In GDM, the sustained maternal hyperglycemic environment promotes increased transplacental glucose transport. This excessive glucose is subsequently converted into adipose tissue deposition in the fetus, ultimately leading to the development of macrosomia (Kc et al., 2015). This phenomenon occurs because the fetal pancreas is highly sensitive to fluctuations in circulating glucose concentrations. Exposure to hyperglycemia rapidly induces fetal hyperinsulinemia (Yan Y. S. et al., 2023). Moreover, while the fetus has the intrinsic capacity for gluconeogenesis, this metabolic capability is limited by the delayed expression and activation of phosphoenolpyruvate carboxykinase (PEPCK), an enzyme whose functional activity is typically not observed until the neonatal period (Vargas et al., 2022). Consequently, the conversion of pyruvate to glucose remains functionally limited before birth, rendering the fetus almost entirely dependent on maternally derived glucose via placental transport during this developmental stage (Santos et al., 2023). Studies have demonstrated that when maternal blood glucose levels are ≤120 mg/dL, the incidence of macrosomia is approximately 20%. However, this risk rises significantly to 35% when blood glucose levels reach 160 mg/dL (Kc et al., 2015).

The placental glucose transport process primarily depends on the GLUT gene family, which comprises 12 members. Among these, GLUT1 serves as the key mediator of glucose transport across the placenta and is predominantly expressed in the syncytiotrophoblast (STB). Under normal physiological conditions, GLUT1 expression on the microvillous membrane is markedly higher than on the basal membrane. During weeks 16–22 and 27–30 of gestation, both the expression levels and transport activity of GLUT1 on the basal membrane are significantly increased (Illsley and Baumann, 2020). Ex vivo and observational studies of human GDM placentas consistently demonstrate increased basal membrane GLUT1 expression, enhanced glucose uptake, and a positive association with fetal birth weight, influenced by maternal pre-pregnancy BMI (Gaither et al., 1999; Stanirowski et al., 2019), suggesting that upregulated expression of placental GLUT1 may play a critical role in the pathogenesis of GDM-related fetal overgrowth. Studies demonstrate that antenatal exercise interventions induce significant downregulation of placental GLUT1 expression in GDM pregnancies, concurrently attenuating the disorder’s adverse effects on cardiac, hepatic, and renal organogenesis in offspring (Tang et al., 2024). Although this protective effect may not be solely attributed to the downregulation of GLUT1, accumulating evidence indicates that maternal hyperglycemia during pregnancy is strongly associated with fetal overgrowth, adverse perinatal outcomes, and even long-term developmental impairments. Therefore, we propose that epigenetic modifications in placental tissue may represent a key regulatory mechanism, exerting long-term influences on offspring metabolic function development through metabolic programming (Picó et al., 2019). Taken together, the aforementioned human observational studies and ex vivo placental experiments consistently indicate a positive association between maternal hyperglycemia, upregulation of placental GLUT1 expression, and fetal birth weight in GDM pregnancies. It is recognized that GLUT1 expression varies with gestational age and maternal pre-pregnancy BMI, both of which may confound the observed associations. Consequently, whether upregulated GLUT1 expression is specifically linked to fetal overgrowth, rather than merely reflecting broader metabolic dysregulation in GDM, remains to be fully elucidated.

Amino acids required for fetal growth and development are primarily utilized in biosynthetic processes such as protein synthesis, carbon storage, and oxidative metabolism, collectively influencing the intrauterine growth rate. The availability of amino acids to the fetus is largely dependent on the placental transport capacity (Vaughan et al., 2017). The human placenta contains more than 15 AA transport systems, among which Systems A and L are the most functionally characterized. Enhanced activity of these AA transport systems is recognized as a key contributor to fetal overgrowth (Shimada et al., 2024).

