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Tain, Y.; Hsu, C. Melatonin Use for Early Life Origins of Hypertension. Encyclopedia. Available online: https://encyclopedia.pub/entry/22807 (accessed on 15 December 2025).
Tain Y, Hsu C. Melatonin Use for Early Life Origins of Hypertension. Encyclopedia. Available at: https://encyclopedia.pub/entry/22807. Accessed December 15, 2025.
Tain, You-Lin, Chien-Ning Hsu. "Melatonin Use for Early Life Origins of Hypertension" Encyclopedia, https://encyclopedia.pub/entry/22807 (accessed December 15, 2025).
Tain, Y., & Hsu, C. (2022, May 11). Melatonin Use for Early Life Origins of Hypertension. In Encyclopedia. https://encyclopedia.pub/entry/22807
Tain, You-Lin and Chien-Ning Hsu. "Melatonin Use for Early Life Origins of Hypertension." Encyclopedia. Web. 11 May, 2022.
Melatonin Use for Early Life Origins of Hypertension
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This entry is adapted from the peer-reviewed paper 10.3390/antiox11050924

 Hypertension represents a major disease burden worldwide. Abundant evidence suggests that hypertension can originate in early life. Adverse programming processes can be prevented by early life intervention—namely, reprogramming—to avoid developing chronic diseases later in life. Melatonin is an endogenously produced hormone with a multifaceted biological function. Although melatonin supplementation has shown benefits for human health, less attention has been paid to exploring its reprogramming effects on the early life origins of hypertension.

Hypertension Melatonin renin–angiotensin system

1. Protective Mechanisms of Melatonin against Early Life Origins of Hypertension

In view of the fact that different early life insult stimuli produce the same outcome―hypertension in later life—there might be some common mechanisms involved in the pathogenesis of the early life origins of hypertension. Notably, data from experimental animal studies have revealed an interplay between melatonin and the aforementioned mechanisms, such as oxidative stress, impaired NO signaling, aberrant renin–angiotensin system (RAS), dysregulated nutrient-sensing signals, epigenetic regulation, glucocorticoid effect, and gut microbiota dysbiosis. 

2. Oxidative Stress

During pregnancy, the low levels of antioxidants in the fetus are inadequate to overcome excessive reactive oxygen species (ROS) under adverse environmental conditions, resulting in oxidative stress damage [1]. Melatonin is a well-known, potent antioxidant molecule against oxidative stress [2][3]. Melatonin is capable of scavenging ROS [4]; stimulating the gene expression of antioxidant enzymes [5]; and protecting lipids, proteins, and nuclear DNA from oxidative damage [2][3]. A previous review demonstrated that several early life insults linked the early life origins of hypertension to oxidative stress [6], including maternal nutritional imbalance, maternal illness, pregnancy complications, medication use in pregnancy, and exposure to environmental chemicals.
Prior studies support the protective effects of maternal melatonin therapy against oxidative stress-related early life origins of hypertension in models of a maternal high-fructose diet [7], maternal dietary restriction [8], maternal L-NAME exposure [9], maternal methyl-donor diet [10], and glucocorticoid exposure [11]. The main beneficial mechanisms underlying the actions of melatonin consisted of decreased ROS-producing enzyme expression, reduced ROS production, increased antioxidant capacity, and decreased oxidative DNA damage. However, one study showed that maternal melatonin treatment reduced the elevation of Blood pressure (BP) in 8-week-old male SHR offspring, which was not related to the activities of catalase, superoxide dismutase, and glutathione reductase [12]. In spite of recent advances in understanding how early life oxidative stress impacts the early life origins of hypertension, further research is required to elucidate the reprogramming mechanisms of melatonin, particularly regarding which developmental window and which organ-specific redox-sensitive signaling pathway are responsible for its beneficial effects.

3. Impaired NO Signaling

NO plays a pivotal role in the regulation of BP. Impaired NO signaling is a common mechanism behind the early life origins of hypertension, while NO-targeting interventions in early life may act as a reprogramming strategy to prevent the development of hypertension in adulthood [13]. NO is formed from the conversion of L-arginine to L-citrulline by nitric oxide synthase (NOS), while asymmetric dimethylarginine (ADMA) can compete with L-arginine for NOS, contributing to impaired NO signaling [14].
Melatonin can reduce ADMA to regulate NO [15]. SHRs exhibited a higher BP than control normotensive Wistar Kyoto (WKY) rats, which was related to increased plasma ADMA levels [16][17]. In young SHRs, the BP-lowering effect of melatonin was associated with an increase in renal dimethylarginine dimethylaminohydrolase (DDAH; ADMA-metabolizing enzymes) activity to decrease ADMA in the plasma and kidneys [16][17]. NO inhibition induced during gestation by the administration of L-NAME elevated offspring BP, which maternal melatonin therapy prevented [9]. Additionally, melatonin use in pregnancy and lactation was of benefit for offspring hypertension coinciding with the restoration of the ADMA-NO balance in several animal models related to the early life origins of hypertension [7][8][18]. In the pediatric CKD model [19], early melatonin therapy prevented CKD-induced hypertension and kidney damage, coinciding with a reduction in ADMA. These results support the notion that the NO signaling pathway may be a core mechanism behind the early life origins of hypertension and the reprogramming effects of melatonin.

