bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 618: Dietary Omega-3 Fatty Acid Compete With Arachidonic Acid For The Formation Of Physiologically Active Cyp-eicosanoids In Man
Authors: Konkel Anne , Fischer Robert , Mehling Heidrun , Kast Petra , Schroeder Christoph , von Schacky Clemens , Rothe Michael , Luft Friedrich C. , Schunck Wolf-Hagen
Published: July 2021

Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA; 20:4 n-6) regulate vascular, renal, and cardiac function. However, the same CYP isoforms that metabolize AA also accept eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3) as alternative substrates, suggesting that the profile of physiologically active CYP-eicosanoids can be modulated
in vivo
by changing the dietary fatty acid composition. After we proved this hypothesis in rodents, we now expanded our studies to humans. The trial included 10 healthy men and 10 women aged 18 to 45 years (EudraCT: 2009-013458-33). They ingested 1 Omacor® capsule (480 mg EPA + 360 mg DHA) daily for the first 4 weeks, and two capsules daily in the subsequent 4 weeks, followed by 8 weeks of wash-out. Fatty acids and CYP-dependent metabolites were determined in blood and urine samples by gas chromatography and LC-MS/MS, respectively. The Omega-3 Index (% EPA + DHA of total fatty acids in red blood cells) increased from 4.98±0.80 to 8.03±1.06 at week 8 (p <0.001 vs. week 0), and declined to 6.33±1.44 at week 16. Concomitantly, the plasma CYP-epoxyeicosanoid index, defined as the ratio of EPA- plus DHA- vs. AA-derived epoxymetabolites ((EEQs+EDPs)/EETs), increased almost 3-fold from 0.83±0.05 to 2.35±0.17 (p <0.001; week 0 vs. week 8), and declined to 1.58±0.53 at week 16. In urine, the corresponding hydrolysis products were detectable and their ratio increased from 1.57±1.19 to 4.74±2.61 after 2g Omacor
®
, and returned to baseline (1.38±0.75) after cessation of supplementation. Among the individual regioisomeric epoxymetabolites, AA-derived 14,15-EET predominated at baseline but was clearly exceeded by the EPA-derived 17,18-EEQ after EPA/DHA supplementation (3.24±0.26 vs.1.88±0.22 at week 0 and 2.96±0.24 vs. 6.15±0.43 ng/ml plasma at week 8). The plasma level of DHA-derived 19,20-EDP increased from 1.23±0.11 at week 0 to 2.52±0.19 at week 8. These results demonstrate that the human CYP-eicosanoid profile is highly susceptible to changes in dietary fatty acids. In particular, EPA/DHA supplementation promotes the formation of 17,18-EEQ that we previously identified as a candidate for mediating vasodilatory and antiarrhythmic effects of omega-3 fatty acids.
Abstract 637: Hydrogen Sulfide Acts on Endothelial Cells to Elicit Dilation.
Authors: Kanagy Nancy L , Osmond Jessica M , Jackson-Weaver Olan , Walker Benjimen R
Published: July 2021

Hydrogen sulfide (H
2
S), produced by the enzyme cystathionine-γ lyase (CSE), dilates arteries by hyperpolarizing and relaxing vascular smooth muscle cells (VSMC) and CSE knock-out causes hypertension and endothelial dysfunction showing the importance of this system. However, it is not clear if H
2
S-induced VSMC depolarization and relaxation is mediated by direct effects on VSMC or indirectly through actions on endothelial cells (EC). We reported previously that disrupting EC prevents H
2
S-induced vasodilation suggesting H
2
S might act directly on EC. Because inhibiting large-conductance Ca
2+
-activated K
+
(BK
Ca
) channels also inhibits H
2
S-induced dilation, we hypothesized that H
2
S activates EC BK
Ca
channels to hyperpolarize EC and increase EC Ca
2+
which stimulates release of a secondary hyperpolarizing factor. Small mesenteric arteries from male Sprague-Dawley rats were used for all experiments. We found that EC disruption prevented H
2
S-induced VSMC membrane potential (
E
m
) hyperpolarization. Blocking EC BK
Ca
channels with luminal application of the BK
Ca
inhibitor, iberiotoxin (IbTx, 100 nM), also prevented NaHS-induced dilation and VSMC hyperpolarization but did not affect resting VSMC
E
m
showing EC specific actions. Sharp electrode recordings in arteries cut open to expose EC demonstrated H
2
S-induced hyperpolarization of EC while Ca
2+
imaging studies in fluor-4 loaded EC showed that H
2
S increases EC Ca
2+
event frequency. Thus H
2
S can act directly on EC. Inhibiting the EC enzyme cytochrome P
450
2C (Cyp2C) with sulfaphenazole also prevented VSMC depolarization and vasodilation. Finally, inhibiting TRPV4 channels to block the target of the Cyp2C product 11,12-EET inhibited NaHS-induced dilation. Combined with our previous report that CSE inhibition decreases BK
Ca
currents in EC, these results suggest that H
2
S stimulates EC BK
Ca
channels and activates Cyp2C upstream of VSMC hyperpolarization and vasodilation.
Abstract 639: Blood Pressure Response To Patterns Of Weather Fluctuations And Effect On Mortality
Authors: Robb Louise A , Jeemon Panniyammakal , Hastie Claire E , McCallum Linsay , Morrison David , Walters Matthew , Dawson Jesse , Sloan William , Meredith Peter , Jones Gregory C , Muir Scott , Dominiczak Anna F , McInnes Gordon T , Padmanabhan Sandosh
Published: July 2021

Background:
Very few studies have looked at longitudinal BP changes in relation to weather variation. There is no data to suggest that specific BP response to changes in weather have an impact on survival.

METHODS:
We analysed >169000 clinic visits of 16000 Glasgow BP Clinic hypertensive patients. Each clinic visit was mapped to the mean West of Scotland monthly weather (temperature, sunshine, rainfall) from meteorological data. Analyses were restricted to pairs of consecutive clinic visits where the weather alternated between two extreme quartiles (Q1->Q4 or Q4->Q1) or remained in the same quartile (Qn->Qn) of each weather parameter. The BP phenotype analysed was the percent change in SBP and DBP between two consecutive clinic measurements at least 30 days apart and within each year. The %ΔBP between groups were tested using paired-T tests. Subjects were categorised into two groups depending on Q1->Q4 or Q4->Q1 BP response compared to Qn->Qn (concordant or discordant). Generalised estimating equations and Cox proportional hazards model were used to model the effect on longitudinal BP and mortality respectively.

