bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin‐15 contributes to decidual natural killer cell loss via interferon‐γ during early pregnancy in the pre‐eclamptic BPH/5 mouse model (1083.1)
Authors: Sones Jenny , Lob Heinrich , Isroff Catherine , Song Jiunn , Williamson Emilie , Davisson Robin 
Published: June 2021

During early pregnancy dNK cells promote decidualization, which is critical for uterine angiogenesis and placentation. IL‐15 activates dNK cells, which release IFN‐γ to orchestrate vessel remodeling for proper placental perfusion. However, high levels of IFN‐ γ induce apoptosis of dNK cells at the maternal‐fetal interface. Reduced perfusion of the fetoplacental unit is a hallmark of PE. Our previous studies showed that BPH/5 mice, a rodent model of spontaneous PE, have increased peripheral inflammation. We hypothesize that peripheral inflammation in early pregnancy contributes to elevated IL‐15, which results in dNK cell apoptosis. Virgin BPH/5 mice had significantly elevated uterine IL‐15 mRNA as compared to C57 controls. Other pro‐inflammatory cytokines were unchanged. At e4.5 and e5.5, when decidualization first begins, we observed significantly increased IL‐15 mRNA in BPH/5 implantation sites compared to controls (60‐fold, 20‐fold respectively, p<0.05, n=4). Further, BPH/5 dNK cell mRNA expression was similar to controls at e4.5 but dramatically reduced at e5.5 (10‐fold, p<0.05, n=4). This finding was confirmed by flow cytometry (BPH/5 0.7 x 103 cells vs C57 9.7 x 103 cells, p<0.05, n=4), and was attributed to a 3‐fold increase in IFN‐γ mRNA. These findings support the hypothesis that early pregnancy events may lead to impaired uterine angiogenesis which precedes the development of PE in this model.Grant Funding Source: #12POST11250010; HL63887, HL84207, 12SDG9160010
Complement components C3a and C5a alter angiogenic balance in placental and endothelial cells (1084.11)
Authors: Gillham Haley , Banek Christopher , Needham Karen , Regal Jean , Gilbert Jeffrey 
Published: June 2021

Recent studies have reported excessive activation of complement during pregnancy may contribute to the pathogenesis of preeclampsia, and inhibition of complement activation reduces blood pressure in an animal model of placental ischemia‐induced hypertension. As previous studies have shown a role for angiogenic balance in reducing blood pressure in placental ischemia induced hypertension and the anti‐angiogenic effects of complement activation products, we hypothesized complement activation products C3a and C5a would have anti‐angiogenic effects in human umbilical vein endothelial cells (HUVECs) and rat placental villi explants. Cells were cultured in physiologic normoxic (8%) or hypoxic (1%) conditions and treated with human C3a, human C5a (10 or 100 nmol/L) or vehicle for 24 hours. Experiments were run in triplicate. In placental explants, hypoxia stimulated secretion of vascular endothelial growth factor (VEGF) into the cell media vs. normoxia (1420 ± 75 vs. 1068 ± 52, P<0.05), and this was decreased (P<0.05) by 10nM (‐23%) and 100nM (‐22%) C3a. Secretion of soluble fms‐like tyrosine kinase‐1 (sFlt‐1) from explants was increased (P<0.05) by 10nM (18%) and 100nM (19%) C3a in normoxic but not hypoxic conditions compared to controls. C3a and C5a (100nM) increased sFlt‐1 secretion from HUVECs in normoxic conditions (P<0.05) when compared to controls (771 ± 22 vs. 776 ± 38 vs. 629 ± 14). Secretion of VEGF from HUVECs was decreased with C5a in both oxygen conditions compared to controls (P<0.05) and there was no effect of C3a. These data suggest that products of excessive complement activation have anti‐angiogenic effects in endothelial cells, impairing placental development and invasion and leading to poor placental perfusion. Further, complement activation products appear to disrupt regulation of angiogenic balance in placental cells, which in turn could contribute to continued placental dysfunction in later pregnancy.Grant Funding Source: Supported by NIH RO1HL114096, 1R15HL109843 and AHA 10SDG2600040
Obese melanocortin‐4 receptor‐deficient rats exhibit attenuated adrenergic vasoconstriction (1084.2)
Authors: Spradley Frank , Palei Ana , Granger Joey 
Published: June 2021

