Aerobic Exercise Upregulates DNA Methylation of Agtr1a and Mas1 Genes to Improve Mesenteric Arterial Function in Spontaneously Hypertensive Rats

Abstract

The imbalance between vasoconstrictive axis and vasodilative axis of the renin-angiotensin system (RAS) is involved in the pathogenesis of hypertension. Exercise modulates components of the RAS and influences vascular function. This study aimed to investigate the balance of RAS axes and the mechanism of DNA methylation of the Agtr1a (AT1aR) and Mas1 (MasR) genes in aerobic exercise-induced improvement of the function of mesenteric arteries (MAs) in hypertension. Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were subjected to exercise training or kept sedentary. Plasma RAS peptides, vascular function, and molecular properties were assessed. Aerobic exercise significantly decreased blood pressure in SHR. Plasma levels of RAS peptides increased in SHR, and the level of Ang II was much higher than Ang-(1–7), whereas exercise efficiently inhibited this inappropriate increase. In addition, Ang II-induced maximal contraction of MAs is largely through Type 1 angiotensin receptors (AT1R), while Mas receptor (MasR) inhibits this contribution. Exercise effectively suppressed hypertension-associated mRNA and protein expression upregulation of AT1R and MasR and increased MasR/AT1R ratio in SHR by triggering hypermethylation of Agtr1a and Mas1 genes, with increasing DNMT1 and DNMT3b protein expression and ratio of SAM/SAH. These findings suggest that aerobic exercise alleviates vascular tone by upregulating the methylation status of the Agtr1a and Mas1 genes and inhibiting the imbalanced increase in the vasoconstrictive and vasodilative axes during hypertension.