Differential effects of Mas receptor deficiency on cardiac function and blood pressure in obese male and female mice

Angiotensin-(1–7) [ANG-(1–7)] acts at Mas receptors (MasR) to oppose effects of angiotensin II (ANG II). Previous studies demonstrated that protection of female mice from obesity-induced hypertension was associated with increased systemic ANG-(1–7), whereas male obese hypertensive mice exhibited increased systemic ANG II. We hypothesized that MasR deficiency ( MasR−/−) augments obesity-induced hypertension in males and abolishes protection of females. Male and female wild-type ( MasR+/+) and MasR−/− mice were fed a low-fat (LF) or high-fat (HF) diet for 16 wk. MasR deficiency had no effect on obesity. At baseline, male and female MasR−/− mice had reduced ejection fraction (EF) and fractional shortening than MasR+/+ mice. Male, but not female, HF-fed MasR+/+ mice had increased systolic and diastolic (DBP) blood pressures compared with LF-fed controls. In HF-fed females, MasR deficiency increased DBP compared with LF-fed controls. In contrast, male HF-fed MasR−/− mice had lower DBP than MasR+/+ mice. We quantified cardiac function after 1 mo of HF feeding in males of each genotype. HF-fed MasR−/− mice had higher left ventricular (LV) wall thickness than MasR+/+ mice. Moreover, MasR+/+, but not MasR−/−, mice displayed reductions in EF from HF feeding that were reversed by ANG-(1–7) infusion. LV fibrosis was reduced in HF-fed MasR+/+ but not MasR−/− ANG-(1–7)-infused mice. These results demonstrate that MasR deficiency promotes obesity-induced hypertension in females. In males, HF feeding reduced cardiac function, which was restored by ANG-(1–7) in MasR+/+ but not MasR−/− mice. MasR agonists may be effective therapies for obesity-associated cardiovascular conditions. NEW & NOTEWORTHY MasR deficiency abolishes protection of female mice from obesity-induced hypertension. Male MasR-deficient obese mice have reduced blood pressure and declines in cardiac function. ANG-(1–7) infusion restores obesity-induced cardiac dysfunction of wild-type, but not MasR-deficient, male mice. MasR agonists may be cardioprotective in obese males and females.

Download Full-text

Abstract P114: Mas Receptor Deficiency Increases Diastolic Blood Pressure and Reduces Cardiac Function in Obese Female Mice

Hypertension ◽

10.1161/hyp.66.suppl_1.p114 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Yu Wang ◽

Robin Shoemaker ◽

Sean Thatcher ◽

Lisa Cassis

Keyword(s):