Placental tissues from women with GDM exhibit significant impairments in amino acid transport function. Increased activity or expression of both System A and System L transporters has been reported in women with GDM and is associated with accelerated fetal growth and fetal overgrowth (Jansson et al., 2006), and studies using primary human trophoblast cells suggest that insulin may enhance AA transport via activation of the Akt and ERK signaling pathways (Castillo-Castrejon et al., 2019). These aberrant placental nutrient transport mechanisms result in sustained elevations of multiple AA levels in umbilical cord blood of fetuses from GDM pregnancies, particularly total branched-chain amino acids (BCAAs), leucine, and valine. These AA not only support placental metabolic activities that promote accelerated fetal growth but are also transported across the placenta into the fetal circulation, leading to disrupted BCAAs metabolism. This metabolic disturbance is not limited to the perinatal period but can persist into childhood (Liu et al., 2023). Abnormalities in BCAAs metabolism are strongly associated with increased cardiac metabolic risk in offspring (Jauhiainen et al., 2021). Macrosomia, a common complication of GDM, is closely linked to an elevated risk of cardiovascular disease (CVD) in adulthood (Contreras-Duarte et al., 2020). These findings suggest that enhanced amino acid transport not only promotes excessive fetal growth but also predisposes macrosomia to long-term CVD risks. Overall, human placental studies indicate that the activity of System A and System L transporters is significantly enhanced in placentas from GDM pregnancies, while in vitro experiments further demonstrate that insulin can modulate this transport activity. However, important knowledge gaps remain. How the expression and function of System A and System L transporters dynamically change across gestation, and how they are regulated by maternal metabolic characteristics such as maternal BMI, have not yet been systematically investigated. Consequently, whether enhanced placental AA transport serves as a primary driver of fetal overgrowth or represents a compensatory response secondary to maternal metabolic disturbances, and how it dynamically interacts with maternal metabolic states (e.g., insulin resistance and hyperaminoacidemia), remain to be elucidated through longitudinal studies incorporating gestational age stratification and repeated sampling across pregnancy.

FFA play essential roles in fetal development, including neural differentiation and fat accumulation (Duttaroy and Basak, 2021). In maternal circulation, fatty acids mainly exist as triglycerides (TG), phospholipids, and cholesterol (Du et al., 2024). From approximately the 12th week of gestation, maternal phospholipid, cholesterol, and TG levels progressively increase due to estrogen stimulation and the development of insulin resistance (Ghio et al., 2011). During late pregnancy, enhanced adipose tissue lipolysis accelerates fat mobilization, and the release of endogenous FFA, together with dietary fatty acids and increased hepatic TG synthesis, leads to elevated maternal circulating TG concentrations (Duttaroy and Basak, 2020; Sivan et al., 1999; Xiang et al., 1999).

Although fetal fat has traditionally been considered to derive primarily from glucose conversion, an alternative hypothesis proposes that maternally derived fatty acids transported across the placenta constitute a major source. In GDM, abnormally elevated maternal lipid levels enhance placental fatty acid transport efficiency, increasing both the number and size of fetal adipocytes and promoting fetal overgrowth (Szabo, 2019). TG cannot cross the syncytiotrophoblast (STB) directly; instead, lipoprotein lipase (LPL) and endothelial lipase (EL) localized on placental microvilli hydrolyze maternal TG into FFA (Chassen and Jansson, 2020). LPL further hydrolyzes maternal chylomicron triglycerides (CM-TG) and very low-density lipoprotein triglycerides (VLDL-TG), thereby enhancing placental FFA uptake and fetal adipose accumulation. Consistently, placental lipase activity positively correlates with neonatal fat content and maternal TG levels (Heerwagen et al., 2018). Epidemiological studies show that elevated maternal TG levels in both GDM and non-GDM pregnancies are associated with an increased risk of LGA and macrosomia, with a substantially higher risk observed in women with GDM (Peng et al., 2025). Compared with normal pregnancies, placentas from women with GDM exhibit increased LPL expression, elevated placental TG content, and higher FFA levels in umbilical cord plasma (Balachandiran et al., 2021b), while EL expression is further upregulated in obese women with GDM (Gauster et al., 2011). Enhanced placental LPL and EL activity facilitates the transfer of greater amounts of FFA into the fetal circulation, potentially contributing to GDM-related fetal overgrowth and increasing the risk of macrosomia.