Results:
For temperature, visits Qn->Qn showed a mean 2% drop in BP consistently while Q4->Q1 showed a mean 4% rise in SBP and Q1->Q4 elicited variable changes in BP around 0. Compared to subjects with a concordant BP response to temperature, those who showed a discordant response had significantly higher mortality (1.35 [95% CI :1.06-.71];p=0.01) and higher follow-up SBP (1.85 [0.24-3.46]; p=0.02).

Conclusions:
Variation in weather has a complex relationship to longitudinal BP and response to weather fluctuations is a predictor of long-term risk and BP control.
Abstract 662: Perivascular Adipose Tissue-derived Prostaglandins Constrict Vessel
Authors: Chang Lin , Villacota Luis , Dou Chunyan , Chen Eugene , Zhang Jifeng
Published: July 2021

Background:
Perivascular adipose tissue (PVAT) is associated with reduced response to vasoconstricting agents in the murine vasculature and also in human small arteries, and this anti-contractile effect is reduced in subjects with metabolic syndrome. However, it was suggested that other vasoconstrictors released from PVAT such as leptin or Angiotensin II causes vasoconstriction, suggesting that PVAT has contractile properties as well. Here we show that prostaglandins and adrenalin signaling derived from PVAT contribute to contractile properties of PVAT.

Results:
The effect of donor PVAT on the vascular tone was evaluated in carotid, thoracic and mesenteric arteries using a myograph chamber in which the PVAT surrounding the tested vessel was completely removed. Fifteen mg of minced PVAT (size of ∼1 mm
3
) from donor C57BL/6J mice into the myograph chamber results in mild vasoconstriction (1.52±0.6mN) on carotid artery rings. This contractile property of PVAT is effective on vessel rings obtained from the thoracic aorta and mesenteric artery as well. PVAT from leptin knockout mice used as a donor causes vasoconstriction similar to that of wild-type mice (1.55±0.5mN leptin knockout vs. 1.52±0.6mN C57BL/6J mice). Pre-incubation of vessel rings with increasing concentrations of nonspecific COX inhibitor (10
-9
M to 10
-6
M indomethacin) inhibits PVAT-induced constriction in a dose-dependent manner (1.55±0.7mN, 1.41±0.6mN, 1.23±0.5mN, 0.95±0.4mN, 0.56±0.6mN, respectively), suggesting that PVAT-derived prostaglandin are responsible for vascular constriction. Similarly, pre-incubation with alpha-adrenergic receptor antagonists blocks PVAT-dependent vasoconstriction. Carotid artery responses to a series of 10
-7
M phenylephrine (PE) addition/wash out (5x) experiments in the myograph chamber cause alpha-adrenergic desensitization. However, in the presence of donor PVAT, carotid arteries have preserved maximal contraction after 5 rounds of PE addition/wash out experiments.

Conclusion:
Our studies indicate that PVAT-derived prostaglandins rather than leptin or other adipokines cause vasoconstriction and reduce vascular alpha-adrenergic desensitization.
Abstract 69: Requirement of Rac1 in Pressure Overload-induced Cardiac Remodeling, and Role of Mineralocorticoid Receptor as a Downstream Pathway
Authors: Ayuzawa Nobuhiro , Nagase Miki , Ueda Kohei , Ishizawa Kenichi , Takeuchi Maki , Kawarazaki Wakako , Yoshida Shigetaka , Fujita Toshiro
Published: July 2021

A Rho family GTPase, Rac1, has emerged as an important molecule involved in cardiac remodeling. Some studies demonstrated the requirement of Rac1 in angiotensin II-induced cardiac hypertrophy and diabetic cardiomyopathy in association with generation of reactive oxygen species (ROS). However its role in pressure overload-induced cardiac remodeling is still unclear. On the other hand, we previously reported that Rac1 can activate mineralocorticoid receptor (MR) in cultured cardiomyocytes. Here we demonstrate the requirement of Rac1 in pressure-overload cardiac remodeling, and putative role of MR as a downstream pathway of Rac1. First, we performed sham or transverse aortic constriction (TAC) surgery in C57BL/6 mice, and examined the effect of Rac1 inhibitor (
NSC23766
) and MR blocker (eplerenone). After 7 weeks, TAC caused severe hypertrophy and dysfunction of left ventricle with significant increase in active form of Rac1. In addition, the amount of MR protein in nuclear fraction, and the expression of some target genes of MR (including serpina3n and serpine-1) in left ventricle were also increased by TAC.
NSC23766
significantly reduced the TAC-induced activation of Rac1, and both
NSC23766
and eplerenone attenuated cardiac hypertrophy and dysfunction, along with inhibition of MR signaling. Furthermore, TAC significantly increased ROS production in left ventricle, which was also attenuated by both of the pharmacological interventions. We next generated cardiomyocyte-specific heterozygous Rac1-deficient mice (Rac1
CM +/−
) and littermate wild-type mice (WT), and performed Sham or TAC surgery. The TAC-induced hypertrophy and dysfunction of left ventricle were significantly suppressed in Rac1
CM +/−
compared with WT (heart/body weight ratio: 6.4 ± 0.86 vs 10.8 ± 0.81 mg/g, ejection fraction 54.1 ± 6.5 vs 33.3 ± 7.3 %, p < 0.05), with inhibition of Rac1 activation. Nuclear translocation of MR protein and increases in expression of the target genes of MR were also significantly attenuated in Rac1
CM +/−
compared with WT. These results indicate that Rac1 plays an essential role in the maladaptive cardiac hypertrophy induced by pressure overload, and that MR is an important downstream pathway of Rac1 in heart.
Abstract 76: Intra-Placental Gene Transfer of Human Insulin-Like Growth Factor-1 Prevents Obesity in an Intra- Uterine Growth Restricted Model Exposed to High Fat Diet Postnatally
Authors: Omar Khaled R , Jones Helen , Balaji Swathi , Nam Young , Kil Kitcheol , Leung Alice , Keswani Sundeep , Crombleholme Timothy , Habli Mounira
Published: July 2021