4. Aberrant RAS

In addition to the regulation of BP, RAS is a notable hormonal cascade controlling kidney development [20][21]. The classic RAS can be defined as the angiotensin-converting enzyme (ACE)/Ang II/angiotensin type 1 receptor (AT1R) axis, which promotes vasoconstriction. Prior research suggests a transient biphasic response with downregulation of the classic RAS in the neonatal stage that becomes normalized with age. Early life insults can disturb this normalization and inappropriately activate the classic RAS axis, resulting in hypertension and kidney disease in adult offspring [22][23][24].
Accumulative evidence suggests that the interplay between melatonin and RAS determines BP [25]. In melatonin-deficient hypertension, the classic RAS axis is activated [26]. Conversely, activation of the classic RAS could be blocked by melatonin therapy, coinciding with the prevention of offspring hypertension, in a variety of animal models, including maternal high-fructose diet [7], maternal dietary restriction [8], and maternal continuous light exposure [27]. Besides the classic RAS axis, the non-classic ACE2/angiotensin (1–7)/Mas receptor axis has also been linked to the early life origins of hypertension [21]. A previous report indicated that maternal melatonin therapy prevents offspring hypertension, accompanied by increased mRNA expression of Agtr1b and Mas1 in a model of combined prenatal dexamethasone exposure and high-fat diet [28]. Hence, these observations indicate a crosstalk between RAS and melatonin, by which both tightly mediate the developmental programming of hypertension.

5. Dysregulated Nutrient-Sensing Signals

Several nutrient-sensing signals are involved in the early life origins of hypertension, including AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptors (PPARs), silent information regulator T1 (SIRT1), and PPARγ co-activator 1α (PGC-1α) [29][30]. Nutrient-sensing signals orchestrate fetal metabolism in response to maternal nutritional status in pregnancy, while these signals can be disturbed by early life nutritional insults. SIRT1 and AMPK can, respectively, deacetylate and acetylate PGC-1α, to mediate PPARs and their target genes, thereby resulting in hypertension later in life [31][32].
Prior research indicates that melatonin’s benefits can be attributed to the activation of nutrient-sensing signals [33][34][35]. Likewise, melatonin’s protection of adult offspring against hypertension is associated with the activation of the AMPK/SIRT1/PGC-1α pathway. A maternal methyl-donor diet led to offspring hypertension accompanied by reduced renal expression of several nutrient-sensing signaling components, comprising AMPKα2, SIRT1, PPARβ, and PPARγ [10]. Another study showed that the use of melatonin in gestation and lactation prevented hypertension programmed by a combined high-fructose plus post-weaning high-salt diet via regulating SIRT1, SIRT4, AMPKα2, AMPKβ2, PPARγ, and PGC-1α in the kidneys [18]. These findings are consistent with previous studies showing that AMPK activation prevents offspring hypertension via regulating nutrient-sensing signals in various models of the early life origins of hypertension [30].

6. Epigenetic Regulation

Epigenetic regulation is another core mechanism underlying the reprogramming effects of melatonin to prevent the early life origins of hypertension [20][36]. Notably, melatonin is involved in epigenetic regulation [37][38]. Epigenetic processes, including DNA methylation, histone modification, and microRNA (miRNA), are known to influence gene expression [39]. Former research revealed that melatonin can serve as an inhibitor of DNA methyltransferases (DNMT) or act as a histone deacetylase (HDAC) inhibitor [37][40]. In an antenatal dexamethasone exposure model, melatonin not only protected against hypertension but also restored the brain reelin mRNA expression levels by reducing DNMT1 expression [11][41]. Melatonin also reduced the binding of methyl-CpG binding protein 2 (MeCP2) and DNMT1 to the reelin promoter [41]. Another study revealed that melatonin and trichostatin A (a HDAC inhibitor) provide similar benefits for neonatal dexamethasone-induced programmed hypertension [40], suggesting a potential protective mechanism underlying HDAC inhibition by melatonin. Although melatonin can regulate the expression of certain miRNAs and their target genes [42], their impact in the early life origins of hypertension remains unclear.
Furthermore, melatonin programs alterations in the renal transcriptome and genes involved in the melatonin signaling pathway during kidney development [38]. Using the RNA next-generation sequencing method to analyze the renal transcriptome, a total of 455, 230, and 132 differentially expressed genes were identified in the kidneys of offspring rats born to melatonin-treated dams at the age of 1, 12, and 16 weeks, respectively. Among them, several genes involved in the biosynthesis of melatonin were significantly up-regulated, including aromatic L-amino acid decarboxylase, tryptophan hydroxylase 1, and N-acetylserotonin methyltransferase. Additionally, several melatonin receptors were up-regulated in the offspring kidneys, including MT2, RORα, and RORβ. Moreover, maternal melatonin therapy mediates several biological pathways during kidney development, including the PPAR signaling pathway, focal adhesion signaling, fatty acid metabolism, the wingless-int (Wnt) signaling pathway, the transforming growth factor (TGF)-β signaling pathway, and the erythroblastic leukemia viral oncogene (ErbB) signaling pathway [38]. These observations support the notion that melatonin can epigenetically regulate specific genes and pathways, by which it prevents programmed hypertension. Its long-term epigenetic changes in later life, however, remain to be elucidated.

