bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 285: Reduced Parasympathetic Activity and Correlation with Plasma Resistin Levels in High Fat Diet Mice
Authors: Hartnett Sigurd , Li Yifan 
Published: July 2021

A trait of most cardiovascular diseases, obesity, and aging is autonomic imbalance with increased sympathetic and decreased parasympathetic activity. While the hyperactive sympathetic nervous system has been extensively researched, little attention has been given to the mechanisms involved in the reduction of the parasympathetic nervous system. This study investigates the peripheral regulation of the parasympathetic nervous system and its association with plasma resistin levels in a high fat diet mice model of obesity.
Male ICR mice were fed a high fat diet (HFD) or low fat diet (LFD) for 14 weeks. At the end of the diet regimen, mice underwent vagal stimulation (VS) tests and were sacrificed for blood and tissue collection. For VS, under anesthesia of intraperitoneal injection with urethane (2 g/kg), the right cervical vagus nerve was stimulated at 2 to 10Hz with pulses of 2ms and 2V while the heart rate was monitored with ECG. The reduction of heart rate by VS was significantly attenuated at 10Hz in HFD mice as compared to LFD mice (-121.3 beats per minute, 95% Confidence Interval [CI] -178 to -64.63, p<0.05, n=5 both groups). To evaluate the contribution of adipokines and cytokines to this reduced parasympathetic response, serum was tested using commercially available kits for resistin, adiponectin, TNFa, and IL6. Whereas no changes were observed in plasma adiponectin, TNFa, or IL6 levels, there was an significant increase in plasma resistin levels in HFD mice as compared to LFD mice (837 pg/mL, 95% CI 294-1379, p<0.01, LFD n=5, HFD n=4). Furthermore, a Pearson product-moment correlation coefficient was calculated to assess the relationship between plasma resistin level and responses in heart rate to VS. There was a strong positive correlation between these two variables (r=0.851, n=8, p<0.01). The molecular mechanisms responsible for the effects of resistin on the cholinergic, parasympathetic system are currently being investigated.
In summary, these results suggest that elevated plasma resistin levels may contribute to a reduction in parasympathetic nervous system activity associated with obesity.
Abstract 320: Gata5 Null Mice: A New Genetic Model Of Low-Renin Salt-Sensitive Hypertension
Authors: Messaoudi Smail , Gutsol Alex , Hébert Richard L , Nemer Mona 
Published: July 2021

GATA5, a transcription factor of the GATA family, is expressed in the kidney where its function is unknown. In mice, inactivation of GATA5 leads to a cardiac hypertrophy similar to that observed in hypertension. We hypothesized that GATA5 in the kidney may participate in blood pressure (BP) regulation.
Blood pressure was measured by tail-cuff in 3-5 month old GATA5 null (G5-KO) mice and their Wild-type (Wt) littermates. Systolic BP was higher in G5-KO mice when compared to Wt in both males (143±4 vs 122±3 mm Hg, p<0.001, n=14-15) and females (137±2 vs 117±3 mm Hg, p<0.001, n=11-12). High salt diet (8% NaCl for 6 weeks) further increased BP in G5-KO mice (p<0.05) but not in Wt. Under regular diet, there were no changes in water consumption (Wt: 4.0±0.2 ml/24h; vs KO-G5: 4.1±0.1 ml/24h) and urine excretion (Wt: 1.3±0.1 ml/24h; vs KO-G5: 1.1±0.1 ml/24h). Aldosterone urinary concentration was unchanged (Wt: 16.8±2.0 pmol/24h; vs KO-G5: 16.9±1.2 pmol/24h) as well as urinary and plasmatic electrolytes (Na+, K+, Cl-) concentrations. We determined that GATA5 was mainly expressed in the proximal tubule. Expression of genes coding proteins involved in sodium reabsorption in that segment (or others) was either unchanged (NHE3, NKCC2 and aENAC) or decreased (αNaK-ATPase -15% p<0.05; βENaC -21% p<0.01) in G5-KO mice. Renin expression was also decreased by 40% (p<0.05). In contrast, renal expression of pro-inflammatory genes was increased in G5-KO mice (MCP1 +155% p<0.005, PAI1 +90% p<0.01, RANTES +95% p<0.01) but the number of macrophages (assessed by F4/80 immunostaining) in kidney was not different and Masson’s trichrome staining revealed no fibrosis. In contrast, periodic acid Schiff staining showed glomerular hypercellularity in KO-G5 mice (p<0.05). Older G5-KO mice (10 months) exhibited more severe lesions: focal segmental glomerulosclerosis with mesangial cell proliferation, glomerular basement membrane thickening and accumulation of mesangial extracellular matrix.
