Abstract
Endothelial dysfunction (ED) is part of the first steps in the development of cardiovascular diseases (CVD). Growth Differentiation Factor 15 (GDF15) is a cytokine belonging to the Transforming Growth Factor β superfamily and its expression is increased both during ED and in CVD. Because high blood levels of GDF15 have been reported during ED, we hypothesized that GDF15 could be produced by endothelial cells in response to a vascular stress, possibly to attenuate endothelial function loss. Since senescence is mainly involved in both vascular stress and endothelial function loss, we used Endothelial Colony Forming Cells generated from adult blood (AB-ECFCs) as a model of endothelial cells to investigate GDF15 expression during cellular senescence. Then, we analyzed the potential role of GDF15 in AB-ECFC functions and senescence. When AB-ECFCs become senescent, they secrete increased levels of GDF15. We investigated GDF15 paracrine effects on non-senescent AB-ECFCs and showed that GDF15 enhanced proliferation, migration, NO production and activated several signaling pathways including AKT, ERK1/2 and SMAD2 without triggering any oxidative stress. Taken together, our results suggest that GDF15 production by senescent AB-ECFCs could act in a paracrine manner on non-senescent AB-ECFCs, and that this interaction could be beneficial to its model cells. Therefore, GDF15 could play a beneficial role in a dysfunctional vascular system as previously reported in patients with CVD, by limiting ED related to vascular stress occurring in these diseases.
Highlights
According to the World Health Organization, cardiovascular diseases (CVD) such as ischemic heart, cerebrovascular and peripheral arterial diseases have been the worldwide leading cause of death over the past 15 years
We found that the levels of Growth Differentiation Factor 15 (GDF15) mRNA (Fig 1A), and intracellular (Fig 1B) and extracellular (Fig 1C) proteins were significantly higher in AB-Endothelial Colony Forming Cells (ECFCs) than in CB-ECFCs (6.6, 2.5 and 8-fold higher, respectively)
Using a Senescence Associated β-galactosidase assay (SA-β-gal), we showed a higher percentage of senescent cells in AB-ECFCs (75.96 ± 4.84%) than in CB-ECFCs (1.97 ± 0.79%, p = 0.0006, n = 7) (Fig 1D)
Summary
According to the World Health Organization, cardiovascular diseases (CVD) such as ischemic heart, cerebrovascular and peripheral arterial diseases have been the worldwide leading cause of death over the past 15 years. Decrease nitric oxide (NO) bioavailability due to an increase in reactive oxygen species (ROS) [4] and a decrease in Nitric Oxide Synthase 3 (NOS3) activity [5] leads to impaired endothelial functions, including reduced vasomotor responses and increased levels of inflammatory and adhesion molecules [6] involved in CVD development. GDF15 is induced in several EC types in culture following a cellular stress such as a high glucose stimulus [19], oxygen concentration changes [20,21] or after chemotherapy treatment [9]. Taken together, these data suggest that GDF15 could play a role in endothelial damage and dysfunction. The functional relationship between GDF15 and EC physiology remains elusive because its biological effects vary according to EC type, environment and concentration [20,22,23]
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