Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Del Gaudio, I.
The role of HDL- associated sphingosine-1-phosphate at the feto-placental vasculature: signaling and metabolism in pregnancy physiology and pathophysiology.
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2020. pp. 101
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Marsche Gunther
- Wadsack Christian
- Altmetrics:
- Abstract:
- Long-term adverse outcomes on offspring health are strictly dependent on proper placental vascular function during pregnancy. Maternal metabolic derangements promote the establishment of a pathological intrauterine environment, which can affect placental maternal-fetal interaction, leading to fetal vascular disturbances. In particular, alterations at the feto-placental endothelium set the bases for a fetal programming with concomitant risk for the fetus to develop chronic diseases in adulthood. Cumulative evidences have shown that, in adult and animal models, the bioactive sphingolipid sphingosine-1-phosphate (S1P) associated with high density lipoprotein (HDL) in the systemic circulation, exerts vasculoprotective properties. However, circulating HDLs in the cord blood possess a peculiar metabolism and function. The thesis presented here, investigated the role of cord blood derived HDL-S1P complexes in the regulation of feto-placental vascular function. Moreover, the thesis broadened the knowledge on the effect of preeclampsia on sphingolipid metabolism at the feto-placental vasculature. In the first part of this thesis, we characterized the cord-blood HDL-S1P complex, to which we referred to as neonatal HDL (nHDL), and we clarified the biological functions mediated by the complex at the feto-placental endothelial barrier. We could show in vitro that nHDL, by delivering S1P to its receptor, promotes proliferation of fetal placental arterial endothelial cells (fPAECs), calcium mobilization, cytoskeleton rearrangements and barrier function. Moreover, ex-vivo vascular reactivity studies on chorionic arteries, highlight the role of nHDL as potent vasodilator, although the role of S1P signaling in this specific effect is still under investigation. This suggest that nHDL plays a key role in preserving the integrity of the feto-placental endothelial barrier. Secondly, the anti-inflammatory action of nHDL-S1P was investigated. Since most of pregnancies-associated disorders are characterized by placental inflammation and dysfunction, we wanted to test the capability of healthy nHDL-S1P to counteract the inflammatory response. In presence of nHDL-S1P, we observed a reduction of pro-inflammatory cytokine expression as well as adhesion molecules, induced by tumor necrosis factor α (TNF-α), suggesting a potent inhibition of inflammatory mechanisms. This evidence was also corroborated by an observed downregulation of the nuclear transcription factor-kappa B (NF-κB) pathway. Furthermore, nHDL was able to attenuate oxidative stress induced by angiotensin II via S1P signaling in fPAECs, highlighting the vasculoprotective actions of the complex. Lastly, sphingolipid metabolism at the feto-placental vasculature in preeclampsia, which is a serious pregnancy complication characterized by high blood pressure and vascular dysfunction, was examined. Our data revealed that the exposure to a preeclamptic intrauterine environment, leads to a pathological remodeling of the feto-placental vasculature. The alterations induced by preeclampsia consist of increased de novo sphingolipid biosynthesis and sphingomyelin (SM) accumulation in placental chorionic vessels. Of note, we observed an impaired S1P signaling in fPAECs, which is consistent with vascular dysfunction. These data demonstrate the pivotal role of bioactive sphingolipid and specifically S1P, in the regulation of vascular homeostasis and barrier function of the human placenta in pregnancy physiology and pathophysiology.