In summary, G5-KO mice are characterized by hypertension, salt sensitivity and glomerular lesions. They represent a new genetic model to study low-renin hypertension (which affects up to 25% of the hypertensive population) and for which the underlying mechanisms remain incompletely understood.
Abstract 334: Selective Pharmacological Kinin Receptor Activation Restores Postischemic Neovascularisation And Hindlimb Perfusion In Diabetic Mice
Authors: Desposito Dorinne , Potier Louis , Chollet Catherine , Gobeil Fernand , Roussel Ronan , Bouby Nadine , Alhenc-Gelas Francois , Waeckel Ludovic 
Published: July 2021

Limb ischemia (LI) is a major complication of several cardiovascular diseases. Hyperglycaemia worsens LI by impairing neovascularisation. Genetic or pharmacological inactivation of the kallikrein-kinin system aggravates LI experimentally while ACE/kininase II inhibition improves its outcome. We assessed whether direct, selective and potent pharmacological activation of kinin receptors, B1 or B2, can have therapeutic effect in mice with LI.
The selective B1 receptor agonist SarLys[Hyp3,Igl5,DPhe8]desArg9-bradykinin (B1-ago) or the selective B2 agonist [Hyp(3),Thi(5),(N)Chg(7),Thi(8)]-bradykinin (B2-ago) were administered by osmotic micropumps (30 nmole/kg.h-1) for 14 days after unilateral femoral artery ligature in mice previously rendered diabetic by streptozotocin. Comparison was made with ligatured, non-agonist treated normoglycaemic (normo) and hyperglycaemic (control-hyper) mice.
Chronic administration of B2-ago had no effect on blood pressure, like B1-ago. B1-ago or B2-ago similarly restored the impaired neovascularisation process in diabetic mice as assessed by microangiography [angiographic score, ischemic/non-ischemic hindlimb ratio (R) 0.99±0.13, 0.60±0.06, 1.09±0.13 and 0.99±0.07 in normo, control-hyper, B1-ago and B2-ago respectively, n=10/group, p<0.01] and by histological capillary density analysis (R: 1.2±0.2, 0.68±0.04, 1.7±0.1, and 1.8±0.1, p<0.01). Both treatments increased blood flow in the ischemic hindfoot measured by laser doppler perfusion imaging (R: 0.62±0.05, 0.47±0.03, 0.76±0.04, 0.69±0.03 in normo, control-hyper, B1-ago and B2-ago respectively, p<0.01).
VEGF content in the ischemic gastrocnemius muscle increased 2 fold (p<0.05) during B1-ago or B2-ago treatment and macrophage infiltration 3 fold (p<0.01). Both treatments increased (0.5 to 1 fold, p<0.05) circulating CD45/CD 11b-positive monocytes and CD34/VEGFR2 endothelium or bone marrow derived progenitor cells but not other bone marrow derived progenitors.
Thus, selective pharmacological activation of either B1 or B2 receptor restores postischemic neovascularisation and tissue perfusion in hyperglycaemic mice. This effect involves mobilisation of macrophages and enhanced VEGF synthesis.