Preeclampsia is a hypertensive disorder of pregnancy associated with placental ischemia‐induced endothelial dysfunction and exaggerated vasoconstriction. Obesity is a major risk factor for the development of preeclampsia but the mechanisms are unclear. Intriguingly, we previously showed that obese MC4R heterozygous (+/‐) rats not subjected to placental ischemia are normotensive with augmented endothelial‐dependent relaxation and smooth muscle relaxation response to a nitric oxide donor. To further examine vascular function in obese pregnancy, we tested the hypothesis that obese MC4R +/‐ pregnant rats have attenuated vasoconstriction. At gestational day 19, third‐order mesenteric arteries were isolated from obese MC4R +/‐ (N=6) and lean MC4R +/+ (N=10) rats and mounted in a wire myograph. Sensitivity (logEC50) to vasoconstriction induced by phenylephrine (PE) was significantly (P<0.05) reduced in obese (‐4.9±0.3M) vs. lean (‐5.6±0.1M) pregnant rats whereas the maximum contractile response (% increase in force) to PE was similar between obese (241±57%) and lean (305±49%) pregnant groups. Vasoconstriction stimulated by depolarization to KCl was similar between obese vs. lean rats: EC50 (56.5±2.9mM vs. 48.1±1.3mM) or maximum response (150±13% vs. 168±13%). In conclusion, these data indicate that pregnancy in obese MC4R +/‐ rats is associated with reduced adrenergic vasoconstriction. However, we speculate that adrenergic vasoconstriction may be exaggerated in obese pregnant animals with placental ischemia‐induced endothelial dysfunction.Grant Funding Source: Supported by HL105324, HL51971.
Antagonism of complement C5a receptor but not C3a receptor attenuates placental ischemia‐induced endothelial dysfunction in rat (1084.8)
Authors: Opacich Jonathan , Johnson Alex , Bauer Ashley , Gilbert Jeffrey , Regal Jean 
Published: June 2021

Preeclampsia is characterized by new‐onset hypertension, abnormal placentation, endothelial dysfunction and increased activation of the complement system generating vasoactive products complement C3a and C5a. Previous studies in the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia‐induced hypertension demonstrated impaired endothelial‐dependent relaxation in isolated blood vessels. In addition, inhibition of complement system activation inhibited the hypertension. Whether complement activation is responsible for the endothelial dysfunction following placental ischemia is unclear. Hypothesis: Complement activation products C3a and C5a mediate endothelial dysfunction following placental ischemia. On gestation day (GD) 14, rats underwent sham surgery or clip placement on ovarian arteries and abdominal aorta (RUPP) to cause placental ischemia and increase blood pressure. Rats were treated once daily with C5a receptor antagonist acetyl‐F‐[Orn‐P‐(D‐Cha)‐WR] (PMX53, 3 mg/kg SC), C3a receptor antagonist N2‐[(2,2‐Diphenylethoxy)acetyl]‐L‐arginine (SB290157, 5 mg/kg IV) or vehicle (10% ethanol/saline) from GD14‐18. On GD19, blood pressure was determined via carotid artery and mesenteric arteries removed. Mesenteric arteries (200‐400µm in diameter) were pre‐contracted with 0.44 µM thromboxane mimetic U46619. Endothelial‐dependent and independent relaxations were determined by fractional relaxation of the U46619 contraction to acetylcholine (ACh, 10 nM‐0.31 mM) and sodium nitroprusside (SNP, 7.7 nM‐0.23 mM), respectively. Maximum fractional relaxation to ACh in arteries from RUPP rats (0.68±0.06) was less than Sham (0.88±0.03; p<0.05) and RUPP rats treated with PMX53 (0.83±0.06) but not RUPP rats treated with SB290157 (0.76±0.07). Relaxation to SNP was not affected by the treatments. These data suggest that C5a, but not C3a, mediates endothelial dysfunction induced by placental ischemia.Grant Funding Source: Supported by NIH HL109843
Early life stress enhances renal expression of T‐cell and B‐cell activation factors (1085.11)
Authors: Obi Ijeoma , Ho Dao , Loria Analia , Pollock Jennifer 
Published: June 2021

