Abstract 133: Endothelial-Specific Interference With PPARγ Increases the Susceptibility to Angiotensin II-Induced Endothelial Dysfunction in Adult Offspring Born from AVP-Infused Pregnancies

Abstract

Mutations in the ligand-activated transcription factor 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 risk to offspring. PE is also associated with vascular dysfunction. We 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 infusion of vasopressin (AVP, 24 ng/hr sc) throughout gestation. Phenotypes of PE were first assessed in pregnant dams and then in adult offspring. 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 were phenotyped in adulthood. Data were stratified to sex, genotype, and exposure to AVP or SAL. At 20 weeks of age, SBP and vasorelaxation responses to acetylcholine were similar in offspring exposed to PE compared to mice born from SAL pregnancies. Adult offspring were next exposed to a sub-pressor dose of Angiotensin II (ANG; 120ng/kg/hr) for 14 days. Adult male ANG-treated E-DN born to PE pregnancies, but not NT mice exhibited significant impairment in ACh-induced relaxation in carotid artery (% relaxation: 62±10 vs 86±11, p<0.05). Adult female ANG-treated E-DN exposed to PE also exhibited a trend for impaired endothelial function compared to NT controls (% relaxation: 63±9 vs 72±10). Endothelial dysfunction in male ANG-treated E-DN born to PE pregnancies was attenuated by tempol (relaxation improved from 56±9% vs 81±12%, p<0.05), indicative of oxidative stress, and by a Rho-kinase inhibitor (relaxation improved from 73±11% vs 89±12%, p<0.05). This data suggests that interference with endothelial PPARγ in pups born from PE pregnancies increases the risk for endothelial dysfunction upon exposure to a cardiovascular stressor in adulthood. Thus, conditions which impair PPARγ activity, such as obesity and diabetes, may predispose adult offspring born from PE pregnancy to cardiovascular disease.