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Endothelial PPARI? (Peroxisome Proliferator-Activated Receptor-I?) Protects From Angiotensin II-Induced Endothelial Dysfunction in Adult Offspring Born From Pregnancies Complicated by Hypertension. Hypertension 2019 07;74(1):173-183

Date

05/21/2019

Pubmed ID

31104564

Pubmed Central ID

PMC6561821

DOI

10.1161/HYPERTENSIONAHA.119.13101

Scopus ID

2-s2.0-85068196613   12 Citations

Abstract

Preeclampsia is a hypertensive disorder of pregnancy associated with vascular dysfunction and cardiovascular risk to offspring. We hypothesize that endothelial PPARI? (peroxisome proliferator-activated receptor-I?) provides cardiovascular protection in offspring from pregnancies complicated by hypertension. C57BL/6J dams were bred with E-V290M sires, which express a dominant-negative allele of PPARI? selectively in the endothelium. Arginine vasopressin was infused throughout gestation. Vasopressin elevated maternal blood pressure at gestational day 14 to 15 and urinary protein at day 17 consistent. Systolic blood pressure and vasodilation responses to acetylcholine were similar in vasopressin-exposed offspring compared to offspring from control pregnancies. We treated offspring with a subpressor dose of angiotensin II to test if hypertension during pregnancy predisposes offspring to hypertension. Male and female angiotensin II-treated E-V290M offspring from vasopressin-exposed but not control pregnancy exhibited significant impairment in acetylcholine-induced relaxation in carotid artery. Endothelial dysfunction in angiotensin II-treated E-V290M vasopressin-exposed offspring was attenuated by tempol, an effect which was more prominent in male offspring. Nrf2 (nuclear factor-E2-related factor) protein levels were significantly elevated in aorta from male E-V290M offspring, but not female offspring compared to controls. Blockade of ROCK (Rho-kinase) signaling and incubation with a ROCK2-specific inhibitor improved endothelial function in both male and female E-V290M offspring from vasopressin-exposed pregnancy. Our data suggest that interference with endothelial PPARI? in offspring from vasopressin-exposed pregnancies increases the risk for endothelial dysfunction on exposure to a cardiovascular stressor in adulthood. This implies that endothelial PPARI? provides protection to cardiovascular stressors in offspring of a pregnancy complicated by hypertension and perhaps in preeclampsia.

Author List

Nair AR, Silva SD Jr, Agbor LN, Wu J, Nakagawa P, Mukohda M, Lu KT, Sandgren JA, Pierce GL, Santillan MK, Grobe JL, Sigmund CD

Authors

Justin L. Grobe PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Pablo Nakagawa PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acetylcholine
Angiotensin II
Animals
Animals, Newborn
Endothelium, Vascular
Female
Gene Expression Regulation, Developmental
Humans
Hypertension, Pregnancy-Induced
Mice, Inbred C57BL
NF-kappa B
Oxidative Stress
PPAR gamma
Pregnancy
Pregnancy, Animal
Protective Agents
Signal Transduction