Cardiovascular Effects of Endothelial‐Specific Interference with PPARγ Activity in Offspring Born from AVP‐induced Preeclamptic Pregnancies

Abstract

PPARγ is a ligand‐activated transcription factor known to regulate metabolic and vascular function. Mutations in PPARγ result in hypertension, and synthetic agonists of PPARγ reduce blood pressure. Previously we found that mice expressing dominant‐negative (DN) PPARγ driven by an endothelium‐specific promoter (E‐DN) exhibit vascular dysfunction. Preeclampsia (PE) is a hypertensive disorder of pregnancy which carries cardiovascular and metabolic risk to offspring. PE is associated with vascular dysfunction, and we therefore hypothesized a role for endothelial PPARγ in the pathogenesis of PE and its sequelae. 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 elevated maternal blood pressure (SBP: 116±3 vs 107±3, p<0.05) at gestational day (GD) 14–15 and urine protein (70±6 vs 27±4 mg/mL, p<0.05) at GD17. Offspring from these pregnancies were phenotyped in adulthood to assess cardiovascular function. Data were stratified to sex, genotype, and maternal exposure to AVP vs SAL. Systolic blood pressure in adult male and female offspring born to AVP‐infused pregnancies was similar to mice born to SAL‐infused control pregnancies. Urinary protein levels were significantly elevated in both male (58±13 vs 32±5 mg/ml, p<0.05) and female (38±3 vs 25±2 mg/ml, p<0.05) adult E‐DN born to PE pregnancies compared to E‐DN controls born from SAL pregnancies. At 20 weeks of age, vasorelaxation responses to acetylcholine (ACh) were not different in offspring exposed to PE compared to mice born from SAL pregnancies. Interestingly, in response to a sub‐pressor dose of Angiotensin II (120 ng/kg/hr for 14 days), a known cardiovascular stressor, adult male E‐DN born to PE pregnancies, but not NT mice exhibited significant impairment in ACh‐induced relaxation in carotid artery (maximum relaxation at 30 μM ACh: 69±4 vs 86±3, p<0.05) and basilar artery (maximum relaxation at 100 μM ACh: 19±7 vs 51±15, p<0.05). Male E‐DN exposed to PE also showed a trend for endothelial dysfunction in carotid artery and basilar artery when compared to sex‐matched E‐DN born from control pregnancies (carotid: max relaxation at 30 μM ACh: 69±4 vs 86±4; basilar: max relaxation at 100 μM ACh: 19±7 vs 64±14). Further, adult female E‐DN exposed to PE also exhibited a trend for impaired endothelial function in carotid artery in response to AngII administration compared to NT controls (Maximum relaxation at 30 μM ACh: 56±12 vs 72±5). No differences in relaxation responses to sodium nitroprusside were observed. These data highlight the impact of in utero exposure to elevated AVP upon cardiovascular function in the mother, and the adverse cardiovascular consequences of PE upon offspring. Moreover, our data suggests that interference with endothelial PPARγ in pups born from AVP‐infused PE pregnancies increases the risk for endothelial dysfunction upon exposure to a cardiovascular stressor in adulthood.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.