We have shown that mesenteric uterine artery ligation in mice significantly reduces fetal birth weight (IUGR) and increases risk of adult onset of hypertension and obesity, which are all reversed by adenoviral mediated hIGF1 (Ad hIGF1) intraplacental gene transfer. We hypothesized that intraplacental Ad hIGF1 in IUGR mice prevents adult onset of obesity even when challenged with environmental stress as fat diet. Laparotomy was done at day 18 on pregnant C57BL/6J mice and divided into 3 groups (n= 16). Control: Sham operated; IUGR: birth weight <10% for gestational age; Treated: IUGR+IGF-1. Pups were delivered on day 20, cross fostered to CD1 mice, sorted by gender at 4 weeks. At 8 weeks, high fat diet (45% fat) was introduced and mice were followed up to 24 weeks. Body weight, fat pad, fasting serum leptin and food consumption were measured. Data analyzed by Chi-square or ANOVA and stratified by sex Compared to sham, IUGR significantly decreases birth weight, which is restored to normal in IUGR+IGF-1(1.12± .1 vs 0.9± .1 vs 1.09± .1 g, p=0.001). Mean body weight differences among the groups persist till 8 weeks. By 14 weeks, male IUGR mice had significant weight gain(obese) compared to sham and treatment groups (fig A). Same trend was seen in female IUGR at 18 weeks. Total fad pad weights were significantly higher in IUGR compared to SHAM, restored to normal in IUGR+IGF-1 (fig B). Compared to sham, IUGR significantly increases fasting serum leptin, restored to normal in IUGR+IGF-1 (2.4±0.2 vs 7.9±1.5 vs 3.4±0.4 pg/ug, p= .01) Our results demonstrate that intraplacental gene transfer with Ad-hIGF-1 reprograms the IUGR fetus and attenuates the risk of adult onset of obesity under environmental stress
Abstract 89: Enhanced TP Sensitivity and HO-dependent CO Release Mediates H2O2-Induced Vasoconstriction and Dilation: A Response Affected by Antioxidants
Authors: Puri Nitin , Zhang Fan , Monu Sumit Ranjan , Zhang Yilun , Abraham Nader G , Nasjletti Alberto
Published: July 2021

Hydrogen peroxide (H2O2) is a non-radical oxidant and is employed to ascertain the role of redox mechanisms in regulation of vascular tone. Where both dilation and constriction have been reported in response to this oxidant; we examined the hypothesis that the ability of H2O2 to affect vasoconstriction or dilatation is conditioned by redox mechanisms and may be amenable to modulation by antioxidants. Freshly isolated rat renal interlobular (RIA) or mesenteric (MA) arteries were used for investigation of the effect of H2O2 on their internal diameter (ID), in the absence or presence of antioxidants including, tempol, PEG-SOD, BHT and biliverdin (BV). In arteries without antioxidant pretreatment, H2O2 (1.0 and 10.0 μM) reduced (p< 0.05) the ID of RIA (90.0±0.6 to 85.0±1.9 and 71.6±1.4 μm, respectively) and MA (90.4±2.3 to 85.0±2.1 and 74.2±1.8 μm, respectively); a response obliterated by all antioxidants used (p<0.05). However, in contrast to tempol and PEG-SOD, antioxidants targeting lipid peroxides and OH. (BHT, BV) not only blocked constriction but also uncovered vasodilation in response to H2O2 (91.3±2.5 to 95.2±2.4 and 102.5±2.8 μm, with BHT), which was also endothelium dependent [Δ ID- BHT+H2O2 (10 μM): 11.85±0.73 vs. in endothelium denuded: 0.80±0.49 μm, p<0.05]. Without enhancing vascular TxB2 synthesis (2.01±0.72 vs. 1.87±0.41 ng/mg/hr) H2O2 caused vasoconstriction which was blocked (p<0.05) by inhibitors of the COX-TXA2 pathway (indomethacin, SQ29548). However, H2O2 treatment sensitized the arteries to a TP agonist- U46619 (EC50: 0.63±0.07 vs. 0.17±0.08 nmol/l, in arteries without and with H2O2, respectively), an effect reversed by PEG-SOD pretreatment. The dilatory response to H2O2 was accompanied by enhanced vascular heme oxygenase (HO)-dependent CO generation (BHT: 157.2±19.9 vs. BHT+H2O2: 301.25±25.3, p<0.05 and BV: 162.6±17.3 vs. BV + H2O2: 255.9±19.9, p<0.05 as opposed to tempol: 135.0±19.9 vs. tempol + H2O2: 125.3±18.6 pmol/mg/hr) and was abolished (p<0.05) by either an inhibitor of HO or in RIA from animals treated with HO-1& 2 AS-ODN. These results demonstrate that H2O2 has antioxidant-modifiable pleotropic vascular effects brought about by enhanced TP sensitivity to constrictor agonist(s) or dilatory HO-derived products.
Abstract 101: Cardiac Deleterious Role of Galectin-3 in Chronic Angiotensin-II Induced Hypertension
Authors: González Germán E , Rhaleb Nour-Eddine , Yang Xiao- P , Carretero Oscar A
Published: July 2021

We previously described that chronic infusion with Angiotensin II (Ang II) increases cardiac Galectin-3 (Gal-3) expression, a carbohydrate-binding lectin present on macrophages. Also, Gal-3 was proposed to be a powerful predictor for mortality in patients with heart failure. Nevertheless, the role of Gal-3 in the pathogenesis of end organ damage (EOD) in hypertension is unknown. Here, we hypothesized that in Ang II-induced hypertension, genetic deletion of Gal-3 prevents innate immunity, EOD, and left ventricular (LV) dysfunction. Male C57 and Gal-3 KO mice were infused with vehicle (V) or Ang II (90 ng/min; s.c.) for 8 weeks and divided into: 1) C57 + V; 2) Gal-3 KO + V; 3) C57 + Ang II and 4) Gal-3 KO + Ang II. Systolic blood pressure (SBP) was measured by plestimography weekly. At 8 week, we evaluated 1) LV ejection fraction (EF) by echocardiography; 2) cardiac hypertrophy by LV weight/tibia length; 3) cardiac fibrosis by picrosirius red staining; 4) infiltrated macrophages by CD68+ staining; 5) ICAM-1 protein expression by Western blot; and 6) serum interleukin (IL)-6 by ELISA. We found that despite a similar increase in SBP and LV hypertrophy in both strains on Ang II, Gal-3 KO mice had better reserved EF and decreased inflammatory and fibrotic responses (see Table).

