Intrauterine Growth Restriction Programs Intergenerational Transmission of Pulmonary Arterial Hypertension and Endothelial Dysfunction via Sperm Epigenetic Modifications

Abstract

Intrauterine life represents a window of phenotypic plasticity which carries consequences for later health in adulthood as well as health of subsequent generations. Intrauterine growth-restricted fetuses (intrauterine growth restriction [IUGR]) have a higher risk of pulmonary arterial hypertension in adulthood. Endothelial dysfunction, characterized by hyperproliferation, invasive migration, and disordered angiogenesis, is a hallmark of pulmonary arterial hypertension pathogenesis. Growing evidence suggests that intergenerational transmission of disease, including metabolic syndrome, can be induced by IUGR. Epigenetic modification of the paternal germline is implicated in this transmission. However, it is unclear whether offspring of individuals born with IUGR are also at risk of developing pulmonary arterial hypertension and endothelial dysfunction. Using a model of maternal caloric restriction to induce IUGR, we found that first and second generations of IUGR exhibited elevated pulmonary arterial pressure, myocardial, and vascular remodeling after prolonged exposure to hypoxia. Primary pulmonary vascular endothelial cells (PVECs) from both first and second generations of IUGR exhibited greater proliferation, migration, and angiogenesis. Moreover, in 2 generations, PVECs-derived ET-1 (endothelin-1) was activated by IUGR and hypoxia, and its knockdown mitigated PVECs dysregulation. Most interestingly, within ET-1 first intron, reduced DNA methylation and enhanced tri-methylation of lysine 4 on histone H3 were observed in PVECs and sperm of first generation of IUGR, with DNA demethylation in PVECs of second generation of IUGR. These results suggest that IUGR permanently altered epigenetic signatures of ET-1 from the sperm and PVECs in the first generation, which was subsequently transferred to PVECs of offspring. This mechanism would yield 2 generations with endothelial dysfunction and pulmonary arterial hypertension–like pathophysiological features in adulthood.

Insights into the Mechanisms of Fetal Growth Restriction-Induced Programming of Hypertension

“…These modifications regulate lineagespecific gene expression in several cellular processes including the pathogenesis of diseases and are a reflection of the interplay between DNA and environmental factors. 25,46 Gene expression is partly dependent on the accessibility of genomic regions like promoters, enhancers, and silencers. These regions are essential for binding transcriptional factors such as activator and repressor proteins to DNA when they regulate gene transcription.…”

“…46 In addition to altering the development of key organs that regulate BP homeostasis, poor fetal environment has been shown to induce epigenetic changes which might influence predisposition to adult hypertension and the transmission of this phenotype to subsequent generations. 7,25,53 Inhibition of DNA methyltransferase (DNMTs) with 5aza2DC and antagonism of histone deacetylase (HDAC) with valproic acid during the fetal life of rats exposed to dexamethasone, inhibited the elevation of BP normally seen in adult rats exposed to glucocorticoids in utero. 54 In addition, epinephrine and phenylethanolamine N-methyltransferase enzyme expression were reduced in these adult IUGR rats, implicating the involvement of DNMTs and HDAC in the epigenetic programming of hypertension in FGR.…”

“…These observations indicate a transgenerational inheritance of endothelial dysfunction through epigenetics. 25 Both maternal malnutrition and dexamethasone exposure have been shown to increase Angiotensin Receptor Type 1a (AGTR1a) expression in the hypothalamic paraventricular nucleus, reduce DNA methyltransferase 3 (DNMT3) expression and its binding to the AGTR1a gene as well as increase DNA demethylation in that gene. 58 These epigenetic modifications may be associated with the increased salt sensitive hypertensive phenotype seen in adult FGR animals.…”

“…FGR has also altered endothelin resulting in an increased angiotensin pressor response. 25 Other vasoconstrictor mechanisms shown to be altered and potentiated by FGR include thromboxane 90 and serotonin signaling. 91 In addition, increases in myogenic tone in FGR animals has been reported.…”

“…12,13 However, organs that are important for the long-term survival such as the kidneys and liver may be deprived of sufficient blood supply and nourishment leading to compromised growth and subsequent organ dysfunction in adult life. 24 Since FGR is now considered a risk factor for adult hypertension, [25][26][27] we aim to give a synopsis of the current knowledge in the field of fetal programming of hypertension, with special attention to evidence from clinical and animal research. We further suggest possible underlying mechanisms, reasons for observed sex differences in this phenomenon, and conclude by discussing the challenges and opportunities available in this dynamic field.…”