Maternal Hypertension Aggravates Vascular Dysfunction After Injury in Male Adult Offspring Through Transgenerational Transmission of N6-Methyladenosine.

Abstract

Whether maternal hypertension contributes to the enhanced susceptibility to vascular remodeling in adult offspring through epigenetic mechanisms remains unclear. We aimed to address this gap in the literature using a transgenerational mouse model. Gestational hypertension was induced in pregnant mice using chronic angiotensin II infusion. Blood pressure was monitored using the tail-cuff method. Two months post-delivery, an N6-methyladenosine epitranscriptomic microarray analysis was performed on the carotid arteries of second-generation mice. A unilateral carotid artery injury model was used to study the postinjury vascular response in vivo. Furthermore, carotid ultrasonography, immunohistochemistry, and molecular biological parameters were assessed in adult offspring. Exposure to maternal hypertension decreased the birth weight of live pups and increased the fetal death rate. Compared with normal offspring, adult offspring with hypertension had wire-induced injury that led to greater vascular remodeling, which was associated with aggravated inflammation imbalance, fibrosis, and oxidative stress. In addition, aberrant N6-methyladenosine methylation, increased N6-methyladenosine levels, and increased METTL3 (methyltransferase-like 3) expression were detected in the vessels of offspring with hypertension. Maternal METTL3 deficiency increased the birth weight of live pups with hypertension, improved vascular dysfunction, and alleviated vascular inflammation in adult offspring with hypertension after injury. Maternal hypertension can induce transgenerational transmission of enhanced susceptibility to vascular remodeling, and the possible underlying mechanism is associated with altered METTL3-mediated N6-methyladenosine methylation. Therefore, this study reveals the role of epigenetic effects across generations and provides new insights into vascular remodeling causes.