Early life stress enhances renal expression of T‐cell and B‐cell activation factors Ijeoma Obi, Dao H. Ho, Analia S. Loria, and Jennifer S. Pollock Experimental Medicine, Georgia Regents University, Augusta, GA 30912 In humans, early life stress (ELS) increases cardiovascular disease (CVD) risk and elevates circulating pro‐inflammatory factors; yet the renal inflammatory consequences of ELS remains unclear. We previously showed that in a rat model of ELS, maternal separation (MatSep), baseline blood pressure and renal immune cell infiltration was similar to normally‐reared rats; however MatSep enhanced renal sensitization to the inflammatory and hypertensive effects of angiotensin II (ANGII). We hypothesized that MatSep promotes baseline expression of renal cortex T‐cell and B‐cell activation markers of adult male Wistar Kyoto rats. MatSep animals underwent separation from dams (3h/day) during postnatal day 2‐14; control (CON) littermates were undisturbed. Renal cortex expression of 84 genes representing T‐cell and B‐cell activation was assessed by real‐time qPCR. We determined that caspase 3, Fms‐related tyrosine kinase 3, interleukin 15, phosphoinositase‐3‐kinase, and prolactin receptor expression was significantly increased in MatSep (1.45, 1.44, 1.50, 1.65 and 2.07 fold change from CON, respectively; p < 0.05). Renal cortical T‐cell and macrophages as determined by histology was not different between groups. These data suggest that upregulation of immune cell activation preceeds the development of MatSep‐induced cardiovascular and renal disease.1F32 HL116145; P01 HL69999Grant Funding Source: 1F32 HL116145; P01 HL69999
Chronic placental ischemia alters expression of placental and fetal insulin‐like growth factor proteins in the rat (1085.12)
Authors: Beasley Kara , Needham Karen , Regal Jean , Lovering Andrew , Gilbert Jeffrey 
Published: June 2021

Preeclampsia is often characterized by placental ischemia and dysregulation of angiogenic growth factors such as IGF and is a major cause of low birth weight and preterm deliveries. These offspring are at increased risk for chronic diseases such as bronchopulmonary dysplasia (BPD), a hypoplastic lung disease defined by preterm birth and neonatal O2 therapy. While O2 therapy and preterm birth clinically define BPD, current models of BPD employ hyperoxia in normally grown term neonates without considering the role of low birth weight and altered fetal endocrine milieu. To that end, we hypothesized chronic placental ischemia would decrease expression of insulin like growth factors (IGF) I and II and related proteins in placental and fetal tissues. Chronic placental ischemia was achieved using the reduced uterine perfusion pressure (RUPP; n 蠅7) model of preeclampsia and fetal growth restriction. Normal pregnant (NP; n 蠅8) rats served as controls and tissues were collected on day 19 of gestation. Placental IGF‐I was decreased in RUPP compared to NP (89.8 ± 10.9 vs. 133.0 ± 13.1ng/ml, p<0.05). Conversely, amniotic fluid IGF‐I (0.25 ± 0.04 vs. 0.16 ± 0.02pg/ml, p<0.05) and IGF‐II (62.7 ± 8.2 vs. 42.0 ± 5.5 pg/ml, p<0.05) were increased in RUPP vs. NP. Fetal hepatic IGF‐2 was increased in RUPP (155.6 ± 12.6 vs. 117.0 ± 6.3pg/ml, p<0.05). Finally, fetal lung IGF‐IRα was not different between the groups. These data indicate chronic placental ischemia alters expression of IGF proteins in placental and fetal tissues and could alter the developmental trajectory of programming susceptible organs such as the lung and kidney.Grant Funding Source: Supported by NIH RO1HL114096 and AHA 10SDG2600040
Synergy of high salt and high fat diet on kidney injury and adiposity (1086.1)
Authors: Jin Chunhua , MacDonell Robert , Speed Joshua , Pollock David 
Published: June 2021