Results:
(MEAN ± SEM at 8 w)

*p<0.05 C57+Ang II and Gal-3 KO+Ang II vs C57+V; ‡ p<0.05 Gal-3 KO+Ang II vs C57+Ang II.

Conclusion:
In Ang II-induced hypertension, deletion of Gal-3 prevents EOD and LV systolic dysfunction without altering blood pressure and LV hypertrophy. This study indicates that the deleterious effects of Ang II could be in part mediated by Gal-3, which enhanced inflammation and fibrosis.
Abstract 156: Angiotensin Ii Regulates Hematopoietic Stem Cell Proliferation, Differentiation, and Engraftment Efficacy
Authors: Kim Seungbum , Scott Edward W , Raizada Mohan K
Published: July 2021

INTRODUCTION:
Emerging evidence indicates that differentiation and mobilization of hematopoietic stem cell (HSC) are critical in the development and establishment of hypertension-linked vascular pathophysiology. This, coupled with the intimate involvement of a hyperactive renin-angiontensin system in hypertension, led us to propose the hypothesis that chronic angiotensin II (Ang II) infusion would regulate HSC proliferation and differentiation at the bone marrow level.

METHODS:
1) Ang II was chronically infused into C57BL6 mice using mini-osmotic pumps (1500ng/kg/min) for 3 weeks. This resulted in an increase in MAP of 45mmHg. Bone marrow, peripheral blood and splenocytes from control and Ang II-treated mice were analyzed using FACS. 2) 0.5-3 X10
4
GFP
+
Sca-1
+
, c-Kit
+
, Lin
-
(SKL) HSC were pre-incubated with Ang II for 24h
in vitro
(100μg/ml), rinsed and injected into lethally irradiated C57BL6 mice. Donor derived GFP
+
cells were analyzed by FACS and histology to evaluate engraftment efficiency.

RESULTS:
We observed a 32% decrease of HSCs in the bone marrow of Ang II treated mice. In addition, there was an 29-52% increase in the number of CX3CR1+/Gr-1- monocyte in the peripheral blood and spleen. These changes in HSC and myeloid cells were blocked by co-treatment of Losartan (60mg/kg/day, ip injection). Next, we investigated if Ang II affects HSC homing and engraftment efficacy, which are critical steps in successful bone marrow transplantation. We observed a significant delay of the homing GFP+ SKL cells that were pre-treated with Ang II in lethally irradiated recipient mice. In addition, the SKL cells treated with Ang II failed to efficiently engraft to the innate osteoblastic niche. Consistent with this observation, colony formation unit-Spleen (CFU-S) in the Ang II infused recipients was reduced to 65% compared to control mice.

CONCLUSION:
These observations demonstrate that hypertension induced by chronic Ang II infusion significantly impairs the engraftment ability of HSC in the bone marrow, which appears to be mediated by the AT1R on HSC and that Ang II accelerates HSC differentiation into myeloid lineage. These multifaceted roles of Ang II indicate that Ang II acts as an important regulator of HSC in the bone marrow.
Abstract 158: Role of Prorenin Receptor in the Enhancement of Renin Activity in the Urine of Diabetic Patients
Authors: Arita Danielle Y , Luffman Christina , Bourgeois Camille T , Thethi Tina , Dawkins Gabrielle , Jaimes Edgar , Satou Ryousuke , Prieto Minolfa C
Published: July 2021

High prorenin levels in the circulation are associated with the progression of diabetic nephropathy and microvascular changes in diabetes. In spite of high plasma prorenin, the urine of diabetes mellitus patients exhibits very low pH and contains high levels of “active” renin, but low levels of prorenin. Prorenin binding to the prorenin receptor (PRR) results in non-proteolytic activation of prorenin and stimulation of intracellular synthesis of transforming growth factor-beta (TGF-β). Furthermore, the PRR cytosolic domain is associated with the vacuolar H+-ATPase, which is involved in acid-base homeostasis by renal intercalated cells. In diabetes, the collecting duct is the major source of prorenin and PRR is upregulated in the kidneys of diabetic rats. We examined the relationships among urine levels of renin (uRen), prorenin (uPro), soluble PRR (sPRR) and TGF-β (uTGF-β) in 93 subjects, including non-diabetes mellitus (Non-DM: n=64); and type-2 diabetes mellitus (DM; n=29) patients. Urine albumin (uAlb), creatinine (uCr) and pH were also assessed. DM patients showed higher uRen levels (DM: 81±21 vs Non-DM: 29±4.5 ng AngI/mL/hr; p<0.001), which were positively associated with uAlb/uCr (p<0.05, r=0.21) and inversely correlated with urine pH (p<0.01, r=-0.38). These values contrasted with uPro levels, which were no different between groups. DM patients showed increased uTGF-β compared to Non-DM (DM: 22±5.3 vs Non-DM: 5.6±1.5 pg/mg uCr; p<0.0001). Urine sPRR levels were positively correlated with urine pH (p<0.0001, r=0.56). No differences were observed in sPRR plasma and urine levels between non-DM and DM patients. However, the plasma levels of sPRR were 12.5 and 18.5-fold higher than in urine of Non-DM and DM, respectively. Treatment with RAS blockers increased sPRR in plasma (DM with RAS blockade: 24,455±2,151 vs DM without RAS blockade: 17,726±1,255 pg/mL, p<0.001) but not in urine. These data suggest that the cell membrane-bound PRR, not the soluble form, might be responsible for the increases in renin activity and TGF-β, as well as in the low pH in the urine of type-2 DM patients. It is likely that prorenin-mediated activation of membrane bound PRR promotes diabetic nephropathy by increasing urinary formation of TGF-β.
Abstract 169: Stable Nitric Oxide Metabolites Levels and Their Relation to the Metabolic Syndrome Components in Essential Hypertension
Authors: Murashko Natalia , Podzolkov Valery , Bragina Anna
Published: July 2021

Objective:
To investigate levels of the stable nitric oxide metabolites (NOx) in relation to components of the metabolic syndrome (MS) in essential hypertension (EH)

Methods:
We examined 124 untreated patients with EH (mean age 51.4 ± 6.5 years, mean hypertension duration 8,5±7,6 years) and 25 healthy volunteers with comparable age (47.2 ± 7.8 years, p>0,05). Plasma leptin levels were measured by radioimmunoassay, plasma NOx - by spectrophotometry. Results were processed with Statistica 6.0 software.