7. Glucocorticoid Effect

Similar to melatonin, glucocorticoid is involved in circadian rhythms [43][44]. During pregnancy, maternal melatonin and glucocorticoid are able to cross the placenta. Hence, both can establish and entrain the fetal circadian clock [43]. There is a crosstalk between glucocorticoid and melatonin, by which both chronobiotics tightly mediate developmental programming processes: melatonin can downregulate glucocorticoid receptor expression [26], while MT receptors could be downregulated following glucocorticoid treatment [45].
Early life glucocorticoid exposure through excessive maternal corticosteroids (e.g., compromised pregnancies) or through exogenous administration (e.g., preterm birth) can impair the fetal hypothalamic–pituitary–adrenal (HPA) axis, resulting in adult diseases, namely glucocorticoid programming [45][46]. Conversely, early life melatonin therapy is beneficial for the prenatal or neonatal glucocorticoid-induced programming of hypertension [11][28][40][47].
Another study demonstrated that melatonin or melatonin receptor agonist agomelatine can prevent offspring hypertension programmed by maternal exposure to continuous light [27]. In spite of the beneficial effects of melatonin use in pregnancy and lactation that have been reported in several models of maternal chronodisruption [44], the interplay between glucocorticoid programming, circadian rhythms, and melatonin in the early life origins of hypertension awaits further clarification.

8. Gut Microbiota Dysbiosis

Lastly, one protective mechanism of melatonin against the early life origins of hypertension might be attributed to its ability to mediate the gut microbiota. Of note is that melatonin is one of the tryptophan-derived metabolites, and many metabolites are gut microbial catabolites regulated by the composition of the gut microbiota [48]. Along with the pineal gland, the gut is one of the main sources of melatonin, and its concentration in the gut is 10–100 times higher than that in the plasma [49]. The gut microbiota and its derived metabolites are involved in the regulation of BP [50][51]. These metabolites include short-chain fatty acids (SCFAs), trimethylamine-N-oxide (TMAO), tryptophan-derived uremic toxins, etc. [48][50][51]. Recent studies suggest that melatonin-mediated gut microbiota changes play a key role in certain diseases [52], although little is known about its impact in hypertension.
There is increasing evidence proposing that the gut microbiota in early life is linked to adult disease in later life [53]. Prior reviews reported a variety of early life insults that induce offspring hypertension related to alterations of the gut microbiota, while gut microbiota-targeted therapy, if applied early, can prevent hypertension in later life [54][55]. Early melatonin therapy protects young rats against CKD-induced hypertension and kidney damage [19]. The beneficial effects of melatonin include reshaping the gut microbiota, increased α-diversity, and enhancement of the abundance of the genus Roseburia and the phylum Proteobacteria. Additionally, melatonin reversed the changes to the plasma TMAO-to-TMA ratio induced by CKD in young rats of both sexes. However, the interaction mechanisms between melatonin and the gut microbiota underlying the early life origins of hypertension need to be further explored.

9. Others

Considering its pleiotropic bioactivities, there might be other mechanisms by which melatonin acts: (1) by activating Nrf2 (nuclear factor erythroid 2-related factor 2) and (2) by increasing the nephron number. Melatonin has been considered as an Nrf2 activator [56]. Nrf2 activation has shown benefits in several models of developmental hypertension [57][58][59]. However, this remains speculative, and the question of whether the reprogramming effects of melatonin with programmed hypertension occur directly through the regulation of Nrf2 deserves further evaluation.
In a prenatal dexamethasone exposure model [11], maternal melatonin therapy prevented offspring hypertension accompanied by the restoration of the nephron number programmed by glucocorticoid. As a reduced nephron number is a key mechanism behind the early life origins of hypertension [60], there might be an interplay between melatonin and mechanisms that determine the nephron number that leads to hypertension of developmental origins.
Although numerous mechanisms are outlined above, additional work is needed to explore other potential mechanisms. A deeper understanding of how melatonin reprograms hypertension in early life is key toward creating optimal interventions for its clinical translation.

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