The western‐style diet is a major risk factor for impaired kidney function and chronic kidney disease. The goal of the present study was to determine the relationship of high salt and high fat diet on kidney injury and adiposity. Male Sprague Dawley rats were placed on one of four specific diets for two weeks: (1) Vehicle (control, 0.4% NaCl); (2) high fat (HF, 36% fat); (3) high salt (HS, 4% NaCl); (4) high fat/high salt (HF/HS, 36% fat, 4% NaCl). At the end of the two‐week treatment, rats were placed in metabolic cages for 24 hour urine collection. HS treated rats had significantly higher protein excretion in compared to HF and HF/HS groups (HS: 35.8±6.7, HF: 11.8±1.9, HF/HS: 14.6±2.6 mg/day, p<0.05). Additionally, the HS group had significantly larger kidneys than control and HF groups (HS: 0.35±0.01, control: 0.30±0.01, HF: 0.29±0.01 g/100 g bwt, p<0.05). Furthermore, HF fed rats had significantly higher epididymal fat to body weight ratio than control or HS or HF/HS diet groups (HF: 0.75±0.05, control: 0.59+0.03, HS: 0.49±0.03, HF/HS: 0.60±0.04 g/100 g bwt, p<0.05). The HF diet is hypercaloric compared to the HS or control diet and so animals consumed less food when on the HF diet. In summary, a high fat consumption attenuated the effects of a high salt diet on renal hypertrophy and damage. In addition, a high salt diet appears to reduce high fat induced adiposity. These findings demonstrate a surprising synergy between these two aspects of the Western diet, fat and salt.Grant Funding Source: PO1 HL‐95499
Resistance arteries from normally‐reared and maternal separation rats display similar vascular reactivity (1087.3)
Authors: Fox Brandon , Loria Analia , Pollock Jennifer 
Published: June 2021

We previously reported that MatSep (3 hours/day from days 2‐14) induces exaggerated angiotensin II (AngII)‐induced vasoreactivity with decreased nitric oxide (NO) buffering capacity in aortae of adult rats compared to control rats (normally‐reared littermates). Also, chronic AngII infusion produced exaggerated hypertension in MatSep rats. The aim of this study was to investigate whether MatSep male and female rats display exaggerated vascular reactivity of resistance arteries. Third‐order mesenteric arteries from adult rats (n=5‐6 per group) were isolated and mounted on wire myographs. Concentration‐response curves were generated for phenylephrine or endothelin and normalized to maximal potassium chloride‐induced constriction. Additionally, we tested acetylcholine and sodium nitroprusside‐induced relaxation. No differences in EC50 or %maximum constriction/dilation were observed between MatSep and control rats. Curves in the presence of L‐NAME revealed similar NO buffering capacity in MatSep and control rats. No sex differences were observed across the study. These data suggest that the abnormal vascular phenotype due to MatSep involves large conduit arteries, sparing smaller resistance arteries. However, resistance arteries are known to play an important role in blood pressure control, and thus, further investigation of these arteries in response to chronic AngII infusion is warranted.Grant Funding Source: Supported by NIH Grants: P01 HL69999, K99 HL111354
Changes in vascular reactivity caused by angiotensin II in heart resistance vessels and isolated vessels of rat aorta in a model of hypertension (1088.1)
Authors: Lopez‐Calderon Emilio , Acevedo‐Villavicencio Nallely , Guevara‐Balcazar Gustavo , Hong‐Chong Enrique , Castillo‐Hernandez Maria 
Published: June 2021

