DNA Methylation-Reprogrammed Ang II (Angiotensin II) Type 1 Receptor-Early Growth Response Gene 1-Protein Kinase C ε Axis Underlies Vascular Hypercontractility in Antenatal Hypoxic Offspring.

As the most common clinical stress during mid and late pregnancy, antenatal hypoxia has profound adverse effects on individual's vascular health later in life, but the underlying mechanisms are still not understood. The purpose of this study was to reveal the mechanisms of the acquired vascular dysfunction in offspring imposed by antenatal hypoxia. Pregnant rats were housed in a normoxic or hypoxic (10.5% oxygen) chamber from gestation day 10 to 21. Male offspring were euthanized at gestational day 21 (fetus) or postnatal 16 weeks old (adult offspring). Mesenteric arteries were collected for examining Ang II (angiotensin II)-mediated vascular contractility, gene expression, and promoter methylation. Antenatal hypoxia increased vascular sensitivity to Ang II, which was resulted by an upregulated AT1R (angiotensin II type 1 receptor). The increased AT1R was correlated with a hypomethylation-mediated activated transcription of Agtr1a (alpha subtype of AT1R). In addition, we presented evidences that there was an AT1R-Egr1 (early growth response gene 1)-PKCε (ε isoform of protein kinase C) axis in vasculature; AT1R could modulate PKCε expression via upregulating Egr1; Egr1 mediated transcription activation of PKCε via Egr1 binding sites in PKCε gene promoter. Overall, antenatal hypoxia activated AT1R-Egr1-PKCε axis in vasculature, eventually predisposed offspring to vascular hypercontractility. This is the first description that antenatal hypoxia resulted in vascular adverse outcomes in postnatal offspring, was strongly associated with reprogrammed gene expression via a DNA methylation-mediated epigenetic mechanism, advancing understanding toward the influence of adverse antenatal factors in early life on long-term vascular health.

Citation

Ting Xu, Xiaorong Fan, Meng Zhao, Meng Wu, Huan Li, Bingyu Ji, Xiaolin Zhu, Lingjun Li, Hongmei Ding, Miao Sun, Zhice Xu, Qinqin Gao. DNA Methylation-Reprogrammed Ang II (Angiotensin II) Type 1 Receptor-Early Growth Response Gene 1-Protein Kinase C ε Axis Underlies Vascular Hypercontractility in Antenatal Hypoxic Offspring. Hypertension (Dallas, Tex. : 1979). 2021 Feb;77(2):491-506

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PMID: 33342239

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