Effects of S1PR2 antagonist on blood pressure and angiogenesis imbalance in preeclampsia rats

Abstract

Preeclampsia (PE), a hypertensive multisystem disorder, can lead to increased maternal and fetal mortality and morbidity. Sphingosine-1-phosphate (S1P) plays various roles, depending on the cell type, by binding to S1P receptors (S1PR). The present study evaluated the changes of S1PRs and investigated the potential role of S1PRs in pregnancy-induced hypertension. PE rats were established by reduced uterine perfusion pressure. The involvement of S1PR2 was evaluated using JTE-013, a specific S1PR2 antagonist, in PE rats. After the treatment, inflammatory cytokines were evaluated using enzyme linked immunosorbent assay, and the expression of vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS) activation and endothelial nitric oxide synthase (eNOS) were evaluated by reverse transcription-quantitative PCR and western blotting. Results showed that S1PR2, but not S1PR1 and S1PR3, was significantly increased in the serum and placenta tissues of PE rats. Notably, JTE-013 significantly decreased blood pressure, attenuated infiltration of inflammatory cells and decreased inflammation, as indicated by the decreased expression of inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β (IL-1β) and IL-6, in placental tissues. Mechanistic studies demonstrated that JTE-013 significantly increased the expression of VEGF and decreased the expression of fms-like tyrosine kinase 1 in placental tissue. Furthermore, JTE-013 prevented iNOS activation and increased eNOS in placental tissue. In summary, the present study demonstrated that S1PR2 contributed to hypertension and angiogenesis imbalance in PE rats.

Inhibition of Sphingosine-1-Phosphate Receptor 2 by JTE013 Enhanced Alveolar Bone Regeneration by Promoting Angiogenesis

“…Previously, we have showed that S1PR2 is highly expressed in murine BMSCs, and treatment with JTE013 enhanced Rac1-GTP level compared to vehicle control [ 11 ]. In murine BMMs, treatment with JTE013 also significantly increased VEGFA , PDGFA , and GDF15 compared with vehicle treatment regardless of Aa infection/ Our results are congruent with Inoki et al [ 30 ] and Zhang et al [ 31 ]’s studies [ 31 ] and support that JTE013 treatment promoted VEGF expression and angiogenesis. In the present study, we observed an increase in p-Akt in uninfected murine BMSCs treated with JTE013.…”

“…By implanting Matrigel in the subcutaneous tissues of mice, the researchers also demonstrated that treatment with JTE013 and S1P increased the number of infiltrating cells and the formation of blood vessels in mice [ 30 ]. In another preeclampsia (a pregnancy-induced hypertensive disorder) study, Zhang et al [ 31 ] showed that treatment with JTE013 reduced blood pressure, attenuated inflammatory cytokines (TNF-α, IL-1β, and IL-6) in placental tissues, and significantly enhanced VEGF levels. However, Chumanevich et al [ 32 ] reported that S1PR2 knockout mice or treatment with JTE013 in cells (mouse bone marrow-derived mast cells and human skin mast cells) attenuated S1P-induced VEGFA levels.…”

A Meta-Analysis of the Differences in Serum Lipid Levels between Pregnant Women with Hypertensive Disorder Complicating Pregnancy and Nonhypertensive Disorder Complicating Pregnancy

“…Hypertensive disorder complicating pregnancy has always been a hot topic and focus of investigation by experts and scholars in obstetrics, which involves the etiology, pathogenesis, risk factors, and prediction and prevention of the disease [ 17 ]. However, the exact etiology and pathogenesis of the disease have not yet “surfaced,” so in order to better predict and prevent the disease, the study of the common clinical risk factors for the disease is of great significance [ 18 ].…”

Endothelial Nitric Oxide Synthase (eNOS) and the Cardiovascular System: in Physiology and in Disease States

“…Previous reviews have summarized how a reduced expression of the endothelial nitric oxide synthase (eNOS) enzyme and subsequent decreased production of NO result in an increased susceptibility/ risk to develop essential hypertension [1,2], preeclampsia [3], diabetic nephropathy [4], retinopathy [5], migraine [6], and…”