Endothelial Colony-Forming Cells Dysfunctions Are Associated with Arterial Hypertension in a Rat Model of Intrauterine Growth Restriction.

Stephanie Simoncini,Nathalie Rosenblatt-Velin,Anne Wilson,Françoise Dignat-George,Anne-Christine Peyter,Angela Rocca,Steeve Menétrey,Hanna Coppola,Florence Sabatier,Jean-Baptiste Armengaud,Leila Zippo,Romain Bedel,Isaline Bachmann,Catherine Yzydorczyk,Umberto Simeoni,Estelle Guillot

doi:10.3390/ijms221810159

Abstract

Infants born after intrauterine growth restriction (IUGR) are at risk of developing arterial hypertension at adulthood. The endothelium plays a major role in the pathogenesis of hypertension. Endothelial colony-forming cells (ECFCs), critical circulating components of the endothelium, are involved in vasculo-and angiogenesis and in endothelium repair. We previously described impaired functionality of ECFCs in cord blood of low-birth-weight newborns. However, whether early ECFC alterations persist thereafter and could be associated with hypertension in individuals born after IUGR remains unknown. A rat model of IUGR was induced by a maternal low-protein diet during gestation versus a control (CTRL) diet. In six-month-old offspring, only IUGR males have increased systolic blood pressure (tail-cuff plethysmography) and microvascular rarefaction (immunofluorescence). ECFCs isolated from bone marrow of IUGR versus CTRL males displayed a decreased proportion of CD31+ versus CD146+ staining on CD45− cells, CD34 expression (flow cytometry, immunofluorescence), reduced proliferation (BrdU incorporation), and an impaired capacity to form capillary-like structures (Matrigel test), associated with an impaired angiogenic profile (immunofluorescence). These dysfunctions were associated with oxidative stress (increased superoxide anion levels (fluorescent dye), decreased superoxide dismutase protein expression, increased DNA damage (immunofluorescence), and stress-induced premature senescence (SIPS; increased beta-galactosidase activity, increased p16INK4a, and decreased sirtuin-1 protein expression). This study demonstrated an impaired functionality of ECFCs at adulthood associated with arterial hypertension in individuals born after IUGR.

Highlights

Subjects born after IUGR are at an increased risk of higher blood pressure during infancy [1], adolescence [2,3], young adulthood [4], and later in life [5,6,7]
Using a recognized rat model of developmental programming of arterial hypertension related to IUGR, we investigated whether the proportion of endothelial colony-forming cells (ECFCs), their proliferative capacity, and their vascular network formation are altered
We evaluated the angiogenic profile of ECFCs by immunofluorescence

Summary

Introduction

Subjects born after IUGR are at an increased risk of higher blood pressure during infancy [1], adolescence [2,3], young adulthood [4], and later in life [5,6,7]. Endothelial colony-forming cells (ECFCs) or late outgrowth EPCs [13] have clonal potential and the capacity to produce mature endothelial cells and promote vascular formation in vitro and in vivo. Ligi et al observed impaired proliferation, vascular network formation, and angiogenic capabilities of ECFCs isolated from the cord blood of low-birth-weight newborns, associated with accelerated senescence [20,21,34]. It is not well identified whether these early dysfunctions of ECFCs persist through adulthood and constitute a possible link between IUGR and arterial hypertension development, and which mechanisms could be involved

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Conclusion