Placental FFA uptake is mediated by specific fatty acid transporters, including fatty acid transport proteins (FATP), fatty acid translocase (FAT/CD36), plasma membrane fatty acid-binding protein (FABPpm), and intracellular fatty acid-binding proteins (FABP). The expression of these transporters is regulated by fatty acid-activated transcription factors such as PPARs, LXR, RXR, and SREBP-1 (Duttaroy and Basak, 2021). Compared with placentas from infants with normal birth weight, placentas associated with macrosomia show significantly higher mRNA and protein expression of PPARα, FABPpm, and FAT/CD36 (Ni et al., 2022). In pregnancies complicated by GDM, dysregulated FABP expression has been linked to excessive fetal lipid accumulation, with placental liver-type fatty acid-binding protein (L-FABP) increased by 64% (Magnusson et al., 2004) and FABP4 and FABP5 significantly upregulated (Scifres et al., 2011). In addition to human placental studies, increased placental expression of FABP2 and FABP3 has been reported in rat models of GDM (Mishra and Kumar, 2023). Elevated glucose levels in placental tissue from GDM pregnancies reduce fatty acid oxidation capacity by approximately 30% while increasing TG accumulation by nearly threefold (Visiedo et al., 2013). Consistently, macrosomic infants born to women with GDM exhibit higher body fat content than those born to mothers with normal glucose tolerance (Martins et al., 2023). However, most available evidence is derived from cross-sectional human placental studies, limiting insights into temporal dynamics and regulatory hierarchies of placental lipid transport. Moreover, pre-pregnancy BMI is associated with altered expression of multiple placental fatty acid transport-related genes (Segura et al., 2017), indicating that maternal obesity and metabolic background factors may interact with these pathways. Overall, current evidence supports a critical regulatory role of placental lipid transport in GDM-related fetal overgrowth, highlighting the need for future studies integrating mechanistic animal models and trophoblast-based systems while controlling for maternal metabolic background.

Cholesterol, as a key structural component of cell membranes and an essential precursor for steroid hormone synthesis, plays an irreplaceable physiological role in fetal growth and development (Chatuphonprasert et al., 2018). Although the fetus possesses endogenous cholesterol synthesis capacity, prior to 19 weeks of gestation, its cholesterol supply primarily depends on maternal provision (Lu et al., 2022). The transport of cholesterol from the maternal to fetal circulation relies on ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) located in STB cells and fetal vascular endothelial cells (Aguilera-Olguín and Leiva, 2022). In addition to direct transport, the placenta also transports cholesterol from the maternal circulation to the fetus by uptake of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL) (Winterhager and Gellhaus, 2017). LDL and HDL in the maternal circulation are taken up by binding to the low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI) on the surface of STB cells, respectively (Aguilera-Olguín and Leiva, 2022). In normal pregnancies, maternal total cholesterol (TC) and TG levels are positively correlated with neonatal birth weight (Kulkarni et al., 2013). A mouse model fed a high-cholesterol diet demonstrated that maternal high-cholesterol intake increases placental cholesterol transport efficiency, leading to lipid deposition in the fetal liver and potentially causing fetal growth and developmental abnormalities (Kuentzel et al., 2022).

