Premature Vascular Aging in Guinea Pigs Affected by Fetal Growth Restriction

Abstract

Cardiovascular risk associated with fetal growth restriction (FGR) could result from an early impaired vascular function. However, whether this effect results in premature vascular aging has not been addressed. We studied the ex vivo reactivity of carotid and femoral arteries in fetal (near term), adults (eight months-old) and aged (16 months-old) guinea pigs in normal (control) and FGR offspring. Additionally, an epigenetic marker of vascular aging (i.e., LINE-1 DNA methylation) was evaluated in human umbilical artery endothelial cells (HUAEC) from control and FGR subjects. Control guinea pig arteries showed an increased contractile response (KCl-induced) and a progressive impairment of NO-mediated relaxing responses as animals get older. FGR was associated with an initial preserved carotid artery reactivity as well as a later significant impairment in NO-mediated responses. Femoral arteries from FGR fetuses showed an increased contractility but a decreased relaxing response compared with control fetuses, and both responses were impaired in FGR-adults. Finally, FGR-HUAEC showed decreased LINE-1 DNA methylation compared with control-HUAEC. These data suggest that the aging of vascular function occurs by changes in NO-mediated responses, with limited alterations in contractile capacity. Further, these effects are accelerated and imposed at early stages of development in subjects exposed to a suboptimal intrauterine environment.

Cardiovascular and Cerebrovascular Implications of Growth Restriction: Mechanisms and Potential Treatments

“…As vascular reactivity is best assessed in vitro, much of our understanding of vascular reactivity has been completed in pre-clinical models. One pre-clinical model of FGR, induced via umbilical artery occlusion in guinea pigs, assessed vascular reactivity in both the carotid and femoral arteries at the end of gestation and as the animals aged [ 44 ]. Paz and colleagues found impaired vascular reactivity in femoral, but not carotid arteries, evidenced by an increase in contractibility and deficits in nitric oxide (NO)-induced vasodilation [ 44 ].…”

“…One pre-clinical model of FGR, induced via umbilical artery occlusion in guinea pigs, assessed vascular reactivity in both the carotid and femoral arteries at the end of gestation and as the animals aged [ 44 ]. Paz and colleagues found impaired vascular reactivity in femoral, but not carotid arteries, evidenced by an increase in contractibility and deficits in nitric oxide (NO)-induced vasodilation [ 44 ]. With age, however, both carotid and femoral vessels had impaired NO-mediated responses.…”

“…With age, however, both carotid and femoral vessels had impaired NO-mediated responses. The authors suggested that although it is accepted that vascular NO-mediated responses decline with aging, exposure to placental insufficiency in utero accelerated the decline in NO-induced vasodilation, particularly in peripheral vessels within the guinea pig [ 44 ]. Adult baboon offspring born growth restricted following maternal nutrient restriction, were also found to have regional differences in the composition of vascular extracellular matrix proteins.…”

Microvascular contributions to age-related macular degeneration (AMD): from mechanisms of choriocapillaris aging to novel interventions

“…Epigenetic changes including alterations in DNA methylation, histone modifications, and microRNA regulation have been hypothesized to contribute to aging processes, including age-related changes in the vasculature and vascular pathologies, such as atherosclerosis (Connelly et al 2013;Nanoudis et al 2017;Nguyen et al 2016;Paz et al 2019;Zhang et al 2018b). This is an active field of research and much remains to be explored regarding the contributions of epigenetic changes to vascular aging.…”

Postnatal growth retardation is associated with deteriorated intestinal mucosal barrier function using a porcine model

“…Growth retardation is a prevalent problem in both human beings and animal food production (Cooke, Ainsworth, & Fenton, 2004). Increasing evidence have illustrated that growth restriction was associated with various chronic metabolic syndrome, such as type 2 diabetes, cardiovascular disease, and stroke in adulthood in human, rodent, baboon, and piglet (Freije, Thamotharan, Lee, Shin, & Devaskar, 2015; Kuo et al, 2017; Martyn, Gale, Jespersen, & Sherriff, 1998; Paz et al, 2019; Vaiserman, 2018). Intestinal injury causes sloughing of IECs leading to host abnormal development unless mucosal barrier is restituted (Ziegler et al, 2018).…”