Results:
Visceral obesity had 64% of hypertensive patients, dyslipidemia - 80.6%, hyperglycemia - 41,6%, MS - 24%. In 32% the MS diagnosis was based on the presence of two additional criteria, in 68% - on three. NOx levels were significantly higher in hypertensives (43,18±21, μmol/l) than in controls (28.3 ± 9.6 μmol/l) (
p
= 0.01). In patients with hyperglycemia NOx concentration was higher (46,5 ± 23,9 μmol/l) than in those without it (38,6±18, μmol/l)(p<0,05). NOx levels correlated with blood glucose levels (r=0,32, p<0,05). NOx concentration did not differ between hypertensives with or without dyslipidemia (43,2±22,2 and 42,05±21,1 μmol/l, accordingly p>0,05). Nonobese hypertensives had lower NOx concentration than obese hypertensives (38,8±17,9 and 48,5±24,7 μmol/l, p<0,05). NOx levels correlated with the presence (r=-0,44, p<0,05) and degree of obesity (r=-0,3, p<0,05). NOx levels were lower in patients with MS (31,6±11,3 and 47,05±20,7 μmol/l, p<0,05). NOx levels decreased with the increase of additional MS criterias: 37,99 ± 12,6 μmol/l in the presence of 2 and 28,3 ± 9,6 μmol/l in the presence of 3 criteria (p<0,05). NOx levels correlated with the amount MS components (r=-0,38, p<0,05). Hypertensives with high leptin levels had lower NOx concentration (29 ± 12,2 μmol/l), compared to hypertensives with normal leptin levels (34,7±10,5 μmol/l) (p<0,05).

Conclusion:
In essential hypertension NOx metabolism differs in relation to metabolic status. Hypertension per se and hyperglycemia increase NOx levels, whereas MS and its essential signsas visceral obesity and high plasma leptin level decrease NOx levels.
Abstract 173: Modulation of the Metabolic Effects of Leptin by the Brain Renin-Angiotensin System
Authors: Claflin Kristin E , Hilzendeger Aline M , Sigmund Curt D , Grobe Justin L
Published: July 2021

Genetic deletion or delivery of antagonists of the renin-angiotensin system (RAS) directly to the brain abolishes both renal and adipose sympathetic nervous activity (SNA) responses to leptin, suggesting a cross-talk between these central cardiovascular / metabolic control systems. To further explore this mechanism of cross-talk, we examined the sensitivity of metabolic responses in mice with transgenic hyperactivity of the brain RAS (“sRA” mice) to acute leptin treatment. sRA mice, previously shown to exhibit hypertension, polydipsia, and elevated SNA and resting metabolic rate, exhibit brain-specific RAS hyperactivity through neuronal expression of human renin via the synapsin promoter and expression of human angiotensinogen via its own promoter. When housed at standard room temperature (23°C), twice-daily leptin injections (1 mg/kg, i.p., 3 hrs into light phase and 2 hrs preceding dark phase of a 12:12-hr cycle) caused significant and similar reductions in body mass (control -0.76±0.13, n=5 male; sRA -0.65±0.09 g/d, n=5 male, P=0.46) and food intake (-1.43±0.69 vs -1.99±0.27 kcal/d, P=0.63) in littermate control and sRA mice. When housed at thermoneutrality (30°C) in an OxyMax (Columbus Instruments) CLAMS apparatus, leptin injections had minimal effects on total daily food intake in control mice (from 7.4±0.6 at baseline to 8.1±0.5 kcal/d with leptin, n=4 male + 4 female, P=0.29), but reduced food intake in sRA mice (from 8.3±0.7 to 6.0±0.4 kcal/d, n=4 male + 4 female, P=0.003). sRA mice were more sensitive to leptin’s suppressive effect on physical activity (control from 998±148 to 655±90, P=0.10; sRA from 1232±304 to 588±41 counts/d, P=0.005). Unexpectedly, leptin had a suppressive effect upon metabolic rate in sRA mice (control from 16.4±1.3 to 16.8±0.9, P=0.44; sRA from 20.2±1.1 to 17.5±0.9 kcal/kg lean/hr, P<0.001). Together, these data support a cross-talk between the brain RAS and leptin signaling in the control of metabolic function. These data suggest a complex and context-dependent mechanism of interaction between leptin and brain angiotensin, with gross alterations in leptin-induced food, physical activity, and metabolic rate responses when tested in a thermoneutral environment.
Abstract 185: Transient Neonatal High Oxygen Exposure Leads to Cardiac Dysfunction and Renin Angiotensin System Activation in Rats
Authors: Bertagnolli Mariane , Huyard Fanny , Cloutier Anik , Sutherland Megan , Lukaszewski Marie-Amélie , Paradis Pierre , Schiffrin Ernesto L , deBlois Denis , Nuyt Anne M
Published: July 2021

Preterm infants are exposed to high oxygen (O2) pressure (relative to intrauterine levels) leading to systemic oxidative stress and impaired vascular development; as children and adults, preterm born subjects have higher blood pressure. In rats, high O2 exposure induces vascular dysfunction, in part mediated by the renin angiotensin system (RAS). However, impact of neonatal high O2 exposure on heart development and whether RAS activation prevails in the heart is unknown. We aimed to assess early heart alterations and activation of RAS after neonatal high O2 exposure.

METHODS AND RESULTS:
Sprague-Dawley pups were kept with their mother in 80% O2 (O2, n=8) or room air (Ctrl, n=8) from days 3-10 of life. Hearts were extracted at day 3 (pre O2-exposure, P3), day 5 (during, P5), 10 (after, P10) and 4 wks to assess myocardium hypertrophy (HE), fibrosis (Masson’s trichrome) and RAS components gene expressions by RT-PCR. Echocardiography was performed at 4 weeks to assess heart function. RAS components mRNA expression in O2 vs Ctrls shows up-regulation of AT1a and ACE2 genes at P5 (AT1a: 152±28 vs 58±16/ACE2: 140±20 vs 77±6% of P3) and P10 (AT1a: 374±35 vs 250±30 /ACE2: 326±70 vs 208±18% of P3) relative to values at P3. With age, AT1b and AT2 expressions decrease in Ctrls, whereas are maintained in O2-exposed rats to values similar to P3 (Ctrl vs O2, P5: AT1b: 18±5 vs 71±12/AT2: 48±20 vs 120±16; P10: AT1b: 33±9 vs 105±26/AT2: 27±8 vs 77±7% of P3). At P10, cardiomyocyte surface area is increased in O2 vs Ctrls (4.9±0.2 vs 2.9±0.1 μm2). At 4 wks, O2 group show increased fibrosis (49±4 vs 29±2 % pixels), left ventricular (LV) cavity diameter (3.6±0.2 vs 3.0±0.1 mm) and systolic dysfunction by decreased fraction of shortening (39±2 vs 47±2 %). AT1b gene expression (2.6±1.7 vs 0.3±0.2) is increased and AT2 receptor (7.5±0.9 vs 6.0±0.6) is decreased in O2 group vs Ctrl.

