Maternal Exercise Improves Vascular Function In SHR Offspring Via Epigenetic Regulation Of Akap5 Gene Expression

Recent studies have shown that maternal exercise improves health of offspring via epigenetic changes. AKAP150 targets protein kinase Cα to the L-type Ca2+ channels (CaV1.2) and thereby enhances vascular tone in arterial smooth muscle during hypertension. However, whether exercise during pregnancy can improve blood pressure and vascular function in hypertensive offspring via epigenetic regulation of AKAP150 gene (Akap5) gene remains unclear. PURPOSE: To investigate the role and mechanism of histone deacetylase SIRT1 epigenetic regulation of Aakp5 expression in improving vascular function in hypertensive offspring by exercise during pregnancy. METHODS: Pregnant Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) were randomly assigned to sedentary (p-WKY-SED and p-SHR-SED) and exercise groups (p-WKY-EX and p-SHR-EX). Exercise groups were subjected to swimming from gestation day 1 (GD1) to GD20. Mesenteric arteries (MAs) at embryonic day 21 (ED21) and 3 months (3 M) were collected for vascular function, electrophysiology, target gene expression, and Akap5 promotor histone acetylation studies in male offspring. RESULTS: Exercise during pregnancy significantly reduced mean arterial pressure in 3 M offspring of SHR (157.21 ± 1.76 vs. 168.37 ± 3.06 mmHg, p < 0.05). Maternal exercise significantly attenuated CaV1.2 contribution to vascular tone (45.21 ± 2.08 vs. 59.77 ± 2.46 % Kmax, p < 0.05), CaV1.2 currents (-13.82 ± 0.72 vs. -17.54 ± 0.96 pA/pF, p < 0.05) and CaV1.2 α1C protein expression in 3 M offspring of SHR. Furthermore, maternal exercise decreased histone H3K9ac level of the promoter region of the Akap5 gene (ED21: 0.75 ± 0.02 vs. 1.31 ± 0.05; p < 0.05 vs. p-SHR-SED) and H3K9ac protein expression, with a concomitant decrease in AKAP150 protein (ED21: 0.89 ± 0.26 vs. 2.62 ± 0.25; 3 M: 1.06 ± 0.32 vs. 2.52 ± 0.31, p < 0.05) and mRNA (ED21: 1.03 ± 0.06 vs. 1.34 ± 0.07; 3 M: 1.08 ± 0.05 vs. 1.82 ± 0.1, p < 0.05) expressions in SHR offspring at ED21 and 3 M. Finally, exercise during pregnancy activated AMPK that upregulated SIRT1 in MAs of SHR offspring. CONCLUSION: Exercise during pregnancy activates an AMPK/SIRT1 signaling axis in fetal offspring MAs, resulting in H3K9 deacetylation of the Akap5 promoter, improving vascular function, and decreasing blood pressure in adult SHR offspring.