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Effects of endothelial‐specific interference with PPARγ activity in offspring born from AVP‐induced preeclamptic pregnancies
Author(s) -
Nair Anand R,
Mukohda Masashi,
Agbor Larry N,
Wu Jing,
Sandgren Jeremy A,
Grobe Justin L,
Sigmund Curt D
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1033.2
Subject(s) - offspring , endocrinology , medicine , preeclampsia , endothelial dysfunction , blood pressure , gestation , vasopressin , pregnancy , biology , genetics
PPARγ is a ligand‐activated transcription factor known to regulate metabolic and vascular function. Dominant‐negative (DN) mutations in PPARγ result in hypertension, and synthetic agonists of PPARγ have been shown to reduce blood pressure. Previously we found that mice expressing DN PPARγ driven by an endothelium‐specific promoter (E‐DN) exhibit vascular dysfunction. Preeclampsia (PE) is a hypertensive disorder of pregnancy which programs cardio/metabolic disease in offspring. PE is associated with vascular dysfunction, and we therefore hypothesized a role for endothelial PPARγ in the pathogenesis of PE and its sequelae. To test this, C57BL/6J dams were bred with E‐DN sires, and symptoms of PE were induced by the infusion of vasopressin (AVP, 24 ng/hr, sc) throughout gestation. We assessed phenotypes of PE first in pregnant dams, and then in offspring as adults. Compared to saline infusion (SAL), AVP induced significant elevations in maternal blood pressure (SBP in SAL 107±3 vs AVP 116±3, p<0.05) at gestational day 14–15 and urine protein (SAL 27±4 vs AVP 70±6 mg/mL, p<0.05) at gestational day 18. Offspring to these pregnancies were then genotyped and allowed to grow to adulthood to assess cardio‐metabolic function across three factors (offspring sex, offspring genotype, and maternal exposure to AVP vs SAL). A few notable findings of this ongoing, longitudinal study include: at 9 weeks of age, male NT mice born to AVP‐infused pregnancies had increased body mass compared to mice born from SAL‐infused pregnancies (21.3±0.1g in AVP‐WT vs 18.7±1.1 in SAL‐WT, p<0.05). In utero exposure to AVP significantly increased urinary protein levels in E‐DN (41±2.7 in AVP‐E‐DN vs 28±3.6 in SAL‐E‐DN, p<0.05) but not in NT mice (39±3.0 in AVP‐NT vs 29±2.0 in SAL‐WT). Exposure to AVP in utero significantly decreased proportional body fat in female NT (5.6±0.3% in AVP‐NT vs 8.6±1.5% in SAL‐NT, p<0.05) but not in E‐DN (5.6±0.4% in AVP‐E‐DN vs 7.3±0.6% in Sal‐E‐DN). E‐DN, but not WT, females born to pregnancies complicated by AVP infusion had increased proportional body fluid mass compared to E‐DN born to SAL pregnancies (6.8±0.1% in AVP‐E‐DN vs 6.0±0.0% in SAL‐E‐DN, p<0.05 and 6.5±0.1% in AVP‐NT vs 5.9±0.0% in SAL‐NT, n.s). These data highlight the impact of in utero exposure to elevated AVP upon cardiovascular function in the mother, and some of the consequences of this manipulation upon offspring. In addition, the data highlight the complex interactions that endothelial‐specific loss of PPARγ may have upon offspring health. Support or Funding Information NIH and AHA funding