CONCLUSION:
Neonatal O2 exposure activates RAS in hearts. AT1 receptor is up-regulated at all ages studied in O2-exposed rat hearts while AT2 is up-regulated at P5 and P10. At 4 wks, AT1/AT2 imbalance prevails in O2 group hearts along with LV dysfunction and enhanced fibrosis and hypertrophy. RAS activation by neonatal O2-exposure might significantly impact in heart development and programming of cardiac dysfunction in rats.
Abstract 189: Toll-like Receptor 2 Blockade Decreases Contractility in Angiotensin II-induced Hypertensive Rat Resistance Arteries
Authors: Hardigan Trevor , Sepulveda Maria-Alicia , Pedrosa Nunes Kenia , Webb R. Clinton
Published: July 2021

Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system that recognize endogenous damage-associated molecular patterns (DAMPS). TLR2 plays a role in cardiovascular diseases such as atherosclerosis and heart failure, but its role in hypertension is unknown. Angiotensin II (ANG), the effector molecule of the renin-angiotensin system, has been shown to cause an immune response leading to an inflammatory profile, in addition to its effects on vascular tone and sodium balance. We hypothesized that signaling through TLR2 in ANG-induced hypertension contributes to an increase in resistance artery contractility and vascular dysfunction. Sprague-Dawley rats were implanted with osmotic mini-pumps dispensing ANG (60 mg/day) for a 28 day period. Systolic blood pressure (measured directly via femoral canulation to confirm the ANG rats as a model of hypertension) was significantly increased in the ANG-treated rats (170 ±4.79 mmHg) vs. control (97 ±6.9 mmHg (p<0.05)). Concentration response curves to norepinephrine (NE; 10-9-10-4 M) were performed in second and third order mesenteric arteries from control and angiotensin-treated rats. Vessels were pre-incubated with and without antibody to TLR2 (1μg) for 35 minutes prior to the concentration-response curves to determine the impact of TLR2 blockade. The EMax (force of contraction as % of maximum KCl response) of the ANG vessels treated with anti-TLR2 was significantly lower than that of the ANG vessels alone (EMax: 129.2±10.69% vs 183.8±16.73%, respectively), and comparable to control-vessel levels (EMax in control vessels: 135.1±4.360%, p<0.05). Additionally, we sought to determine protein levels of TLR2 and downstream signaling protein MyD88 in the mesenteric arteries. In the arteries from the ANG treated animals, TLR2 expression was significantly increased 2.95±0.20 fold above control, and MyD88 expression was increased 1.35±0.06 fold above control (p<0.05). This suggests that TLR2 signaling leads to augmented contractility and is associated with the vascular dysfunction observed in hypertension.
Abstract 20: Endothelial αEnac Subunit is Involved in Shear Stress Sensing and Endothelium Stiffness In Vivo
Authors: Tarjus Antoine , Jeggle Pia , Fassot Céline , El Moghrabi Soumaya , Oberleitner Hans , Henrion Daniel , Kusche-Vihrog Krisitna , Jaisser Frédéric
Published: July 2021

The Epithelial Sodium Channel (ENaC) is a key actor in renal sodium homeostasis. The expression of α β γ ENaC subunits has been shown in the endothelium and vascular smooth muscle, suggesting a role in vascular function. We recently demonstrated that endothelial ENaC is involved in aldosterone-modulated endothelial stiffness. It has been proposed that ENaC may act as a mechanosensor, as a member of the degenerin channel family acting as sensors in C. elegans. We hypothesized that the endothelial αENaC subunit is involved in shear stress sensing in the vascular tree. We used mice with conditional αENaC subunit gene inactivation in the endothelium only (Endo-αENaC Knock Out mice) and their controls. Renal function was explored using metabolic cages. Vascular reactivity was assessed by pressure myograph in mesenteric arteries. Endothelial stiffness was analyzed by Atomic Force Microscopy (AFM) in open aortic rings. Renal function and sodium excretion (in basal state and after 1 mM NaCl acute challenge) were not affected, indicating that endothelial ENaC is not involved in sodium balance. Endothelial stiffness was decreased in aorta by acute incubation with benzamil (15min, 1μM) and by the absence of αENaC expression in the endothelium (Cortical stiffness; WT 0.9±0.15, WT Benzamil 0.6±0.10, KO 0.6±0.12, KO Benzamil 0.6±0.11 pN/nm). Ex vivo vascular contraction induced by phenylephrine and potassium chloride were not modified in Endo-αENaC Knock Out mice, nor the vasodilatory response to acetylcholine. Myogenic tone was also similar between the two groups. However, a striking difference was observed regarding flow-mediated vasodilation that is blunted in Endo-αENaC Knock Out mice. Similar results were observed after acute ex vivo benzamil (1μM) treatment in WT mesenteric arteries. In aorta, phosphorylation of eNOS, Akt and Myosin Light Chain were increased in Endo αENaC KO mice as compared to WT (1.00±0.3 vs 2.28±0.2, 1.00±0.1 vs 1.58±0.3, 1.00±0.3 vs 1.65±0.2). Our results demonstrate that the αENaC subunit in endothelial cells is part of the flow-sensing machinery in the vessel. We also showed that in vivo ENaC inhibition (using genetic or pharmacological approaches) reduces endothelial stiffness. Whether these two findings are linked remain to be explored.
Abstract 221: Sympathetic and Metabolic Consequences of Deleting the Insulin Receptor from Proopiomelanocortin Neurons
Authors: Muta Kenjiro , Morgan Donald A , Bell Balyssa B , Rahmouni Kamal
Published: July 2021