Abstract 409: Reproducibility of White Coat and Masked Hypertension Definitions One Year after the Diagnosis
Authors: DE LA SIERRA ALEJANDRO , BANEGAS JOSE R , VINYOLES ERNEST , GOROSTIDI MANUEL , SEGURA JULIAN , DE LA CRUZ JUAN J , RUILOPE LUIS M 
Published: July 2021

A significant number of subjects present discordant results when BP is measured both at the clinic and by 24-hour ABPM. The aim of the study was to assess the reproducibility of a diagnosis of normotension (NT), white coat hypertension (WCH), masked hypertension (MH) and sustained hypertension (SH) in a cohort of untreated subjects who underwent a second ABPM without being treated with antihypertensive drugs.
From the Spanish ABPM Registry, we selected 843 untreated subjects who underwent at least 2 BP examinations (both at the clinic and by ABPM) separated by 2 months or more (median,IQR: 13; 6-28 months), and who did not receive antihypertensive drug treatment in the period lasting between the 2 examinations. The 4 above mentioned categories were defined by normal (<140/90 mmHg) or elevated BP at the clinic (mean of 2 measurements), and by normal (<130/80 mmHg) or elevated 24-hour BP.
At baseline, 140 (17%), 206 (25%), 78 (9%), and 414 (49%) had NT, WCH, MH, and SH, respectively. At the 2nd clinic and ABPM examination 52% of NT, 55% of WCH, 47% of MH, and 82% of SH fall into the same category. In both the WCH and MH categories, the most frequent switch was to SH (26% and 33%, respectively). When patients who changed or remained in the same category were compared, there were no differences in clinical variables, such as age, gender, or prevalence of obesity, diabetes, or previous cardiovascular disease. Both clinic and ambulatory BP were higher in patients who fall into the same category in both examinations, but this was driven by the higher reproducibility of SH. In the specific group of WCH (206 patients) there were no significant BP differences at baseline between the 114 who maintained such diagnosis, compared to the 54 patients who developed SH. Conversely, in the 78 patients with MH at baseline, those who developed SH at the 2nd examination (26) had higher levels of clinic diastolic BP (84±4 vs. 80±5 mmHg; p=0.006), compared with those who remained with MH (37).
In conclusion, the diagnosis of SH is highly reproducible after one year of the first diagnosis. However, a diagnosis of WCH or MH requires a close follow-up, as almost 50% of patients do not show the same diagnosis and develop SH. There is no a specific clinical pattern which can be of help to predict which patients will develop SH.
Abstract 454: Plgf Mediates A Neuroimmune Interaction In The Spleen To Allow The Onset Of Hypertension
Authors: Carnevale Daniela , Pallante Fabio , Fardella Valentina , De Lucia Massimiliano , Fardella Stefania , Iacobucci Roberta , Lembo Giuseppe 
Published: July 2021

In the past several years, there has been mounting interest in the roles played by immunity in hypertension, an health problem affecting over 1 billion people worldwide. An emerging area of investigation revealed that adaptive immunity is a central player of hypertension, since mice devoid of T lymphocytes were protected from AngII-induced hypertension. However, how hypertensive stimuli like AngII can afford this, is still enigmatic.
Here we found an unprecedented splenic neuroimmune pathway driven by Placental Growth Factor (PlGF) during hypertension. The hypertensive response induced by chronic AngII infusion (28days) was completely prevented in PlGF KO mice (WT AngII 140±2 vs PlGF KO AngII 103±3 mmHg), as well as the typical end organ damage and immune cells infiltration. To determine whether the involvement of PlGF had a causal role or was merely a consequence of the failure in BP raise, we analyzed vessels and kidney early after AngII infusion (3days), before BP increase (WT AngII 108±3 vs PlGF KO AngII 105±1), finding that PlGF absence already protected from T cells infiltration. We also uncover that the splenic PlGF is essential for hypertension, through a noradrenergic drive mediated by the celiac ganglion. An intact neuroimmune interaction of the celiac ganglion on the spleen was needed to have PlGF release upon AngII and chimeric mice, generated by spleen transplantation, demonstrated that the ablation of PlGF in the spleen (KO spleen into WT mice) was sufficient to protect from hypertension. At the molecular level, we found that PlGF released in the spleen exerted a repression of the tissue protein of inflammation Timp3 through p53. In particular, while in WT splenocytes the Timp3 transcriptional repressor region was bound by its molecular repressor p53 upon AngII, PlGF KO splenocytes showed the Timp3 repressor region free from p53, as evidenced by ChIP. Finally, we demonstrated that this pathway is necessary to control T cells costimulation, through the regulation of CD86 expression, and allow their deployment toward classical organs involved in hypertension. Overall, we demonstrate that PlGF mediates the neuroimmune interaction in the spleen, organizing a unique and non redundant response that allows and is necessary for the onset of hypertension.
