Sphingosine‐1‐Phosphate Type 1 Receptor and eNOS Signaling Pathway Play a Role in High Blood Pressure of Intrauterine Growth Restricted Mouse
Authors: Gagen Brennan R. , Swayze Thomas , Intapad Suttira 
Published: June 2021

Intrauterine growth restriction (IUGR) programs hypertension and cardiovascular (CV) disease in later life, but the underlying mechanisms remain unclear. The bioactive sphingolipid metabolite sphingosine‐1‐phosphate (S1P) is critically involved in CV development in the fetus and plays a significant role in the regulation of CV health in adulthood. S1P receptors (S1PRs) are widely expressed in CV system. We previously reported that IUGR offspring have an increase in blood pressure (BP) and have an alteration in renal S1PRs expression during‐ and post‐nephrogenesis. We also found that a nonspecific S1PRs agonist FTY720 (Fingolimod) administration decreased BP of IUGR offspring. However, which S1PR subtype and downstream signaling play a role in the decreasing of BP in IUGR is unknown. In this study, we tested the hypothesis that vascular S1P receptors type 1 (S1PR1) contributes to high BP in male IUGR mouse. Pregnant C57bl/6J mice underwent sham or reduced uterine perfusion (RUP) at day 13 of gestation with delivery at full term. IUGR offspring (from RUP dam) had a lower birth weight than control (p<0.05). At 24 weeks of age, male control and IUGR mice were subjected to telemetry probes implantation, and BP was measured after one week of recovery. IUGR offspring had a significantly higher BP compared to male control, and acute administration of FTY720 (1 mg/kgBW i.p), a nonspecific S1P receptor agonist, significantly decreased BP in IUGR similar to our previously reported data. SEW2871 (3 mg/kgBW i.p), a specific S1PR1 agonist, transiently decreased BP in IUGR (7.1±2.3 mmHg, p< 0.05, N=6) after one hour of treatment and the BP returned to normal level within 4 hrs. To determine the signaling pathway underlying this decreased BP after S1PR1 activation, another set of animals with SEW2871 or vehicle i.p. injections were euthanized after one hour of treatment, and the thoracic aorta was collected for western blot analysis (N=3 per group). Endothelial nitric oxide synthase (eNOS) phosphorylation at serine 1177 (p‐eNOS) and serine 473 phosphorylated Akt (p‐Akt) expressions were significantly increased in IUGR+SEW2871 vs IUGR+vehicle, p< 0.05 (p‐eNOS: 2.0 fold and ; p‐Akt:1.5 fold). p‐eNOS, p‐Akt, total eNOS and total Akt were not significantly different among control+vehicle, control+SEW2871, and IUGR+vehicle groups. Phosphorylated p38 MAPK was 3 folds lower in IUGR+vehicle as compared to control+vehicle, p< 0.05. SEW2871 did not up‐regulate p38 MAPK in control but significantly increased in IUGR (1.7 fold vs IUGR+vehicle, p< 0.05). Phosphorylated p44/42 MAPK was not different between groups. Together our data suggest that activation of S1PR1 decrease BP in IUGR through eNOS, Akt and MAPK pathways. Thus, S1P signaling is a putative mechanism underlying the developmental programming of hypertension in IUGR mice.

Support or Funding Information

Dr. Intapad was supported by funding from the AHA 16SDG27770041, ASN Kidney Research Career Development grant, and Start‐up funds from Tulane University.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.