Hypothalamic insulin receptor (IR) signaling has been implicated in the regulation of energy homeostasis and sympathetic nerve activity (SNA). Recent studies demonstrated that the sympathetic action of insulin emanates from the hypothalamic arcuate nucleus (ARC). However, the specific neuronal population within the ARC that mediates the sympathetic effect of insulin is unknown. We hypothesized that proopiomelanocortin (POMC) neurons of the ARC which contain the insulin receptor (IR) are critical for the increases in SNA in response to insulin. To test this, we generated mice lacking the IR specifically in POMC neurons (IRΔPOMC mice) by crossing the IRflox/flox mice with POMCCre mice. First, we visualized POMC promoter-driven Cre recombinase expression by crossing POMCCre mice with tdTomato reporter mice. tdTomato fluorescence was detected mainly in the ARC and overlapped with staining for β-endorphin (a POMC proteolytic product). As previously reported, body weight of IRΔPOMC mice (at 12 weeks of age: 23±1 g, n=8) was not significantly different (p=0.21) from littermate controls (25±2 g, n=8). There was also no significant difference in fat pad weights (brown adipose tissue, peri-gonadal and peri-renal) between IRΔPOMC mice and littermate controls. Next, we used direct multifiber nerve recording to assess the sympathetic effects of insulin. In wild type mice, intracerebroventricular (ICV) administration of insulin (100 μU) caused a robust increase in lumbar SNA (202±36%, n=7). Surprisingly, genetic deletion of the IR from POMC neurons by loxP-Cre recombination did not alter the sympathetic response as indicated by the comparable (p=0.24 vs. littermate controls) increase in lumbar SNA in the IRΔPOMC mice in response to ICV insulin (264±40%, n=7). Ongoing studies are aimed to determine whether deletion of the IR from POMC neurons interferes with the ability of insulin to increase SNA subserving tissues other than the hindlimb. We conclude that insulin receptor signaling in POMC neurons does not mediate the lumbar sympathetic nerve activation evoked by insulin.
Abstract 28: Formation of Podocyte-Derived Microparticles in Diabetic Glomerular Injury
Authors: Burger Dylan , Thibodeau Jean-Francois , Holterman Chet , Burns Kevin D , Kennedy Christopher R
Published: July 2021

Hypertension is a significant cause of progressive kidney disease, particularly in the presence of diabetes. Under such conditions, increased glomerular capillary pressure subjects podocytes, specialized glomerular epithelial cells critical to filtration, to mechanical stress resulting in podocyte injury/dysfunction. Microparticles (MPs) are small (0.1-1.0 μm), membranous vesicles shed from the cell surface following injury. However, whether podocyte MP formation reflects glomerular injury is unknown. We examined MP formation by podocytes in vitro and in vivo. Conditionally immortalized human podocytes were exposed to 10% equibiaxial cyclic stretch (a mimic of increased intraglomerular pressure), high glucose (HG, 25 mM), mannitol (osmotic control), angiotensin II (Ang II, 500 nM) or transforming growth factor beta (TGF-β, 5 ng/mL). Additionally, urinary podocyte MPs were quantified in two mouse models of diabetic kidney disease: streptozotocin (STZ) and OVE26. MPs were characterized by nanoparticle tracking analysis and quantified by Annexin V (total MPs) or podocalyxin (podocyte MPs) labeling and flow cytometry. Podocyte-derived vesicles were identifiable in both media and urine samples with a mean size of 236 nm by nanoparticle tracking analysis. In vitro, cyclic stretch was associated with a 3-fold increase in MP release after 24 hours (P<0.01, n=6). HG increased MP release 5-fold after 24 hours (P<0.05, n=6). Mannitol had no effect on MP formation by either normal or stretched podocytes and neither Ang II, nor TGF-β altered podocyte MP formation over 24 hours. In vivo, both models of diabetes displayed typical hallmarks of renal injury (proteinuria, mesangial expansion). In OVE26 mice urinary podocyte MPs were elevated compared with their wild-type littermates (17479±8329 vs. 7 ±7, P<0.05, n=5-7). Similarly, STZ-treated mice displayed increased urinary podocyte MPs as compared with untreated (18035±3813 vs. 43±34, P<0.001, n=9-18) and urinary MPs levels were positively correlated with albuminuria (r2=0.74, P<0.01). Our results suggest that podocytes produce MPs which are released into urine and are indicative of glomerular injury. Such processes may be mediated by intraglomerular capillary pressure and hyperglycemia.
Abstract 286: Acute Toll-like Receptors 4 Activiation by Lipopolysaccharide Attenuates Afferent Arteriolar Autoregulatory Behavior
Authors: Van Beusecum Justin P , Cook Anthony K , Zhang Shali , Goulopoulou Styliani , Guan Zhengrong , Inscho Edward W
Published: July 2021

Pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) activate toll like receptors (TLRs) that stimulate the innate immune system. Immune system activation is linked to blunted renal autoregulatory behavior. Lipopolysaccharide (LPS), a component of the bacterial wall of gram-negative bacteria, is a ligand for TLR4. Preliminary experiments indicates that TLR4 protein expression is increased approximately by 28% (n=2) in small intrarenal arteries after 4 hours of acute LPS treatment versus control. Accordingly, we hypothesize that acute LPS treatment blunts afferent arteriolar autoregulatory behavior through TLR4 activation. Rats received a bolus injection of LPS (1mg/kg I.P.) and kidneys were harvested 4 hours later for juxtamedullary nephron studies. At a perfusion pressure of 100 mmHg, baseline arteriolar diameters in LPS treated kidneys averaged 11.9 ± 0.5μm (n=15) compared to 14.5 ± 0.7μm (n=14) in untreated controls (P < 0.05). Autoregulatory behavior was assessed in these same groups by increasing perfusion pressure in 15 mmHg increments from 65 to 170 mmHg. In control kidneys, afferent arteriolar diameter decreased by 29 ± 5 % (n=6) as perfusion pressure increased from 65 to 170 mmHg. In LPS treated kidneys, afferent arteriolar diameter actually increased by 3 ± 8% (P < 0.05; n=7) over the same pressure range, indicating marked blunting of pressure-induced vasoconstriction. P2 receptors have been implicated in autoregulatory resistance adjustments. Therefore, we assessed afferent arteriolar responsiveness to P2 receptor activation
in vitro.
In control kidneys, log concentrations of ATP (10
-8
- 10
-4
mol/L) reduced arteriolar diameter by 4 ± 1, 10 ± 2, 17 ± 4, 26 ± 5, and 32 ± 5% respectively (P < 0.05; n=8). In LPS treated kidneys, ATP reduced arteriolar diameter similarly by 6 ± 1, 11 ± 2, 15 ± 3, 18 ± 4, and 21 ± 5% respectively (P < 0.05; n=8). No significant difference in afferent arteriolar reactivity to ATP was found between the two groups. These data support the hypothesis that TLR4 activation by acute LPS treatment attenuates afferent arteriolar autoregulatory behavior. Accordingly, these data may open novel therapeutic approaches for prevention of inflammatory kidney disease.
Abstract 300: Targeted Deletion of Matrix Metalloproteinase 2 Prevents Angiotensin II-Induced Endothelial Dysfunction and Vascular Remodeling, Oxidative Stress and Inflammation
Authors: Barhoumi Tlili , Mian Muhammad Oneeb Rehman , Rehman Asia , Idris-Khodja Nourredine , Paradis Pierre , Schiffrin Ernesto L
Published: July 2021