Numerous studies have demonstrated that GDM is strongly associated with maternal lipid metabolism disorders. A meta-analysis revealed that, compared to non-GDM pregnancies, GDM patients exhibit significantly elevated serum TG, TC and LDL levels, while HDL levels are decreased (Hu et al., 2021). This lipid dysregulation is clearly linked to adverse perinatal outcomes: elevated TG levels during mid-to-late pregnancy are associated with an increased risk of LGA infants, macrosomia, and neonatal complications, whereas higher HDL levels show a negative correlation with the risk of LGA and adverse neonatal outcomes (Shi et al., 2023). Upregulation of ABCA1 and ABCG1 expression has been observed in human placental endothelial cells isolated from GDM pregnancies (Sun et al., 2018). The protein expression of placental SR-BI is elevated in normal-weight GDM women compared to both healthy controls and overweight/obese GDM subjects. Meanwhile, both mRNA and protein expression levels of LDLR and very low-density lipoprotein receptor (VLDLR) are significantly increased in the placentas of GDM women, regardless of body weight status (Dubé et al., 2013; Fruscalzo et al., 2021). Although the precise mechanisms underlying placental cholesterol and lipoprotein transport in GDM remain incompletely understood, accumulating evidence suggests that disturbances in cholesterol and lipoprotein metabolism may represent a key pathophysiological mechanism contributing to GDM-related fetal overgrowth. It is noteworthy that current research has insufficiently addressed the temporal dynamics of placental cholesterol metabolism, failing to systematically elucidate its regulatory patterns on fetal development across different stages of pregnancy. Additionally, factors such as maternal obesity, dietary structure, and genetic background may influence placental function through pathways like epigenetic modifications, yet existing evidence remains inadequate to unravel the network effects of these complex interactions. Future studies should establish longitudinal research models spanning the entire gestation period, integrating multi-omics technologies and spatial transcriptomics to dynamically dissect the spatiotemporally specific regulatory mechanisms of the placental cholesterol transport system in the pathological progression of GDM.

Numerous studies have demonstrated that the IGF system plays a central regulatory role in bodily growth and development, particularly during embryogenesis, the maintenance of metabolic homeostasis, and fundamental biological processes such as cell proliferation and differentiation, where it performs indispensable functions (Díaz Del Moral et al., 2021). The ligands of the IGF system include IGF-I, IGF-II, and insulin, which also contribute significantly to placental development through interactions with their specific receptors (Martín-Estal and Castorena-Torres, 2022).

Compared with those in normal pregnancies, maternal circulating and fetal serum IGF-I concentrations are markedly elevated in pregnancies complicated by GDM. A human prospective observational cohort study showed that maternal plasma IGF-I levels increased by an average of 55.4% between 24–28 and 32–35 weeks of gestation. Moreover, with every 1 standard deviation increase in maternal circulating IGF-I levels, fetal birth weight increased by 75 g, placental weight increased by 20 g, and the risk of macrosomia rose by 1.91-fold (Luo et al., 2012). Notably, lncRNA-SNX17 expression is significantly upregulated in placental tissues from pregnancies affected by GDM-induced macrosomia. Further experiments using human trophoblast cell lines have shown that overexpression of lncRNA-SNX17 suppresses miR-517a expression and elevates IGF-I levels, thereby promoting trophoblast cell proliferation (Guiyu et al., 2022). Furthermore, growth hormone (GH) exerts its effects through the classical GH-insulin-like growth factor-I (GH-IGF-I) axis, influencing pregnancy outcomes in women with GDM. Suppression of the GH-IGF-I axis leads to short stature in offspring, while excessive activation of this axis results in pathological fetal overgrowth (Reynolds et al., 2017; Chesnokova, 2022). Observational human studies have shown that maternal serum GH-V concentrations are significantly higher in GDM pregnancies resulting in LGA infants compared to control pregnancies, and maternal IGF-I levels are also markedly elevated in GDM pregnancies (Liao et al., 2017).

Additionally, elevated IGF-II levels are also detected in the umbilical cord blood of women with GDM (Wang W. J. et al., 2020). Evidence from human observational studies and in vitro human trophoblast experiments has indicated that the expression levels of the IGF-II/H19 gene in the umbilical cord blood of GDM patients are significantly correlated with the development of macrosomia. A potential molecular mechanism may involve the maternal hyperglycemic environment, which can alter the methylation status of the IGF-II and H19 gene promoters in trophoblast cells, thereby increasing the expression of IGF-II/H19 (Su et al., 2016; Zhang Q. et al., 2022). Furthermore, studies in GDM mouse models have demonstrated that epigenetic changes in IGF-II/H19 can be inherited across generations (Ding et al., 2012). Dysregulation of this epigenetic control mechanism may contribute to fetal overgrowth, with potential transgenerational effects.

