Intrauterine growth restriction-induced deleterious adaptations in endothelial progenitor cells: possible mechanism to impair endothelial function

Abstract

Intrauterine growth restriction (IUGR) can induce deleterious changes in the modulatory ability of the vascular endothelium, contributing to an increased risk of developing cardiovascular diseases in the long term. However, the mechanisms involved are not fully understood. Emerging evidence has suggested the potential role of endothelial progenitor cells (EPCs) in vascular health and repair. Therefore, we aimed to evaluate the effects of IUGR on vascular reactivity and EPCs derived from the peripheral blood (PB) and bone marrow (BM) in vitro. Pregnant Wistar rats were fed an ad libitum diet (control group) or 50% of the ad libitum diet (restricted group) throughout gestation. We determined vascular reactivity, nitric oxide (NO) concentration, and endothelial nitric oxide synthase (eNOS) protein expression by evaluating the thoracic aorta of adult male offspring from both groups (aged: 19-20 weeks). Moreover, the amount, functional capacity, and senescence of EPCs were assessed in vitro. Our results indicated that IUGR reduced vasodilation via acetylcholine in aorta rings, decreased NO levels, and increased eNOS phosphorylation at Thr495. The amount of EPCs was similar between both groups; however, IUGR decreased the functional capacity of EPCs from the PB and BM. Furthermore, the senescence process was accelerated in BM-derived EPCs from IUGR rats. In summary, our findings demonstrated the deleterious changes in EPCs from IUGR rats, such as reduced EPC function and accelerated senescence in vitro. These findings may contribute towards elucidating the possible mechanisms involved in endothelial dysfunction induced by fetal programming.

Neonatal and Long-Term Consequences of Fetal Growth Restriction

“…The abnormal aortic and carotid wall thickness detected in FGR fetuses and infants could be the result of vascular remodelling beginning before birth, which may contribute to the occurrence of cardiac dysfunction during adulthood [67, 68]. The pathogenesis is still unclear, but animal models of FGR have demonstrated morphological changes in myocardium and vascular wall, with consequent myocardial dysfunction, vascular remodeling and fibrosis [69, 70].…”

Intrauterine Growth Restriction Weakens Anticontractile Influence of NO in Coronary Arteries of Adult Rats 

“…Endothelium-dependent dilations to acetylcholine were similar in mesenteric arteries of control and IUGR groups, which is supported by some previously reported data 29,30 . However, several other studies utilizing different from our animal models have revealed that IUGR can lead to endothelial dysfunction by reducing the contribution of NO to the reactions of agonist-induced endothelium-dependent arterial relaxation [9][10][11][12] . Of note, such endothelium-dependent relaxations and anticontractile in uence of endothelium (when endothelium counteracts vasocontraction via tonically released NO, see 33 ) represent two different aspects of endothelial functioning and can differentially change under pathologies affecting cardiovascular system 16,18,33−35 .…”

“…The increasing number of studies has revealed that cardiovascular consequences of IUGR do not disappear in adulthood and may manifest themselves as an increase in systemic blood pressure 7 or dysregulation of vascular functioning 8 . Among the various mechanisms of vascular functioning affected by this pathology, several studies have shown the weakened reactions of agonist-induced endotheliumdependent relaxation due to reduced nitric oxide (NO) bioavailability [9][10][11][12] . However, the in uence of IUGR on two vasomotоr mechanisms that are usually affected in the development of cardiovascular diseases has never been addressed.…”

Fetal programming and its effects on vascular pulmonary circulation

“…Another study also demonstrates that the IUGR condition in rats affects the function of both endothelium cells and their progenitors. Specifically, IUGR appears to induce vasodilatation, by modulating the expression and function of some molecules and pathways, such as acetylcholine and nitric oxide (NO) pathways, respectively [18] . Metabolic alterations related to IUGR condition have been also demonstrated to contribute to an altered development of endothelium and its dysfunction [19] .…”