Endothelial‐Specific Interference with PPARγ Causes Endothelial Dysfunction with Sex‐ Specific Mechanisms in Offspring Born from AVP‐infused Pregnancies
Authors: Nair Anand R. , Silva Sebastiao Donato , Agbor Larry N. , Lu Ko‐Ting , Wu Jing , Mukohda Masashi , Grobe Justin L , Sigmund Curt D. 
Published: June 2021

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 and carries cardiovascular risk to offspring. PE is also associated with vascular dysfunction. Therefore, 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. Adult male and female offspring were exposed to a sub‐pressor dose of Angiotensin II (ANG; 120ng/kg/hr) for 14 days as a cardiovascular stressor. Male and female ANG‐treated E‐DN born to PE pregnancies, but not control pregnancies, exhibited significant impairment in ACh‐induced relaxation in carotid artery (% relaxation: Males − 56±9 vs 81±11, p<0.05; Females − 68±10 vs 84±11, p<0.05). Endothelial dysfunction in male ANG‐treated E‐DN born to PE pregnancies was attenuated by tempol (relaxation improved from 53±9% vs 84±12%, p<0.05), indicative of a role for oxidative stress. Interestingly, tempol did not rescue endothelial dysfunction in female E‐DN exposed to PE (% relaxation: 69±10% vs 81±11%, ns). In keeping with this, Nrf2 protein levels was significantly elevated in aorta from male E‐DN (1.9±0.2 vs 0.2±0.1, p<0.05), but not females (1.2±0.3 vs 0.6±0.2, ns) compared to genotype‐ and sex‐matched controls, suggesting that the mechanism of endothelial dysfunction might differ between sexes. Blockade of Rho‐kinase (ROCK) signaling with Y‐27632 improved endothelium‐dependent relaxation in male and female E‐DN offspring born from PE pregnancies (% relaxation: Males − 60±10 vs 87±12, p<0.05; Females − 69±10 vs 98±13, p<0.05). We observed a significant 4‐fold increase in ROCK2 protein levels in aorta from both male and female E‐DN mice exposed to PE (Males – 2.3±0.5 vs 0.6±0.4, p<0.05; Females − 1.9±0.5 vs 0.5±0.2, p<0.05). No changes were observed in ROCK1 expression. Further, incubation with a ROCK2 specific inhibitor, SLX‐2119, significantly improved relaxation in male and female E‐DN (Males – relaxation improved from 72±11 vs 91±10, p<0.05; Females – relaxation improved from 68±10 vs 94±12, p<0.05). Our 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. Moreover, potential mechanisms accounting for endothelial dysfunction in offspring born from complicated pregnancies might be sex‐dependent.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.