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Background: Patients with preeclampsia demonstrate increases in placental leptin production in midgestation, and an associated increase in late gestation plasma leptin levels. The consequences of mid-late gestation increases in leptin production in pregnancy is unknown. Our previous work indicates that leptin infusion induces endothelial dysfunction in nonpregnant female mice via leptin-mediated aldosterone production and endothelial mineralocorticoid receptor (ECMR) activation, which is ablated by ECMR deletion. Therefore, we hypothesized that leptin infusion in mid-gestation of pregnancy induces endothelial dysfunction and hypertension, hallmarks of clinical preeclampsia, which are prevented by ECMR deletion. Methods: Leptin was infused via miniosmotic pump (0.9 mg/kg per day) into timed-pregnant ECMR-intact (WT) and littermate-mice with ECMR deletion (KO) on gestation day (GD)11-18. Results: Leptin infusion decreased fetal weight and placental efficiency in WT mice compared with WT+vehicle. Radiotelemetry recording demonstrated that blood pressure increased in leptin-infused WT mice during infusion. Leptin infusion reduced endothelial-dependent relaxation responses to acetylcholine (ACh) in both resistance (second-order mesenteric) and conduit (aorta) vessels in WT pregnant mice. Leptin infusion increased placental ET-1 (endothelin-1) production evidenced by increased PPET-1 (preproendothelin-1) and ECE-1 (endothelin-converting enzyme-1) expressions in WT mice. Adrenal aldosterone synthase ( CYP11B2 ) and angiotensin II type 1 receptor b ( AT1Rb ) expression increased with leptin infusion in pregnant WT mice. KO pregnant mice demonstrated protection from leptin-induced reductions in pup weight, placental efficiency, increased BP, and endothelial dysfunction. Conclusions: Collectively, these data indicate that leptin infusion in midgestation induces endothelial dysfunction, hypertension, and fetal growth restriction in pregnant mice, which is ablated by ECMR deletion.

HIV is currently a major health concern with over 37 million individuals worldwide living with HIV and 1.7 million newly infected people in 2019. Thanks to the onset of combination antiretroviral therapy (cART) patients with HIV (PWH) live much longer but now exhibit accelerated development of metabolic and cardiovascular disease (CVD). Obesity currently affects 10% of the HIV population and clinical evidence indicates that 35% of PWH exhibit hypertension. However, the etiopathology of obesity and CVD remains ill‐defined in PWH. Notably, the respective contribution of viral infection and cART to cardiometabolic disorders remains unknown. The goal of this study is to take advantage of a transgenic mouse model (Tg26) that expresses 7 out of the 9 viral HIV proteins and mimics patients with a repressed virus, to decipher the contribution of viral infection to metabolic and cardiovascular dysfunction in male and female mice. Wild‐type (WT) and Tg26 mice were analyzed for body composition, energy expenditure (CLAMS cages), and glycemic impairment with glucose tolerance tests (GTT). Viral infection did not alter body weight in male and female Tg26 mice, but led to a significant reduction in both visceral (male: WT=0.049+/−0.008 vs. Tg26=0.030+/−0.006/female: WT=0.017+/−0.001 vs. Tg26=0.013+/−0.0004) and subcutaneous (male: WT=0.015+/−0.0007 vs. Tg26=0.011+/−0.0007/ female: WT=0.019+/−0.002 vs. Tg26=0.013+/−0.0007) adipose tissues in both in male and female Tg26 mice. Energy substrate utilization analysis via indirect calorimetry revealed a significant increase in the respiration exchange ratio in male Tg26 mice and a trend towards an increase in female mice (male: P<0.05/ female: P<0.1), indicating increased fat metabolism in male and female Tg26 mice. Similarly, energy expenditure tended to increase in male and was significantly increased in female Tg26 mice (male: P<0.1/ female: P<0.05). Measurement of glycemic impairment via GTT showed a trend towards impaired glycaemia only in male Tg26 mice (P<0.1). Cardiovascular dysfunction was studied via analysis of aorta reactivity using wire myography and blood pressure via radio‐telemetry. Our results indicated that both male and female Tg26 mice exhibit impaired endothelium dependent relaxation as reflected by a decrease in acetylcholine mediated relaxation with no impairment in smooth muscle cell relaxation (male: P<0.05/ female: P<0.05). Vascular constriction to phenylephrine and KCl was preserved in both male and female Tg26 mice. Blood pressure analysis of Tg26 mice via telemetry indicated that HIV increases blood pressure (male: WT=112.3+/−1.3 vs Tg26=121.9+/−4.0 mmHg/ female: WT=110.6+/−3.01/ Tg26=120.3+/−6.9 mmHg) in male and female Tg26 mice. Collectively, these data indicate that HIV viral infection increases energy expenditure and fat metabolism leading to decreased fat mass but also impairs endothelial function and elevate blood pressure, indicating that viral infection per se is a contributor to the metabolic and cardiovascular derangements exhibited by HIV pat...

