Maternal Exposure to Perinatal High Salt Diet Dysregulates Vascular Oxygen-Sensing Mechanism(s) in Weanling Offspring

The heritability of salt-sensitive hypertension suggests an origin in early life. The normal response to salt stress in salt-resistant individuals is inhibition of prolyl hydroxylase domain-containing proteins 2 (PHD2), which leads to an increase in the production of hypoxia-inducible factor-1 alpha (HIF-1α) and activation of its target antihypertensive genes (nitric oxide synthase (NOS-3) and heme oxygenase-1 (HO-1)) and consequently, the prevention of hypertension. However, this adaptive mechanism is impaired in salt-sensitive hypertension. To investigate the effects of perinatal maternal high salt diet (HSD) on vascular oxygen-sensing mechanisms in weanling offspring, female Dahl salt-resistant (SR) and salt-sensitive (SS) rats were mated with corresponding SR and SS males and were placed on either 0.3% NaCl normal salt diet (NSD) or 8% NaCl HSD post-positive mating for the duration of pregnancy and lactation. Trunk blood was collected from sacrificed 4-week-old weanling offspring (100-120g) for biochemical assays of plasma direct (DB) and total bilirubin (TB), nitric oxide (NO) and Asymmetric Dimethyl Arginine (ADMA). Tissue RNA in abdominal aorta extracted with Qiagen miniprep was converted to cDNA, and NOS3 (eNOS), HMOX-1 (HO-1), HIF-1α, and EGLN1 (PHD2) gene expression were measured using real-time quantitative PCR (rt-qPCR) methods. Perinatal HSD reduced DB (1.43±0.15 vs. 0.128±0.05 mg/dL; p<0.01) and TB (14.8±2.16 vs. 9.42±0.43 mg/dL; p<0.01) concentrations in SR rats. However, DB was elevated in SS HSD compared to SR HSD (0.128±0.05 vs. 0.93±0.27 p<0.0.01). TB concentrations were reduced in SS NSD (14.8±2.16 vs. 7.79±1.39 p<0.01) and SS HSD (14.8±2.16 vs. 4.49±0.26 p<0.001) when compared with SR NSD (control). NO concentration was higher in SR HSD compared with SR NSD (14.3±1.42 vs. 21.5±1.5 nmol/L; p<0.05); however, NO concentration was lower in SS HSD when compared with SR HSD (21.5±1.53 vs. 14.0±0.76 p<0.05). Perinatal HSD increased ADMA concentrations in both SR (359±29.8 vs. 626±47.2 µmol/L; p<0.01) and SS (501±35.1 vs. 787±68.5, p<0.001). Changes in gene expression are presented as fold changes compared to the control group (SR NSD). There was a decrease in vascular NOS3 gene expression in both SS NSD (1.57±0.39 vs. 0.36± 0.11, p<0.01) and SS HSD (1.57±0.39 vs. 0.72± 0.11, p<0.05). HOMX-1 gene expression was reduced in SS HSD (1.43±0.29 vs. 0.04±0.02, p<0.01). The HIF-1α gene expression in SR HSD was higher (2.11±0.16 vs. 5.12±0.85, p<0.001). However, there was a decrease in expression of vascular HIF-1α gene in SS NSD (2.11±0.16 vs. 0.25±0.13, p<0.01) and SS HSD (2.11±0.16 vs. 0.014+0.009, p<0.001). Likewise, expression of the ENGL1 gene in SS NSD (6.89±0.96vs.1.33±0.62 p<0.001) and SS HSD (6.89±0.96 vs. 0.02±0.003, p<0.0001) were reduced. Findings of this study reveal that perinatal maternal HSD diet dysregulates vascular oxygen-sensing mechanisms in offspring revealing that this mechanism is involved in the fetal programming of salt-sensitive hypertension. This study is supported by the Fogarty International Center of the National Institutes of Health under Award Number K43TW011009. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.