis and oxidation. Fetal serum from pregnancies with obesity induced metabolic adaptations in HUVECs that varied according to fetal growth outcome. Obese-SGA serum reduced CPT1A (p=0.012) and ATP5A (p=0.002) expression compared with lean-AGA, indicating reduced fatty acid oxidation and mitochondrial activity. The fatty acid synthesis marker ACAC was elevated in obese-AGA serum-treated cells compared to lean-AGA (p=0.012). HUVEC activation, measured by ICAM1, differed by fetal growth outcome and was higher in obese-SGA and obese-AGA groups than obese-LGA (p<0.01).
Conclusions: Placental endothelial cells respond to the altered metabolic environment of pregnancies with obesity. Differences across fetal growth outcomes suggest that endothelial metabolism may influence placental adaptation and fetal growth.