INTRODUCTION:
Hypertension is a major, prevalent risk factor for the development and progression of cerebrovascular disease. Maternal exercise during pregnancy has emerged as a potentially promising approach to protect offspring from hypertension, but the mechanisms involved are far from clarified. Here, we demonstrate that maternal exercise mediates placenta miR-29a-3p induced TET1 pathway to repress BKCa channel expression, contributing to the improvement of cerebrovascular function in hypertensive offspring. These findings may lead to novel therapeutic approaches to limit the transmission of hypertension to the next generation.
METHODS:
Normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were bred within their strains. Pregnant rats were randomized into sedentary (p-WKY-SED, p-SHR-SED) or exercise (p-WKY-EX, p-SHR-EX) groups, with the latter undergoing swimming exercise during pregnancy. Offspring at embryonic day 21 (ED21) and 3 months (3M) were assessed using cerebral ischemia-reperfusion, isolated microvessels, patch-clamp, molecular detection, and cerebral artery culture to investigate alterations in blood pressure, cerebral infarct area, vascular tension, ion channel function, protein expression, and methylation levels.
RESULTS:
1) Maternal exercise dramatically increased the body weight and placental efficiency of hypertensive fetuses, which benefited their growth and development (P<0.05), and also significantly improved the vascular tension and cerebral ischemia-reperfusion injury area in hypertensive adult offspring (P<0.05). 2) Maternal exercise can effectively reduce the regulatory effect of the CaV1.2 channel on vascular tension and decrease its whole-cell current density in hypertensive male offspring rats (P<0.05), but it does not significantly affect the expression of the α1C subunit (P>0.05). 3) Maternal exercise significantly downregulated the expression of BKCa channel β1 subunit and its whole-cell current in cerebral vessels of offspring with hypertension (P<0.05), concomitant with increased methylation levels at specific CpG sites in the promoter region of Kcnmb1 (P<0.05). 4) Compared to the p-SHR-SED group, the expression of TET1 in the offspring rats of the p-SHR-EX group were significantly decreased (P<0.05). 5) Exercise during pregnancy can significantly increase the expression of miR-29a-3p in the plasma of hypertensive pregnant rats and fetuses, as well as in the cerebral arteries of the hypertensive fetuses and 3M offspring rats (P<0.05). 6) The expression of pri-, and miR-29a-3p in the placentas of the p-SHR-EX group was significantly higher than that in the p-SHR-SED group (P<0.05). 7) Transfection with miR-29a-3p mimic dramatically decreased the expression of TET1 and β1 (P<0.05).
CONCLUSION:
Maternal exercise improves cerebrovascular function in hypertensive offspring partially through the placental secretion of miR-29a-3p, which targets TET1 to induce methylation of the Kcnmb1 promoter region and inhibition of BKCa channel expression.