Hao Luo1,2, Cong Lan1,2, Chao Fan1,2, Xue Gong1,2, Caiyu Chen1,2, Cheng Yu2,3, Jialiang Wang1,2, Xiaoli Luo1,2, Cuimei Hu1,2, Pedro A Jose4,5, Zaicheng Xu1,2, Chunyu Zeng1,2,6. 1. Department of Cardiology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Rd, Chongqing 400042, P.R. China. 2. Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China. 3. Department of Cardiology, Fujian Heart Center, Provincial Institute of Coronary Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian, China. 4. Division of Renal Diseases & Hypertension, Department of Medicine and Pharmacology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA. 5. Department of Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA. 6. Cardiovascular Research Center of Chongqing College, Department of Cardiology of Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China.
Abstract
AIMS: Exposure to maternal diabetes is associated with increased prevalence of hypertension in the offspring. The mechanisms underlying the prenatal programming of hypertension remain unclear. Because endoplasmic reticulum (ER) stress plays a key role in vascular endothelial dysfunction in hypertension, we investigated whether aberrant ER stress causes endothelial dysfunction and high blood pressure in the offspring of dams with diabetes. METHODS AND RESULTS: Pregnant Sprague-Dawley rats were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at Day 0 of gestation. Compared with control mother offspring (CMO), the diabetic mother offspring (DMO) had higher blood pressure and impaired endothelium-dependent relaxation in mesenteric arteries, accompanied by decreased AMPK phosphorylation and PPARδ expression, increased ER stress markers, and reactive oxygen species (ROS) levels. The inhibition of ER stress reversed these aberrant changes in DMO. Ex vivo treatment of mesenteric arteries with an AMPK agonist (A769662) or a PPARδ agonist (GW1516) improved the impaired EDR in DMO and reversed the tunicamycin-induced ER stress, ROS production, and EDR impairment in mesenteric arteries from CMO. The effects of A769662 were abolished by co-treatment with GSK0660 (PPARδ antagonist), whereas the effects of GW1516 were unaffected by Compound C (AMPK inhibitor). CONCLUSION: These results suggest an abnormal foetal programming of vascular endothelial function in offspring of rats with maternal diabetes that is associated with increased ER stress, which can be ascribed to down-regulation of AMPK/PPARδ signalling cascade. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Exposure to maternal diabetes is associated with increased prevalence of hypertension in the offspring. The mechanisms underlying the prenatal programming of hypertension remain unclear. Because endoplasmic reticulum (ER) stress plays a key role in vascular endothelial dysfunction in hypertension, we investigated whether aberrant ER stress causes endothelial dysfunction and high blood pressure in the offspring of dams with diabetes. METHODS AND RESULTS: Pregnant Sprague-Dawley rats were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at Day 0 of gestation. Compared with control mother offspring (CMO), the diabetic mother offspring (DMO) had higher blood pressure and impaired endothelium-dependent relaxation in mesenteric arteries, accompanied by decreased AMPK phosphorylation and PPARδ expression, increased ER stress markers, and reactive oxygen species (ROS) levels. The inhibition of ER stress reversed these aberrant changes in DMO. Ex vivo treatment of mesenteric arteries with an AMPK agonist (A769662) or a PPARδ agonist (GW1516) improved the impaired EDR in DMO and reversed the tunicamycin-induced ER stress, ROS production, and EDR impairment in mesenteric arteries from CMO. The effects of A769662 were abolished by co-treatment with GSK0660 (PPARδ antagonist), whereas the effects of GW1516 were unaffected by Compound C (AMPK inhibitor). CONCLUSION: These results suggest an abnormal foetal programming of vascular endothelial function in offspring of rats with maternal diabetes that is associated with increased ER stress, which can be ascribed to down-regulation of AMPK/PPARδ signalling cascade. Published on behalf of the European Society of Cardiology. All rights reserved.