Abstract 546: Arterial Stiffness And Pulse Pressure Predict Kidney Disease Progression In Chronic Kidney Disease
Authors: Townsend Raymond , Bansal Nisha , Chirinos Julio , Cuevas Magdalena , Ford Virginia , Grunwald Juan , Hsu Chi-yuan , Roy Jason , Kallem Krishan , Rahman Mahboob , Chai Boyang , Weir Matthew , Wright Jackson , Feldman Harold I 
Published: July 2021

Brachial pulse pressure (bPP) predicts kidney function in CKD. Pulse wave velocity (PWV) may provide additional prediction of CKD progression, and was evaluated longitudinally in CKD patients enrolled in the CRIC cohort. bPP was used because it shows superior CKD progression prediction in humans.
There were 2821 participants in CRIC who underwent an assessment of PWV most of whom were studied at their second year follow-up visit. Of these 43 % were women, 48% diabetic, mean age 60 years and mean estimated GFR of 44.6 mL/min/1.73m2. Blacks were 40%, whites 44%, and Hispanics 12%. Mean blood pressure was 127/70 mmHg; mean bPP was 54 mmHg. The interaction of PWV with bPP on the occurrence of ESRD (dialysis or a transplant) [left panel of figure] and a combined endpoint of halving of the eGFR or ESRD [right panel], was analyzed used Cox regression. Events by tertiles of PWV (<7.9 msec; 7.9-10.3 m/sec; >10.3m/sec) and bPP (<46 mmHg, 46-62 mmHg, >62 mmHg) are shown in the figure.
There were significant interactions between PWV and bPP for both outcomes. For ESRD the hazard ratio of the highest tertiles of PWV/bPP compared with the lowest was 3.18 (p<0.001). For the combined ESRD or halving of eGFR the HR was 2.65 (p<0.001). In multivariable regression important predictors of CKD progression in this model were age, male gender, non-white race/ethnicity, initial eGFR, and proteinuria.PWV showed a strong and graded interaction with bPP in the prediction of ESRD and the combined outcome of halving of GFR or ESRD. A greater appreciation of the role of arterial stiffness in CKD is an important step towards pursuing the mechanisms underlying how this measure may influence the course of kidney disease progression.
Abstract 632: Vasomera, a Novel VPAC2-Selective Vasoactive Intestinal Peptide Agonist, Improves Arterial Elastance and Ventriculo-Arterial Coupling in Rats with Induced Diastolic Dysfunction via Renoprival Hypertension
Authors: del Rio Carlos L , Ueyama Yukie , Georgopoulos Lynne , Arnold Sue , Hamlin Robert L 
Published: July 2021

Vasomera™ is a first-in-class stable long-acting vasoactive intestinal peptide (VIP) agonist, with preferential actions on the G-protein-coupled VPAC2-receptors; VIP mediates cardiopulmonary regulation and has been proposed as a therapeutic target for both hypertension and systolic dysfunction. Here, the acute effects of Vasomera in load-independent function and ventriculo-arterial coupling were in evaluated in a rats with chronic diastolic dysfunction, mimicking heart failure with preserved ejection fraction (HFpEF).
Diastolic dysfunction, as demonstrated by altered E/A ratios via echocardiography, was induced by renoprival hypertension secondary to renal wrapping (RW). Conditioned rats (n = 5) were instrumented for the determination of left-ventricular (LV) hemodynamics as well as load-independent fnction and ventriculo-arterial coupling (via pressure-volume relationships); data were evaluated before/after a single-dose continuous IV infusion of Vasomera (7.5 μg/kg/min IV).