Hypertension is a disease with high morbidity and mortality and is considered one of the main etiological factors of multiple pathologies. One of the regulatory mechanisms of blood pressure is the Renin Angiotensin System (RAS), so much so that the first‐line drugs in the treatment of hypertension are directed to some of the components of the RAS. One therapy that has been shown clinically to improve the condition of patients with hypertension is hyperbaric oxygenation (HBO). HBO has been shown to improve vascular smooth muscle relaxation. The aim of this study is analyze the effect of HBO on the RAS. Methods: hypertension was induced in male Wistar rats. Hypertensive rats received HBO and at the end of the treatment were sacrificed getting heart, thoracic and abdominal aorta; and then they were placed in an isolated organ system where we made concentration response curves to Ang II. Conclusion:HBO therapy reduces the reactivity in coronary resistance arteries under Ang II stimulation and reduced vascular reactivity in both segments of the hypertensive rat aorta. This suggests that HBO could possibly be used with hypertensive patients to reduce the use of drugs in therapy.Grant Funding Source: COFAA / IPN
Molecular mechanisms associated to reversion of proteinuria by RAS antagonists in renovascular hypertensive rats (1088.4)
Authors: Correa Jose , Girardi Adriana , Salles Thiago , Boaro Karoline , Loredo Felipe , Yogi Alvaro , Callera Glaucia , Touyz Rhian , Bendhack Lusiane , Krieger Jose 
Published: June 2021

The present work aimed to compare the effects of monotheraphy versus combined therapy of enalapril and losartan and investigate the mechanisms by which these antihypertensive agents revert proteinuria in 2K‐1C hypertensive rats. To this end, male Wistar rats were subjected to 2K‐1C surgery or sham‐operation (2K). After six weeks, rats were treated with losartan (30mg/Kg/day), enalapril (20mg/Kg/day), losartan+enalapril (20+30mg/Kg/day) or saline by gavage for 14 days. Systolic blood pressure (SBP, mmHg) was higher in 2K‐1C (247±5) than in 2K (129±2, P<0.0001). Losartan (197±6, P<0.05) and enalapril (205±7, n=8, P<0.05) progressively reduced 2K‐1C SBP, with an additional hypotensive effect in the group treated with both drugs (173±16mmHg, P<0.001). Plasma levels of Ang II and TBARS were similar in 2K and 2K‐1C rats and were not changed by the treatments. Albuminuria was remarkably increased in 2K‐1C control rats when compared to 2K control rats. Treatment of 2K‐1C rats with losartan and enalapril similarly reduced albumin excretion when compared to the untreated 2K‐1C. A more pronounced reduction of albuminuria was observed in rats treated with combined therapy. Lucigenin‐derived chemiluminescence was not different in the right and left kidneys of 2K and 2K‐1C rats. Treatments had no effect upon NADPH oxidase activity. The expression of glomerular proteins, including nephrin and podocin, and of proximal tubular protein such as megalin and the Cl/H+ exchanger ClC‐5 were much lower in 2K1C compared to 2K. Treatment with enalapril or losartan partially reverted whereas combined therapy completely restored the expression levels of nephrin and podocin. Taken together, these results suggest that the antiproteinuric effects induced by RAS inhibitors in 2K‐1C rats does not involve inhibition of ROS, but is associated with normalization of the expression of nephrin and podocin in the glomeruli.Grant Funding Source: Supported by FAPESP, CAPES, CNPq, CIHR and Heart and Stroke Foundation of Canada.
Endothelium‐targeted deletion of Nox4 attenuates hypoxia‐induced increases in right ventricular pressure (1089.19)
Authors: Sutliff Roy , Kleinhenz Jennifer , Ma Jing , Hart C. 
Published: June 2021