Background:
Matrix metalloproteinase 2 (MMP2) is involved in vascular remodeling in atherosclerosis. Whether MMP2 plays a role in angiotensin (Ang) II-induced hypertension, vascular remodeling, oxidative stress and inflammation is unknown. We hypothesized that
Mmp2
knockout will prevent Ang II-induced vascular injury.

Methods:
Ten to 12-week-old male
Mmp2
knockout (

Mmp2
-/-

) and wild type (WT) mice were infused with Ang II (1000 ng/kg/min, sc) for 14 days. Systolic blood pressure (SBP) was measured by telemetry. Mesenteric arteries (MA) were studied by pressurized myography. NADPH oxidase activity was evaluated by lucigenin chemiluminescence, and aortic reactive oxygen species (ROS) generation using dihydroethidium staining. Aortic expression of vascular cell adhesion protein 1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1), and monocyte/macrophage infiltration were assessed by immunofluorescence. Spleen T cells and monocytes were assessed by flow cytometry.

Results:
Ang II increased SBP by 50 mmHg (
P
<0.01), decreased vasodilatory responses to acetylcholine by 70 % (
P
<0.01), induced MA hypertrophic remodeling, indicated by a 1.5-fold increase (
P
<0.01) in media-to-lumen ratio and 1.3-fold increase (
P
<0.05) in media cross-sectional area, and enhanced MA stiffness (
P
<0.01), as shown by a leftward shift of the stress/strain relationship, in WT mice. Ang II increased NADPH oxidase activity 1.4-fold in aorta (
P
<0.05), 2-fold in the heart (
P
<0.01) and 2.6-fold in the renal cortex (
P
<0.01) and aortic ROS generation 25-fold in WT mice (
P
<0.01). Ang II increased aortic VCAM-1 and MCP-1 expression 3- and 6-fold, respectively, and monocyte/macrophage infiltration 8-fold in WT (
P
<0.05). Ang II increased ≥1.8-fold spleen activated CD4
+
CD69
+
and CD8
+
CD69
+
T cells and pro-inflammatory Ly-6C
hi
monocytes (
P
<0.001) in WT mice.
Mmp
knockout prevented or reduced all of the above except SBP elevation (
P
<0.05).

Conclusion:
MMP2 plays a role in Ang II-induced endothelial dysfunction, vascular remodeling, oxidative stress and inflammation but not in blood pressure elevation.
Abstract 301: Nebivolol Attenuates Prooxidant and Profibrotic Mechanisms and Decreases Vascular Remodeling in Renovascular Hypertension
Authors: Ceron Carla S , Rizzi Elen , Guimaraes Danielle A , Martins-Oliveira Alisson , Gerlach Raquel F , Tanus-Santos Jose E
Published: July 2021

Nebivolol and metoprolol are β1-adrenergic receptor blockers with different properties. We hypothesized that nebivolol, but not metoprolol, could attenuate prooxidant and profibrotic mechanisms of hypertension vascular remodeling. Hypertension was induced in male Wistar rats by clipping the left renal artery. Six weeks after surgery, hypertensive and sham rats were treated with nebivolol (Nebi 10 mg/kg/day), metoprolol (Meto 20 mg/kg/day) or vehicle for four weeks. Systolic blood pressure was monitored weekly. Morphologic changes in the aortic wall were studied in picrosirius red sections. Aortic NAD(P)H activity was evaluated by luminescence. Nitrotyrosine staining was evaluated to assess peroxynitrite formation by immunohistochemistry. TGF-β and matrix metalloproteinase-9 (MMP-9) levels were determined by immunofluorescence, and p-ERK 1/2 expression by western blotting. Both β1-receptor antagonists exerted very similar antihypertensive effects (156 ± 8 mmHg and 151 ± 9 mmHg, respectively, versus 206 ± 7 mmHg in hypertensive controls; both P<0.05). However, while metoprolol had no significant effects, nebivolol significantly (all P<0.05) attenuated vascular collagen surface (237944 ± 59567, 69784 ± 17686, 183215 ± 30338 μm2, respectively, in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups), attenuated hypertension-induced increases in aortic NAD(P)H oxidase activity (253887 ± 13712, 143765 ± 15642, and 232465 ± 14352 AU, respectively in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups), in nitrotyrosine levels (166.3 ± 2.9, 145.3 ± 1.5, 172.1 ± 7.3 AU, respectively, in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups), in TGF-β upregulation (7.2 ± 0.12, 6.5 ± 0.03, 7.0 ± 0.3 AU, respectively, in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups) and in MMP-9 levels (18.27 ± 0.8, 12.73 ± 0.4, 15.76 ± 1.4 AU, respectively in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups). No effects on p-ERK 1/2 expression were found with both drugs (P>0.05) (1.0 ± 0.16, 0.92 ± 0.15, 0.87 ± 0.37 AU, respectively, in the 2K1C, 2K1C+Nebi, and 2K1C+Meto groups). These results show for the first time that nebivolol, but not metoprolol, attenuates prooxidant and profibrotic mechanisms involving TGF-β and MMP-9, which promote vascular remodeling in hypertension.