Key result
CGP42112 reduces diet-induced hypertension by ~20 mmHg in controls but fails after gestational hypoxia.
Why the study?
It was unknown whether female offspring exposed to gestational intermittent hypoxia exhibit increased susceptibility to hypertension and cardiovascular dysfunction on an HFHS diet, and if AT2R activation could reverse it.
Does the AT2R agonist CGP42112 mitigate high-fat high-sucrose diet-induced hypertension and endothelial dysfunction in female offspring exposed to gestational intermittent hypoxia?
Does the AT2R agonist CGP42112 mitigate high-fat high-sucrose diet-induced hypertension and endothelial dysfunction in female offspring exposed to gestational intermittent hypoxia?
Gestational intermittent hypoxia programs long-term vascular dysfunction and AT2R insensitivity in female offspring, potentially contributing to resistant hypertension in adulthood.
Answers are grounded in this paper and cite their sources.
Gestational hypoxia may program AT2R insensitivity limiting agonist response; leaves open targeted therapies for programmed hypertension in offspring.
Background: Gestational intermittent hypoxia (GIH), a hallmark of maternal obstructive sleep apnea, sex-differentially causes hypertension and endothelial dysfunction in adult male offspring but not in females. This study investigated whether the GIH-exposed female offspring, a "protected" group against the hypertensive effects of maternal GIH exposure, exhibit increased susceptibility to hypertension and cardiovascular dysfunction when fed a high-fat high-sucrose (HFHS) diet and whether this effect could be reversed by pharmacological intervention activating the angiotensin II type 2 receptor (AT2R). Methods: Female offspring of control and GIH-exposed (10.5% O2, 8 h/d, E10-21) dams were assigned either an HFHS diet or a standard diet from 12 weeks of age. Blood pressure was monitored. At 28 weeks, a systemic CGP42112 (AT2R agonist) or saline infusion was administered through the osmotic pump. At 30 weeks, the heart was weighed and collected for H&E staining, mesenteric arteries for vascular reactivity assessment and protein analysis, and plasma for ELISA. Results: The HFHS diet induced similar increases in body weight gain and blood pressure in control and GIH female offspring. HFHS feeding did not affect heart structure, but impaired endothelial-dependent vascular relaxation with associated decreased AT2R and eNOS expression and reduced plasma bradykinin levels in both control and GIH offspring. CGP42112 administration effectively mitigated HFHS-induced hypertension and endothelial dysfunction only in control offspring, accompanied by restored AT2R, eNOS, and bradykinin levels, but not in the GIH counterparts. Conclusion: These findings suggest that GIH induces endothelial dysfunction and AT2R insensitivity in female offspring exposed to an HFHS diet.
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Song et al. (2024) studied Female offspring exposed to gestational intermittent hypoxia on a high-fat high-sucrose diet. CGP42112 (AT2R agonist) vs. Saline-filled osmotic minipumps (vehicle) was evaluated on Mean arterial blood pressure and endothelial-dependent vascular relaxation at 30 weeks of age. CGP42112 mitigated high-fat high-sucrose diet-induced hypertension in control female offspring (mean BP decrease of 20 mmHg) but was ineffective in gestational intermittent hypoxia-exposed offspring (mean decrease of 8 mmHg).
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