ABSTRACT Excessive fat intake is a well‐established risk for hypertension; perinatal nutritional imbalances could increase vascular risks, but underlying mechanisms remain unclear. Endothelin‐1 (ET‐1), a potent vasoconstrictor, is implicated in cardiovascular diseases. This study aimed to address this gap by investigating ET‐1 receptor‐mediated pathways with high‐fat‐diet (HFD) during pregnancy and lactation. Vascular function, Ca 2 + signaling, molecular expression, and DNA methylation were assessed in mesenteric arteries (MA) of offspring. HFD offspring exhibited increased fetal/adult weight, thickened MA wall, and enhanced ET‐1‐mediated vasoconstriction. Mechanistically, perinatal HFD upregulated ET‐1 receptors (ETAR/ETBR) via hypomethylation of their gene promoters (Ednra/Ednrb), which augmented ET‐1‐induced Ca 2 + currents, fluorescence Ca 2 + transients, and vascular tone. Which relied on the PKC‐LTCC axis (strengthened by PKC activator and LTCC agonist) and altered intracellular Ca 2 + handling (via ryanodine receptors and sarcoplasmic/endoplasmic reticulum Ca 2 + ‐ATPase), but were independent of IP3 receptors. ETAR/ETBR blockers attenuated the hypercontractility, confirming receptor‐mediated effects. This is the first study to reveal that perinatal HFD persistently enhances vascular re‐activity via DNA hypomethylation of ET receptors and PKC‐LTCC axis. These findings not only reveal a mechanism linking perinatal HFD to adult vascular hypercontractility but also highlight ET receptors and DNA methylation as potential targets for early intervention of developmental origins of cardiovascular disease.
Zheng et al. (Sun,) studied this question.