IGF activity is regulated not only by the availability of IGF receptors but also by the insulin-like growth factor-binding protein family (IGFBPs 1–6), which can bind to both IGF-I and IGF-II. In most cases, IGFBPs inhibit the biological actions of IGF through competitive binding mechanisms (Bach, 2018). IGFBP-7, also known as insulin-like growth factor-binding protein-related protein 1 (IGFBP-rP1), exhibits a higher affinity for insulin than for IGF and has been shown to interact with IGF-1R. IGFBP-rP1 functions as an IGF antagonist by directly binding to the receptor and inhibiting IGF-1R activation (Artico et al., 2021). Studies have reported that the levels of IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-rP1 are significantly reduced in the umbilical cord blood from pregnancies complicated by GDM. Moreover, IGFBP-1 and IGFBP-2 show a negative correlation with fetal birth weight (Lappas, 2015). These findings suggest that fetal overgrowth may result from the downregulation of IGFBP and IGFBP-rP1 expression, which increases IGF bioavailability and consequently accelerates fetal growth and development abnormally. Current evidence linking the IGF system to GDM-related fetal overgrowth is derived primarily from observational human studies demonstrating correlations between circulating or umbilical cord IGF levels and fetal growth outcomes. Although trophoblast cell models indicate that IGF signaling regulates placental gene expression and cellular proliferation, direct mechanistic evidence from animal intervention studies or integrated placental functional models is still lacking to confirm whether IGF actively drives placental nutrient transport and fetal metabolic programming in vivo. Therefore, future research should integrate spatially and temporally resolved placental tissue analyses, conditional genetic animal models, and longitudinal clinical cohort data to clarify the specific causal role of IGF signaling in GDM-related fetal overgrowth and its potential translational relevance.

The placental mTOR signaling pathway plays a central role in regulating fetal growth (Rosario et al., 2023a). The mTORC1 signaling pathway primarily promotes protein synthesis through two distinct mechanisms: first, it regulates the function of the eukaryotic initiation factor 4E (eIF4E) by phosphorylating the 4E-binding protein (4E-BP); second, it phosphorylates ribosomal protein S6 kinase 1 (S6K1), which in turn modulates the activity of eIF4B and enhances ribosomal biosynthesis capacity (Panwar et al., 2023). Placental tissues from macrosomic offspring of GDM mothers exhibited significantly enhanced mTORC1 signaling pathway activity (Sati et al., 2016). Furthermore, study based on human-derived placental tissues has further demonstrated that phosphorylation levels of the two aforementioned mTORC1 downstream targets (S6K1 and 4EBP-1) exhibit positive correlations with neonatal birth weight (Jansson et al., 2013). Although no direct evidence currently confirms that the mTORC1 signaling pathway causes macrosomia by promoting protein synthesis, its excessive activation may represent a potential contributing factor to fetal overgrowth.

As an E3 ubiquitin ligase, neuronal precursor cell expressed developmentally downregulated 4–2 (Nedd4-2) catalyzes protein ubiquitination leading to proteasomal degradation. Using primary human trophoblast models, Rosario F.J et al. first demonstrated a novel regulatory relationship between the mTORC1 signaling pathway and ubiquitination-a common post-translational modification. Their findings revealed that mTORC1 activation suppresses Nedd4-2 expression, thereby reducing ubiquitination of placental AA transporters. This subsequently enhances the transport capacity of SNAT2 and LAT1, ultimately promoting amino acid uptake in trophoblast cells. These discoveries may provide new perspectives for exploring mechanisms underlying fetal overgrowth (Rosario et al., 2016).