The complex pathobiology of pulmonary hypertension (PH) involves reactive oxygen species (ROS) and increased pulmonary vascular resistance. NADPH oxidase 4 (Nox4) has been shown to be an important source of ROS in PH, and systemic administration of a Nox4 pharmacological inhibitor attenuated hypoxia‐induced PH. To further explore the role of pulmonary vascular Nox4 in hypoxia‐induced PH, a floxed Nox4 mouse model was crossed with mice that: 1) express Cre recombinase driven by the tie‐2 promoter to target deletion of endothelial Nox4 (eNox4), or 2) express Cre recombinase driven by the smooth muscle myosin heavy chain promoter to target deletion of smooth muscle Nox4 (smNox4). Littermate controls, eNox4 and smNox4 mice were exposed to normoxia (21% O2) or hypoxia (10% O2) for 3 weeks. PH development was assessed by measuring right ventricular systolic pressures (RVSP) and right ventricular hypertrophy (RVH). Hypoxia‐induced increases in RVSP were attenuated in the eNox4 model (N=5; p<0.05) whereas the RVSP in smNox4 knockout mice was not different than controls. In contrast, hypoxia‐induced RVH was no different than controls in either the eNox4 or smNox4 mice. These studies suggest that endothelial Nox4 promotes pulmonary vascular derangements involved in PH pathogenesis.Grant Funding Source: Supported by VA Merit Review 1I01BX001910 (CMH) and NIH grant R01 HL102167 (CMH and RLS).
Augmentation area index: a novel approach to disease severity and outcome in patients with WHO group I and group III pulmonary hypertension (1089.2)
Authors: Shterental Sebastian , Alam Mian , Bachman Timothy , Corotto Paul , Gupta Shikha , Longhini Anthony , Nguyen Daniel , Sciurba Frank , Simon Marc , Champion Hunter 
Published: June 2021

Background: Pulmonary hypertension (PH) has a poor outcome overwhelmingly related to right ventricular (RV) failure. Augmentation area index (AI) could capture hemodynamic effects of vessel stiffening on this processes. We studied AI’s relationship to other hemodynamic measures and to clinical outcomes.Methods: This is a retrospective, exploratory clinical and hemodynamic data analysis of PH patients diagnosed with idiopathic pulmonary arterial hypertension (IPAH) or chronic obstructive pulmonary disease (COPD) who were catheterized at UPMC Presbyterian Hospital from 1/1/2006 to 3/26/2012. AI was calculated in a blinded fashion from RV pressure wave‐forms using validated image analysis software. We used linear regression to study the relationships between AI and hemodynamic parameters, multiple regression to study the primary outcome of time to death or transplantation, and logistic regression to study secondary outcome of being World Health Organization functional category 1 or 2 versus 3 or 4.Results: Clinical and hemodynamic data were analyzed for 63 patients. Mean age was 56.3 years (SD 15.0) and 67% were female. There was a positive correlation between AI and PVR (R2=.16 t=2.85 p=0.007) and a negative correlation between AI and CI (R2=.07, t=‐2.04, p=0.046). When adjusted for calcium channel blocker treatment and pulse pressure, AI was a significant predictor of time to death or transplant (R2=0.67, F(3,16)=11, p<.001). Logistic regression testing of AI as the primary predictor of clinical function adjusted for systemic hypertension, tobacco use, prostacyclin treatment, body‐surface area and peripheral vascular resistance, yielded an odds ratio of 1.12 (p=.001, partial p= 0.014).Conclusion: In patients with different etiologies of PH, AI could be a significant predictor of clinical outcome. A novel approach to the pulmonary system, it correlates with other hemodynamic values previously shown to be significant markers of disease progression.Grant Funding Source: NIH TPPG