Prenatal exercise reprograms the development of hypertension progress and improves vascular health in SHR offspring

Upregulation of L-type voltage-gated Ca²⁺ (Ca_V1.2) channel in the arterial myocytes is a hallmark feature of hypertension. However, whether maternal exercise during pregnancy has a sustained beneficial effect on the offspring of spontaneously hypertensive rats (SHRs) through epigenetic regulation of Ca_V1.2 channel is largely unknown.

Pregnant SHRs and Wistar-Kyoto rats were subjected to swimming and the vascular molecular and functional properties of male offspring were evaluated at embryonic (E) 20.5 day, 3 months (3 M), and 6 months (6 M).

Exercise during pregnancy significantly decreased the resting blood pressure at 3 M but not 6 M in the offspring of SHR. Prenatal exercise significantly reduced the cardiovascular reactivity, the contribution of Ca_V1.2 channel to the vascular tone, and the whole-cell current density of Ca_V1.2 channel in both 3 M and 6 M offspring of SHR. Moreover, maternal exercise triggered hypermethylation of the promoter region of the Ca_V1.2 α1C gene (CACNA1C), with a concomitant decrease in its protein and mRNA expressions in SHR offspring at E20.5, 3 M, and 6 M. Tissue culture experiments further confirmed that 5-Aza-2'-deoxycytidine increased the structure and functional expression of Ca_V1.2 channel by inhibiting the DNA methylation of CACNA1C. However, the improvement of prenatal exercise on the blood pressure, function, and expression of Ca_V1.2 channel was attenuated in the offspring of SHRs at 6 M compared to the 3 M readout.

These data suggest that prenatal exercise improves the vascular function by the hypermethylation of CACNA1C in the arterial myocytes and delays the development of hypertension in the offspring of SHRs. However, these effects fade out with age.