A human prospective cohort study has demonstrated that reduced AMPK phosphorylation in placental tissue is associated with activation of the mTORC1 signaling pathway, a phenomenon that is significantly linked to fetal overgrowth (Keleher et al., 2020). Among 50 GDM patients with blood glucose levels maintained within the normal range, 23 delivered macrosomia and 27 delivered infants with normal birth weight. Analyses of placentas from these pregnancies revealed a significant positive correlation between placental IGF-I activity and mTOR signaling pathway activity, as well as a negative correlation between AMPKα phosphorylation levels and fetal birth weight (Shang and Wen, 2018). Compared with placentas from normal pregnancies, those from GDM pregnancies complicated by LGA infants exhibited lower AMPKα phosphorylation levels and higher mTOR phosphorylation levels (Hung et al., 2021). In placentas from small-for-gestational-age (SGA) fetuses, LAT1 expression was decreased (Chen et al., 2015), whereas LAT1 expression was upregulated in LGA placentas. LAT1 is encoded by the SLC7A5 gene, and studies have shown that overexpression of SLC7A5 in primary human trophoblast cells not only significantly enhances systemic L-amino acid transport function but also increases systemic A-amino acid transport efficiency by 38%. Furthermore, LAT1 upregulation promotes activation of the mTOR signaling pathway by suppressing AMPK signaling activity (Rosario et al., 2023b). These findings collectively demonstrate intricate interconnections between the mTOR signaling pathway and fetal growth-regulatory networks, revealing its central regulatory role in governing fetal development (Figure 2). Importantly, dysregulated activation of mTOR-related pathways may constitute the pivotal mechanism underlying GDM-induced fetal overgrowth. However, current evidence on the role of the mTOR signaling pathway in placental function regulation in GDM primarily originates from observational studies or ex vivo placental models, which limits interpretability to some extent. It is important to note that placental mTOR pathway activity is highly dependent on dynamic regulation by multiple factors, including maternal nutrient supply, hormonal levels, and oxidative stress. Existing experimental systems struggle to accurately replicate this complex and time-varying physiological environment. Additionally, mTOR signaling is highly sensitive to cellular context, and significant differences may exist across different trophoblast subtypes, developmental stages, and fetal sex. However, these critical variables are often inadequately accounted for in current research. Future studies urgently need to integrate cell-specific genetic models, dynamic functional analyses, and longitudinal study designs spanning different gestational stages to more precisely dissect the specific roles of mTOR signaling in placental adaptive regulation and fetal growth control.

Apoptosis is a naturally occurring process in placental cells and plays a crucial role in placental growth, development, and aging. Maintaining a balance between trophoblast cell apoptosis and proliferation is essential for normal placental development (Xie et al., 2024). In patients with GDM, an increased number of trophoblast cells and enhanced proliferation activity have been observed in placental tissues, accompanied by a reduction in apoptosis (Duan et al., 2023), which may contribute to increased placental weight. Elevated placental weight has been significantly associated with the development of LGA infants (Hung et al., 2020). The epidermal growth factor receptor (EGFR) serves as a key regulator of cell proliferation, human growth and development, and embryogenesis. It is highly expressed in placental tissues and plays a pivotal role in regulating placental growth and development through its involvement in critical physiological processes such as trophoblast cell fusion (Clemente and Bird, 2023). In mouse experiments, it has been confirmed that after excluding the interference of maternal blood sugar and blood lipids on nutrient supply, EGFR can still significantly promote the proliferation of placental sponge trophoblast cells and lead to an increase in placental volume (Dackor et al., 2009). Recent studies have identified a positive feedback regulatory loop involving glycoprotein hormone alpha subunit (CGA), EGFR, and transcription factor GATA binding protein 2 (GATA2), which contributes to the pathological proliferation of placentas in GDM-induced macrosomia (Xu et al., 2024). Moreover, increased expression of proliferating cell nuclear antigen (PCNA) has been observed in placentas associated with GDM-induced macrosomia. In vitro studies have demonstrated that a high-glucose environment significantly stimulates trophoblast cell proliferation and activates the phosphorylation of the ERK1/2 signaling pathway. Notably, specific inhibitors of ERK1/2 can effectively suppress this hyperproliferative response induced by high glucose levels (Zheng et al., 2022). Additionally, elevated expression of FABP4 has been observed in placentas of macrosomic infants born to mothers with GDM. Importantly, FABP4 has been demonstrated to enhance the proliferative and migratory capacities of human trophoblast cells (Yan et al., 2016; Yang et al., 2020).