Vasomera decreased the estimated arterial elastance (Ea: -20 ± 5%, P < 0.05) with negligible changes in heart rate (-4 ± 2%). Improved inotropy (Ees: +28 ± 8% and PRSW: +22 ± 3%, P < 0.05) was observed post-treatment, suggesting improved ventriculo-arterial coupling (Ea/Ees: -37 ± 5%, P < 0.05). Concomitantly, Vasomera reduced filling pressures (EDP: -30 ± 8%, P < 0.05), accelerated the time-constant of relaxation (tau: -24 ± 3%, P < 0.05) and improved compliance (EDPVR: -26 ± 5%, P < 0.05).
Vasomera, a novel VPAC2 agonist, improved arterial elastance and ventriculo-arterial coupling, while improving indices of diastolic function (i.e., lusitropy) in animals with chronic renoprival hypertension mimicking HFpEF.
Abstract 652: dTGR: A New Rat Model For Systemic Hypertensive Retinopathy
Authors: Reichhart Nadine , Haase Nadine , Herrspiegel Christina , Müller Dominik N , Crespo-Garcia Sergio , Skosyrski Sergej , Dechend Ralf , Strauß Olaf 
Published: July 2021

Retinal vascular alterations represent an important but understudied form of microvascular target endorgan damage (TOD). To understand the pathomechanisms underlying hypertensive retinopathy, we used a double transgenic rat model (dTGR) established for TOD, which expresses both the rat and human RAS. Purpose of the study is to assess whether systemic hypertension affects retinal structure and function similar to the characteristic pathology in humans.
We investigated the retinal phenotype by using immunohistochemistry of retinal whole mount preparations or sagittal sections, qPCR as well as functional analysis by Ganzfeld and pattern electro-retinography (ERG).
Whole mount preparations revealed focal avascular areas, pathological vessels with irregularities in shape and diameter as well as neovascular tufts in dTGR rats compared to control animals. In sagittal sections we detected a loss of retinal ganglion cells. GFAP staining revealed activation of astrocytes in the ganglion cell layer (GCL) and astrocytosis of the optic nerve. VEGF-positive staining could be detected in the ganglion cell layer (GCL) and the inner nuclear layer (INL).
To further substantiate the loss of ganglion cells detected in immunohistochemistry and to obtain a correlated functional analysis, pattern ERG were recorded. By using a stimulation with different pattern sizes (15° and 5-7°) at 2.4hz of the black and white checkerboard we showed that the positive component after about 50ms (P50) of the pattern ERG was significantly smaller in dTGR compared to control rats at 5-7° pattern size whereas the P50 at 15° remained unchanged. This indicates a loss of ganglion cells in the retina.
qPCR revealed a non-detectable local renin expression, increase in MCP1 and sFLT1 expression and decrease in the expression of tight-junction proteins claudin-1 and occludin.
Thus we present a first animal model for hypertensive retinopathy showing functional and structural alterations of the retina. Differential gene expression analysis suggests a strong local inflammatory response, loss of the blood/retina barrier and surprisingly low activity of the local renin-angiotensin-system. Further studies are warranted to investigate the local pathomechanisms.
Abstract 047: Genetics and Environmental Influences on Ambulatory Blood Pressure in Rats Compared With Circadian Blood Pressure Variability in Human
Authors: Lee Mary S , Lee John S , Lee Jong Y , Azar Silvia H , Halberg Franz 
Published: July 2021

Genetic susceptibility is an important factor in raising blood pressure (BP). Daily (circadian) rhythm characteristics are considered essential parameters for recognizing and treating increased risks in BP. To examine BP in genetics with environmental modifications, one-cell homozygous embryos were transferred into spontaneously hypertensive (SHR, pup:shr) or normotensive (WKY, pup:wky) rats' oviducts (embryos: s, w; oviduct-uterine: S, W) in a reciprocal fashion. Pups were cross-suckled at birth (nurses S, W) and weaned to normal diets at day-21. At Day-120, telemetered BPs were monitored for 5 consecutive days every 4 min and analyzed by the method of ANOVA. Ambulatory BP in 20 adolescents and adults were monitored automatically around the clock at 30-min to hourly intervals and analyzed by the least square rhythmometry method.
