Down-regulation of AMPK/PPARδ signalling promotes endoplasmic reticulum stress-induced endothelial dysfunction in adult rat offspring exposed to maternal diabetes

Hao Luo, Department of Cardiology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Rd, Chongqing 400042, P.R. China.
Cong Lan, Department of Cardiology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Rd, Chongqing 400042, P.R. China.
Chao Fan, Department of Cardiology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Rd, Chongqing 400042, P.R. China.
Xue Gong, Department of Cardiology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Rd, Chongqing 400042, P.R. China.
Caiyu Chen, Department of Cardiology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Rd, Chongqing 400042, P.R. China.
Cheng Yu, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China.
Jialiang Wang, Department of Cardiology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Rd, Chongqing 400042, P.R. China.
Xiaoli Luo, Department of Cardiology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Rd, Chongqing 400042, P.R. China.
Cuimei Hu, Department of Cardiology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Rd, Chongqing 400042, P.R. China.
Pedro A. Jose, Division of Renal Diseases & Hypertension, Department of Medicine and Pharmacology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Zaicheng Xu, Department of Cardiology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Rd, Chongqing 400042, P.R. China.
Chunyu Zeng, Department of Cardiology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Rd, Chongqing 400042, P.R. China.

Document Type

Journal Article

Publication Date

7-27-2022

Journal

Cardiovascular research

Volume

118

Issue

10

DOI

10.1093/cvr/cvab280

Keywords

Endoplasmic reticulum stress; Endothelial function; Foetal programming; Gestational diabetes; Hypertension

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.

Department

Medicine

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