Axes de recherche
Reversibility of endothelial progenitor cells dysfunctions in an intrauterine growth restriction rat model: role of the Sirtuin-activating compounds
Infants born after intrauterine growth restriction (IUGR) are particularly at risk to develop hypertension later in life. The vascular endothelium is a major contributor to arterial hypertension, thanks to its circulating component, the endothelial progenitor cells (EPCs), which can be discriminated in early and late EPCs also named endothelial colony-forming cells (ECFCs). Only ECFCs are able to regenerate an injured monolayer of vascular endothelial cells. Therefore, an altered status of ECFCs is a marker of endothelial dysfunction and so of vascular health.
In a rat model of IUGR induced by an exposure to maternal low protein diet during gestation, vs. a control (CTRL) group, we have observed that only adult male offspring displayed increased systolic blood pressure, impaired endothelium-dependent vasodilation. We also observed in ECFCs, isolated from bone marrow, a decreased of their number, an impaired proliferation and a reduced vascular network formation. These alterations were associated with features of oxidative stress and cellular senescence, in relation with a decreased functionality of Sirtuin-1, a NAD+-histone deacetylase.
We hypothesized that restoring Sirtuin-1 functionality in vitro would reverse the dysfunctions of ECFCs related to oxidative stress and cellular senescence.
In ECFCs from IUGR vs. CTRL groups :
1) We will overexpress Sirtuin-1 expression, we will treat these cells with Resveratrol, and with a NAD+ precursor, nicotinamide riboside.
Following these different treatments :
2) We will explore their capacities of proliferation (BrdU incorporation) and of vascular network formation (matrigel).
3) We will investigate the cellular/molecular mechanisms related to oxidative stress (superoxide anion production, antioxidant defenses) and senescence (β-galactosidase activity, p53, p21, p16, pRb/Rb, Sirtuin-1) pathways.
This study will open the way to develop, thereafter, preventive strategies in vivo to reverse vascular dysfunctions related to IUGR.