In addition to pathological proliferation, emerging evidence suggests that the increased placental weight and fetal overgrowth observed in patients with GDM may be attributed to dysregulation of gene expression and protein synthesis related to autophagy and apoptosis in placental tissues. These molecular alterations can impair autophagy and reduce apoptosis in trophoblast cells, ultimately contributing to placental tissue remodeling. A decrease in the levels of autophagy- and apoptosis-related proteins has been observed in placentas from GDM pregnancies complicated by LGA fetuses. In vitro cell culture studies have further confirmed that a high-glucose environment can impair autophagy and suppress apoptosis in trophoblast cells (Hung et al., 2020). MicroRNAs also play a regulatory role in this process. Research using plasma-derived exosomes from GDM patients and trophoblast cell models has revealed that the miR-99 family inhibits autophagy in GDM placental trophoblast cells by upregulating myotubularin-related protein 3 (MTMR3) expression (Liu and Lv, 2025). Another study revealed that elevated expression of matrix metalloproteinases (MMPs) in the placentas of GDM patients enhances the expression of CSF3R splice variants and activates the PI3K/Akt signaling pathway, thereby reducing trophoblast cell apoptosis (Zhang Y. et al., 2024). The dual pathological alterations characterized by aberrant proliferation of placental trophoblast cells accompanied by suppressed autophagy and diminished apoptosis may constitute a critical pathogenic mechanism underlying the development of GDM-induced macrosomia. It should be particularly noted that current research on the imbalance of trophoblast proliferation/apoptosis and the development of macrosomia in GDM primarily relies on in vitro cell models treated with high glucose or postpartum placental samples. These models struggle to replicate the dynamic microenvironmental changes at the maternal-fetal interface during pregnancy. There is a notable lack of longitudinal studies on the temporal evolution of trophoblast behavior across different stages of pregnancy, making it difficult to determine whether the observed cellular phenotypes represent a persistent pathological state or a stage-specific adaptive response. Future studies should establish three-dimensional placental organoid models capable of simulating the dynamic fluctuations in blood glucose levels during pregnancy, combined with live-cell imaging techniques, to analyze the causal relationship between abnormal trophoblast behavior and fetal growth trajectories in both spatial and temporal dimensions.

Placental angiogenesis is a tightly regulated dual-phase process governed by the balance between pro-angiogenic and anti-angiogenic factors. Altered placental vascular function can impair fetal development and increase the long-term risk of CVD in offspring (Lorigo and Cairrao, 2022). This process is dynamically regulated by vascular active factors, particularly vascular endothelial growth factor (VEGF), which plays a central role in placental vascular development, especially during early pregnancy (Huang et al., 2021). Structural analyses have demonstrated that placentas from women with GDM exhibit enhanced vascular perfusion and maternal-fetal exchange capacity, characterized by increased villous surface area, higher numbers of small villi and villous vessels, increased capillary density, branching, and surface area (Nanobashvili et al., 2018; Yao et al., 2023; Moreli et al., 2024). These structural adaptations may represent a key mechanism contributing to fetal overgrowth in a hyperglycemic intrauterine environment.

The VEGF family includes VEGF-A, -B, -C, -D, -E, -F, and placental growth factor (PIGF), which exert their effects through VEGF receptor-1 (VEGFR-1/Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4) (Melincovici et al., 2018). VEGFR-2, predominantly expressed in endothelial cells and their precursors, mediates the major pro-angiogenic effects of VEGF due to its strong tyrosine kinase activity, promoting endothelial proliferation, migration, and vessel formation (Wang X. et al., 2020). In contrast, VEGFR-1 exhibits high ligand affinity but weak kinase activity, functioning primarily as a negative regulator by competitively binding VEGF-A and limiting VEGFR-2 activation during early vascular development (Huang et al., 2021). In placentas from women with GDM, Flt-1 mRNA and protein levels are significantly reduced, whereas KDR protein expression is abnormally elevated (Troncoso et al., 2017). Immunolocalization studies further show that in mild hyperglycemia, VEGF and VEGFR-2 are strongly expressed in endothelial and trophoblast cells, while VEGFR-1 expression remains weak. In contrast, in GDM placentas, VEGFR-1 is strongly expressed in both vascular and trophoblastic cells, whereas VEGF and VEGFR-2 expression is markedly reduced in placental capillary endothelial cells (Pietro et al., 2010). These findings suggest that intrauterine hyperglycemia initially induces mild hypoxia and compensatory angiogenesis, whereas severe metabolic dysregulation leads to pronounced placental hypoxia and impaired functional capillary formation, although the underlying mechanisms remain incompletely understood (Pietro et al., 2010).