Obesity increases preeclampsia (PE) risk. Plasma leptin levels increase with body weight in women with PE, and in addition, placental ischemia, an initiating event of PE, also increases plasma leptin. Our lab has shown that hyperleptinemia induces endothelial dysfunction and hypertension in female mice via endothelial mineralocorticoid receptor (ECMR) activation and that high progesterone levels of pregnancy increases ECMR expression. We hypothesized that leptin infusion induces PE-like endothelial dysfunction in pregnant mice, which is abrogated by ECMR deletion. Pregnant mice were infused with leptin by miniosmotic pump (0.9mg/kg/day, s.c.) on gestation day (GD) 11-18. Leptin decreased pup wt (0.86±0.04g ECMR +/+ vs 0.52±0.11 ECMR +/+ +leptin, *P<0.05). and increased fetal resorption (3±39% ECMR +/+ vs 42±32 ECMR +/+ +leptin, P=0.09). ECMR deletion rescued pup weight (0.91±0.06g ECMR -/- vs 1.0±0.07 ECMR -/- +leptin) and protected fetal resorptions (2±2% ECMR -/- vs 0±0 ECMR -/- +leptin) in leptin-infused pregnant mice. In association, placental efficiency (pup/placenta ratio) decreased with leptin in ECMR +/+ (9.7±0.7 ECMR +/+ vs 7.9±0.6 ECMR +/+ +leptin, *P<0.05), but not ECMR -/- (9.6±0.5 ECMR -/- vs 9.4±1.2 ECMR -/- +leptin) mice. Leptin infusion reduced endothelial function (acetylcholine-mediated relaxation) in aortas of ECMR +/+ , but not ECMR -/- , pregnant mice (2-way ANOVA, repeated measures, *P<0.05). Relaxation responses to acetylcholine with LNAME showed restoration of endothelial function in ECMR -/- +leptin mice was due to preserved NO bioavailability. No changes in endothelial-independent sodium nitroprusside or contractile responses to phenylephrine, serotonin or KCl were observed. ECMR deletion reduced aorta IL-1β mRNA (0.5±0.1-fold change ECMR +/+ +leptin vs 0.2±0.1-fold change ECMR -/- +leptin, P=0.06) levels and also placental growth factor mRNA (1.0±0.3-fold change ECMR +/+ +leptin vs 01.3±0.1 ECMR -/- +leptin, P=0.05) in placental tissues. Collectively, these data indicate that ECMR deletion protects pregnant mice from adverse fetal growth and demise in association with increasing NO vascular bioavailability, reducing vascular inflammation and improving placental function in a leptin-infused model of PE.

Preeclampsia (PE), a hypertensive disorder of pregnancy, induces adverse pregnancy outcomes including fetal growth restriction (FGR) and afflicts ~5‐10% of pregnancies. Compelling clinical data indicate that PE risk and severity in pregnant women is strongly associated with endothelial dysfunction. Previous work by our group shows that deletion of endothelial cell mineralocorticoid receptors (ECMR) improves endothelial function in premenopausal hypertensive female mice, however whether ECMR promotes endothelial dysfunction in PE is unknown. We tested the hypothesis that ECMR deletion improves FGR and endothelial function in a mouse model of PE, the reduced uterine perfusion pressure (RUPP) mouse. Pregnant ECMR‐intact (WT) and ECMR‐deficient (KO) mice were randomized to RUPP or sham surgery on GD13 and sacrificed on GD18 (WT Sham=6, WT RUPP=5, KO Sham=7, KO RUPP=6). Vascular function was measured via wire myography on 2nd order mesenteric arteries. Conscious blood pressure was measured by radiotelemetry throughout pregnancy in a subset of mice. RUPP surgery did not decrease maternal weights in either WT or KO mice (P>0.05) at GD18. RUPP surgery significantly decreased GD18 pup weight, a measure of FGR, (726±20mg WT+Sham vs 660±11mg WT+RUPP, *P<0.05) and trended to decrease placental efficiency (pup/placenta weight) (8.23±0.23 WT+Sham vs 7.45±0.22 WT+RUPP P=0.13) in WT pregnant mice. ECMR deletion protected pregnant mice both from RUPP‐induced reductions in pup weight (710±20mg KO+Sham vs 690±20mg KO+RUPP) and decreases in placental efficiency (7.63±0.19 KO+Sham vs 7.76±0.31 KO+RUPP). RUPP reduced acetylcholine‐mediated relaxation (10‐9‐3x10‐5 M) in mesenteric arteries of WT pregnant mice but not KO pregnant mice (*P<0.05, 2‐way ANOVA, repeated measures), indicating RUPP induced endothelial dysfunction in WT mice only. Preincubation with nitric oxide (NO) synthase inhibitor LNAME ablated differences in Ach‐mediated relaxation between WT+sham and WT+RUPP mice (P>0.05), indicating that reductions in endothelial function in WT+RUPP mice were mediated by reduced NO. However, ECMR deletion as a variable increased Ach‐mediated relaxation in the presence of LNAME in both Sham and RUPP mice (*P<0.05). Therefore, ECMR deletion may have protected pregnant mice from endothelial dysfunction via a non‐NO mechanism. RUPP did not increase a‐receptor agonist phenylephrine (Phe)‐induced constriction in WT mice, however, ECMR deletion as a variable decreased Phe‐mediated constriction independent of RUPP surgery indicating that ECMR deletion reduces smooth muscle‐mediated vasoconstriction in pregnant sham and RUPP mice. These data indicate that specific deletion of ECMR improves vascular function to increase vasodilation and prevent constriction in PE pregnancy. Preliminary data further indicates that systolic blood pressure increased from GD8‐18 (pre‐post RUPP) in WT+RUPP but decreased in KO+RUPP pregnant mice (2.7 vs ‐8.6 DmmHg, respectively, N=1). Lastly RUPP surgery trended to increase plasma levels of the ECMR agonist corticoste...