Adult vascular dysfunction in foetal growth‐restricted guinea‐pigs is associated with a neonate‐adult switching in Nos3 DNA methylation

Abstract

Aim Foetal growth restriction (FGR) is associated with endothelial dysfunction and cardiovascular diseases in adult subjects. Early vascular remodelling and epigenetic changes occurring on key endothelial genes might precede this altered vascular function. Further, it has been proposed that oxidative stress during development may determine some of these epigenetic modifications. To address this issue, we studied the in vivo and ex vivo vascular function and Nos3 promoter DNA methylation in arteries from eight‐month‐old guinea‐pig born from control, FGR‐treated and FGR‐NAC‐treated pregnancies. Methods Femoral and carotid arteries in vivo vascular function were determined by Doppler, whilst ex vivo vascular function and biomechanical properties were assessed by wire myography. Levels of eNOS mRNA and site‐specific DNA methylation in Nos3 promoter in aorta endothelial cells (AEC) were determined by qPCR and pyrosequencing respectively. Results FGR adult showed an increased femoral vascular resistance (P < .05), stiffness (P < .05) and arterial remodelling (P < .01), along with an impaired NO‐mediated relaxation (P < .001). These effects were prevented by maternal treatment with NAC. Endothelial‐NOS mRNA levels were decreased in FGR adult compared with control and FGR‐NAC (P < .05), associated with increased DNA methylation levels (P < .01). Comparison of Nos3 DNA methylation in AEC showed a differential methylation pattern between foetal and adult guinea‐pigs (P < .05). Conclusion Altogether, these data suggest that adult vascular dysfunction in the FGR does not result from early changes in Nos3 promoter DNA methylation, but from an altered vessel structure established during foetal development.

Premature Vascular Aging in Guinea Pigs Affected by Fetal Growth Restriction

“…The contractile and relaxing responses in FGR guinea pig arteries, both carotid and femoral, followed a pattern of accelerated aging, an effect that was evident since late gestation in femoral arteries but not in carotid vessels. Notably, the changes in NO-mediated responses occurred parallel to life-course modifications in eNOS expression and activation [40,41]. Comparable studies in fetal growth-restricted rats have shown sex-specific early aging in the vascular responses of mesenteric arteries, occurring in females but not in male offspring [23,35].…”

“…Previous reports have shown that FGR, in human and animal models, results in comparable epigenetic changes in the endothelium. For instance, a similar epigenetic effects occurs in the gene coding for eNOS ( NOS3 or Nos3 ) in human [43,44], guinea pig [40,41], and rat [45] FGR endothelial cells. Conversely, LINE-1 has been suggested to correlate with aging, cardiovascular risk, and metabolic dysfunction in humans [46,47,48,49,50], conditions prompted by an impaired fetal growth.…”

“…In this context, here we provide further evidence, by studying a single cell type, that FGR results in epigenetic markers in the endothelium that would be also associated with accelerated aging. However, whether these markers remain at long-term need to be elucidated [41].…”

Pregnancy

“…16 Foetal growth restriction is associated with, among other pathologies, vascular dysfunction later in life. 2 Krause et al 17 showed recently how altered vessel structures developing during the foetal period persist and precede this altered vascular function in adult life.…”

MiRNAs Regulating Oxidative Stress: A Correlation with Doppler Sonography of Uteroplacental Complex and Clinical State Assessments of Newborns in Fetal Growth Restriction

“…A decrease in uteroplacental perfusion due to increased vascular resistance leads to ischemic reperfusion injury and/or hyperoxia/reoxygenation, the production of excessive amounts of reactive oxygen species (ROS) and uncontrolled oxidative stress (OS) [ 5 , 6 ]. The latter can play a central role in programming the long-term consequences of the development of cardiovascular diseases in the fetus: an increase of superoxide and nitric oxide production with the formation of prooxidant peroxy-nitrite under OS leads to vascular dysfunction [ 7 ].…”