Endothelial PPARγ (Peroxisome Proliferator-Activated Receptor-γ) Protects From Angiotensin II-Induced Endothelial Dysfunction in Adult Offspring Born From Pregnancies Complicated by Hypertension

Anand R Nair; Sebastiao D Silva Jr; Larry N Agbor; Jing Wu; Pablo Nakagawa; Masashi Mukohda; Ko-Ting Lu; Jeremy A Sandgren; Gary L Pierce; Mark K Santillan; Justin L Grobe; Curt D Sigmund

doi:10.1161/HYPERTENSIONAHA.119.13101

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Endothelial PPARγ (Peroxisome Proliferator-Activated Receptor-γ) Protects From Angiotensin II-Induced Endothelial Dysfunction in Adult Offspring Born From Pregnancies Complicated by Hypertension

Journal article

Open access

Peer reviewed

Endothelial PPARγ (Peroxisome Proliferator-Activated Receptor-γ) Protects From Angiotensin II-Induced Endothelial Dysfunction in Adult Offspring Born From Pregnancies Complicated by Hypertension

Anand R Nair, Sebastiao D Silva Jr, Larry N Agbor, Jing Wu, Pablo Nakagawa, Masashi Mukohda, Ko-Ting Lu, Jeremy A Sandgren, Gary L Pierce, Mark K Santillan, …

Hypertension (Dallas, Tex. 1979), Vol.74(1), pp.173-183

07/2019

DOI: 10.1161/HYPERTENSIONAHA.119.13101

PMCID: PMC6561821

PMID: 31104564

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https://doi.org/10.1161/HYPERTENSIONAHA.119.13101View

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Abstract

Preeclampsia is a hypertensive disorder of pregnancy associated with vascular dysfunction and cardiovascular risk to offspring. We hypothesize that endothelial PPARγ (peroxisome proliferator-activated receptor-γ) 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 PPARγ 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 PPARγ in offspring from vasopressin-exposed pregnancies increases the risk for endothelial dysfunction on exposure to a cardiovascular stressor in adulthood. This implies that endothelial PPARγ provides protection to cardiovascular stressors in offspring of a pregnancy complicated by hypertension and perhaps in preeclampsia.

Pregnancy

Animals, Newborn

Pregnancy, Animal

Angiotensin II - pharmacology

Acetylcholine - pharmacology

Humans

Mice, Inbred C57BL

Oxidative Stress - physiology

Hypertension, Pregnancy-Induced - physiopathology

NF-kappa B - metabolism

Signal Transduction - genetics

Hypertension, Pregnancy-Induced - genetics

Animals

Endothelium, Vascular - metabolism

Gene Expression Regulation, Developmental

Protective Agents - pharmacology

Female

PPAR gamma - genetics

Details

Title: Subtitle: Endothelial PPARγ (Peroxisome Proliferator-Activated Receptor-γ) Protects From Angiotensin II-Induced Endothelial Dysfunction in Adult Offspring Born From Pregnancies Complicated by Hypertension
Creators: Anand R Nair - From the Department of Pharmacology (A.R.N., S.D.S., L.N.A., J.W., P.N., M.M., K.-T.L., J.A.S., J.L.G., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Sebastiao D Silva Jr - University of Iowa
Larry N Agbor - From the Department of Pharmacology (A.R.N., S.D.S., L.N.A., J.W., P.N., M.M., K.-T.L., J.A.S., J.L.G., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Jing Wu - Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (S.D.S., J.W., P.N., K.-T.L., J.L.G., C.D.S.)
Pablo Nakagawa - From the Department of Pharmacology (A.R.N., S.D.S., L.N.A., J.W., P.N., M.M., K.-T.L., J.A.S., J.L.G., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Masashi Mukohda - From the Department of Pharmacology (A.R.N., S.D.S., L.N.A., J.W., P.N., M.M., K.-T.L., J.A.S., J.L.G., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Ko-Ting Lu - Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (S.D.S., J.W., P.N., K.-T.L., J.L.G., C.D.S.)
Jeremy A Sandgren - From the Department of Pharmacology (A.R.N., S.D.S., L.N.A., J.W., P.N., M.M., K.-T.L., J.A.S., J.L.G., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Gary L Pierce - Department of Health and Human Physiology (G.L.P.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Mark K Santillan - Department of Obstetrics and Gynecology (M.K.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa
Justin L Grobe - Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (S.D.S., J.W., P.N., K.-T.L., J.L.G., C.D.S.)
Curt D Sigmund - Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, Milwaukee (S.D.S., J.W., P.N., K.-T.L., J.L.G., C.D.S.)
Resource Type: Journal article
Publication Details: Hypertension (Dallas, Tex. 1979), Vol.74(1), pp.173-183
DOI: 10.1161/HYPERTENSIONAHA.119.13101
PMID: 31104564
PMCID: PMC6561821
NLM abbreviation: Hypertension
ISSN: 0194-911X
eISSN: 1524-4563
Publisher: United States
Grant note: R01 HL125603 / NHLBI NIH HHS T32 HL007121 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS R01 HL131689 / NHLBI NIH HHS R35 HL144807 / NHLBI NIH HHS P01 HL084207 / NHLBI NIH HHS T32 HL134643 / NHLBI NIH HHS T32 DK007690 / NIDDK NIH HHS R01 HL134850 / NHLBI NIH HHS
Language: English
Date published: 07/2019
Academic Unit: Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Obstetrics and Gynecology; Neuroscience and Pharmacology; Health, Sport, and Human Physiology ; Internal Medicine
Record Identifier: 9983930623602771

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