As expected, shr BPs were markedly reduced when they were transplanted to the W-uterine and/or the W-lactation milieu (sSS vs. sSW, sWS and sWW: 197 vs.178, 147 and 178 mm Hg). BP in wky was significantly altered only in the wSW group (wWW vs, wSW: 127 vs.131 mm Hg). All subjects showed significant circadian fluctuations with a peak in the late afternoon hours in most human subjects and rats as a nocturnal animal mostly close to midnight hours, while shr with W-uterine (sWS) a bit delayed peak hour (00:45) and with combined W-uterine/W-nursing (sWW) a bit earlier peak hour (20:12). Circadian double amplitudes (2A) in the human subjects varied from 8 to 26 mm Hg with higher 2A in elder adults, and 3-8 mm Hg in rats with significantly higher fluctuations in shr groups as compared to that of wWW (7.5±0.7 for sSS, 8.3±0.6 for sSW vs. 4.7±0.3 mm Hg for wWW).
The hypertensive-prone shr strain showed significantly lowered BPs in a normotensive WKY uterine environment and/or by WKY nursing mothers, indicating that environment influences can strongly modify genetic factors, yet the lowered shr MESORs by the WKY environments remained above the MESORs encountered in wky donors. Chronomes broader than circadian should be considered in interpreting BP responses as a gauge of vascular disease status.
Abstract 117: NOS1β Mediates the Difference Between Juxtamedullary and Superficial Glomerular Injury with Aging
Authors: Wei Jin , Wang Shaohui , Zhang Jie , Jiang Kun , Yip Kay-Pong , Liu Ruisheng 
Published: July 2021

Renal function measured by glomerular filtration rate (GFR) declines with aging. But the mechanism has not been clarified. Nitric oxide synthase 1 β (NOS1β) is highly expressed in the macula densa (MD) and modulates tubuloglomerular feedback (TGF), which is an important mechanism for GFR regulation. We hypothesized that expression of NOS1β in MD decreases with aging, which enhances TGF response and contributes to the decline of GFR. We further hypothesized that NOS1β expression in superficial (SF) MD is lower than that of juxtamedullary (JM) MD, which contribute to more severe renal injury in renal cortex with aging.
First, GFR was measured by plasma FITC-inulin clearance after a single bolus injection in conscious 12-week young mice and 20-month-old C57/BL6 mice. GFR was reduced by 36.4% in aged mice (236±9.7 vs 150±7.6 μl/min).
Then we compared the glomerular injury in 20-month-old C57/BL6 mice with 12-week mice. The aged mice have significant severed injury compared to the young mice as indicated by injury scores (3.6) and expanded fractional mesangial area (FMA) per glomerulus (26.4%). In addition, injuries were more evident in SF glomeruli with larger FMA (29.3%) than that in JM glomeruli (16.9%). Next we measured NOS1β protein abundance and found that NOS1β protein in aged mice was reduced by 73% compared to young mice. In addition, we compared the NOS1β abundance between SF and JM glomeruli in aged and young mice. NOS1β protein level decreased by more than 90% in SF nephrons in aged mice compared with the young mice. In contrast, there was no significant changes in NOS1β expression in JM nephron between aged and young mice.
To determine whether NOS1β mediates the changes in GFR and renal injury, we repeated the experiments in age matched MD specific NOS1β knock out (MD-NOS1KO) mice. In MD-NOS1KO mice, GFR in aged mice was reduced by 29.5% (203±15.7 vs 143±13.2 μl/min) compared young mice. Aged MD-NOS1KO mice had more severer renal injury compared with age-match wild type mice with higher injury score (4.7 vs 3.6), increased FMA (40.9% vs 26.4%) and occurrence of glomerulosclerosis (GS 30.8% ), but diminished difference between JM glomerulus (FMA37.4%, GS34.1%) and SF glomerulus (FMA42.2%, GS29.7%).