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TNF-alpha is increased in women with IUGR and placental insufficiency but normal in those with IUGR and normal placental perfusion. We suggest that elevations of TNF-alpha could be a specific phenomenon of certain subsets of IUGR, identifying cases with placental dysfunction.

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25Aim/hypothesis: Placenta of women with gestational diabetes mellitus (GDM) exhibits an 26 altered lipid metabolism. The mechanism by which GDM is linked to alterations in placental lipid 27 metabolism remains obscure. We hypothesized that high-glucose levels reduce mitochondrial fatty 28 acid oxidation (FAO) and increase triglyceride accumulation in human placenta. 29 Methods:To test this hypothesis, we measured FAO, fatty acid esterification, de novo fatty 30 acid synthesis, triglyceride levels and carnitine palmitoyltransferase activities (CPT) in placental 31 explants of women with GDM or with no pregnancy complication. 32 Results:In women with GDM, FAO was reduced by ~30% without change in mitochondrial 33 content, and triglyceride content was 3-fold higher than control group. Likewise, in placental 34

Endothelial cell senescence is a hallmark of vascular aging that predisposes to vascular disease. We aimed to explore the capacity of the renin–angiotensin system (RAS) heptapeptide angiotensin (Ang)‐(1‐7) to counteract human endothelial cell senescence and to identify intracellular pathways mediating its potential protective action. In human umbilical vein endothelial cell (HUVEC) cultures, Ang II promoted cell senescence, as revealed by the enhancement in senescence‐associated galactosidase (SA‐β‐gal+) positive staining, total and telomeric DNA damage, adhesion molecule expression, and human mononuclear adhesion to HUVEC monolayers. By activating the G protein‐coupled receptor Mas, Ang‐(1‐7) inhibited the pro‐senescence action of Ang II, but also of a non‐RAS stressor such as the cytokine IL‐1β. Moreover, Ang‐(1‐7) enhanced endothelial klotho levels, while klotho silencing resulted in the loss of the anti‐senescence action of the heptapeptide. Indeed, both Ang‐(1‐7) and recombinant klotho activated the cytoprotective Nrf2/heme oxygenase‐1 (HO‐1) pathway. The HO‐1 inhibitor tin protoporphyrin IX prevented the anti‐senescence action evoked by Ang‐(1‐7) or recombinant klotho. Overall, the present study identifies Ang‐(1‐7) as an anti‐senescence peptide displaying its protective action beyond the RAS by consecutively activating klotho and Nrf2/HO‐1. Ang‐(1‐7) mimetic drugs may thus prove useful to prevent endothelial cell senescence and its related vascular complications.