In addition to angiogenic signaling, placental barrier integrity is disrupted in GDM patients. Key adhesion and junctional proteins, including vascular endothelial cadherin, β-catenin, occludin, and zonula occludens-1, are significantly downregulated in GDM placentas (Babawale et al., 2000; Villota et al., 2021), potentially impairing maternal-fetal substance exchange. Connexin 43 (Cx43), a regulator of monocyte-endothelial adhesion, is markedly upregulated in umbilical vein endothelial cells from GDM pregnancies, activating the PI3K/AKT/NF-κB pathway and increasing ICAM-1 and VCAM-1 expression (Zhang et al., 2021). This promotes excessive monocyte-endothelial adhesion, amplifies inflammatory signaling, and further aggravates vascular dysfunction (Khambule and George, 2019), thereby compromising placental barrier integrity and facilitating excessive nutrient transfer to the fetus.

Insulin also plays a crucial regulatory role in placental vascular biology. It exerts its physiological effects through activation of insulin receptors, which include two subtypes-IR-A and IR-B-both of which are expressed in fetal placental endothelial cells, such as human umbilical vein endothelial cells (HUVECs) and human placental microvascular endothelial cells (hPMECs) (Westermeier et al., 2016). Activation of the insulin signaling pathway via the PI3K/Akt cascade enhances the expression and activity of endothelial nitric oxide synthase (eNOS), leading to increased production of nitric oxide (NO) (Subiabre et al., 2020). Current evidence suggests that in HUVECs derived from GDM, both IR-A and IR-B expression levels are significantly elevated, accompanied by enhanced Akt signaling activity, as well as increased eNOS activity and NO synthesis (Westermeier et al., 2015; Vedika et al., 2023). eNOS plays a pivotal role in promoting fetal growth and development and enhancing placental perfusion (Krause, 2021).

Cellular responses to hypoxia are mediated largely by hypoxia-inducible factor-1 (HIF-1), composed of HIF-1α and HIF-1β, which regulates angiogenesis, glycolysis, and cell proliferation (Yang et al., 2021). In GDM pregnancies, fetal hyperinsulinemia and insulin-induced eNOS activation increase metabolic demand and oxygen consumption, predisposing the fetus to hypoxia (Desoye and van Poppel, 2015). Both eNOS activation and hypoxic stress contribute to the stabilization and transcriptional activation of HIF-1, which subsequently upregulates VEGF expression and promotes angiogenesis (Krause, 2021). In women with GDM, the combined actions of VEGF, insulin signaling, and HIF-1 coordinately regulate placental angiogenesis and barrier function, thereby enhancing nutrient transport to the fetus and influencing both placental and fetal growth and development (Figure 3). However, it remains important to recognize that many of the observed structural and molecular changes-such as enhanced vascular density, upregulated VEGF signaling, and altered junctional protein expression-may represent compensatory adaptations aimed at maintaining adequate nutrient and oxygen delivery under metabolic stress, rather than purely pathological processes. Moreover, most existing studies rely on expression-level analyses of angiogenic factors, adhesion molecules, or signaling components, while direct functional assessments of placental permeability, transendothelial transport capacity, or barrier integrity remain limited. As a result, it is still unclear to what extent these molecular alterations translate into quantitative changes in nutrient flux across the maternal-fetal interface. The frequent coexistence of enhanced angiogenesis with impaired barrier organization further suggests a complex balance between adaptive vascular expansion and compromised structural integrity. Future studies should therefore integrate functional permeability assays, in vivo or ex vivo placental perfusion models, and quantitative measurements of nutrient transfer to distinguish adaptive angiogenic remodeling from maladaptive barrier disruption. With the continuous advancement of research, progress continues to be made in exploring the molecular mechanisms of GDM-related fetal overgrowth. Table 1 summarizes the relevant research results in recent years.