Perinatal High-Fat Diet Induces Vascular Hypercontractility via DNA Hypomethylation of Endothelin Receptors and PKC-LTCC Axis Activation in Male Offspring.

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, Ca2 + 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 Ca2 + currents, fluorescence Ca2 + transients, and vascular tone. Which relied on the PKC-LTCC axis (strengthened by PKC activator and LTCC agonist) and altered intracellular Ca2 + handling (via ryanodine receptors and sarcoplasmic/endoplasmic reticulum Ca2 +-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.