Blood Pressure ◽

Cardiac Function ◽

Plasma Concentrations ◽

Reduce Blood Pressure ◽

Left Ventricular ◽

Whole Body ◽

Female Mice ◽

Obese Female ◽

Induced Hypertension ◽

Blood Pressures

Objective: We recently demonstrated that protection of female mice from obesity-induced hypertension was associated with increased plasma concentrations of angiotensin-(1-7) (Ang-(1-7)). Ang-(1-7) is a ligand for Mas receptors (MasR), where the peptide has been reported to promote endothelial release of nitric oxide and reduce blood pressure. In this study, we hypothesized that MasR deficiency will abolish protection of female high fat (HF)-fed mice from the development of obesity-induced hypertension. Methods and Results: Female (8 weeks, C57BL/6) wild type (MasR+/+) and whole body MasR deficient mice (MasR-/-) were fed a HF diet (60% Kcal as fat) for 16 weeks. MasR deficiency had no effect on the development of obesity or glucose intolerance in HF-fed female mice. At week 16 of HF feeding, blood pressure was quantified by radiotelemetry. Deficiency of MasR resulted in a significant decrease in pulse pressures of HF-fed females (24hr average: MasR+/+, 37.7 ± 1.5 mmHg; MasR-/-, 33.1 ± 1.0 mmHg; P<0.05). Diastolic blood pressures (DBP) of HF-fed female MasR-/- mice were modestly elevated during the night cycle compared to controls (DBP night: MasR+/+, 91.5 ± 2.0 mmHg; MasR-/-, 96.6 ± 1.3 mmHg; P=0.06). However, systolic blood pressure, mean arterial pressure and heart rate were not significantly different between genotypes. Assessment of left ventricular function by ultrasound demonstrated significant reductions in stroke volume (MasR+/+, 44.3 ± 1.6 μl; MasR-/-, 36.3 ± 2.1 μl), ejection fraction (MasR+/+, 57.1 ± 1.2; MasR-/-, 50.1 ± 2.7%) and fractional shortening (MasR+/+, 29.7 ± 0.8; MasR-/-, 25.3 ± 1.7%) in HF-fed MasR-/- females compared to controls. Conclusion: These results demonstrate that MasR deficiency promotes elevated diastolic blood pressures and reduced cardiac function in obese female mice, suggesting that the Ang-(1-7)/MasR axis protects females from obesity-hypertension. Moreover, these results suggest that MasR agonists may be effective therapies for obesity-associated cardiovascular conditions.

Download Full-text

The Orphan Receptor GPR35 Contributes to Angiotensin II–Induced Hypertension and Cardiac Dysfunction in Mice

American Journal of Hypertension ◽

10.1093/ajh/hpy073 ◽

2018 ◽

Vol 31 (9) ◽

pp. 1049-1058 ◽

Cited By ~ 4

Author(s):

Nina Divorty ◽

Graeme Milligan ◽

Delyth Graham ◽

Stuart A Nicklin

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Cardiac Function ◽

Knockout Mice ◽

Messenger Rna ◽

Orphan Receptor ◽

Rna Expression ◽

Ang Ii ◽

Wild Type ◽

Induced Hypertension

Abstract BACKGROUND The orphan receptor G protein–coupled receptor 35 (GPR35) has been associated with a range of diseases, including cancer, inflammatory bowel disease, diabetes, hypertension, and heart failure. To assess the potential for GPR35 as a therapeutic target in cardiovascular disease, this study investigated the cardiovascular phenotype of a GPR35 knockout mouse under both basal conditions and following pathophysiological stimulation. METHODS Blood pressure was monitored in male wild-type and GPR35 knockout mice over 7–14 days using implantable telemetry. Cardiac function and dimensions were assessed using echocardiography, and cardiomyocyte morphology evaluated histologically. Two weeks of angiotensin II (Ang II) infusion was used to investigate the effects of GPR35 deficiency under pathophysiological conditions. Gpr35 messenger RNA expression in cardiovascular tissues was assessed using quantitative polymerase chain reaction. RESULTS There were no significant differences in blood pressure, cardiac function, or cardiomyocyte morphology in GPR35 knockout mice compared with wild-type mice. Following Ang II infusion, GPR35 knockout mice were protected from significant increases in systolic, diastolic, and mean arterial blood pressure or impaired left ventricular systolic function, in contrast to wild-type mice. There were no significant differences in Gpr35 messenger RNA expression in heart, kidney, and aorta following Ang II infusion in wild-type mice. CONCLUSIONS Although GPR35 does not appear to influence basal cardiovascular regulation, these findings demonstrate that it plays an important pathological role in the development of Ang II–induced hypertension and impaired cardiac function. This suggests that GPR35 is a potential novel drug target for therapeutic intervention in hypertension.

Download Full-text

Abstract P033: PRESSOR, NATRIURETIC, AND RENAL RESPONSES IN ANGIOTENSIN II-INDUCED HYPERTENSION IN MALE AND FEMALE WILD-TYPE AND PROXIMAL TUBULE-SPECIFIC AT 1A RECEPTOR KNOCKOUT MICE

Hypertension ◽

10.1161/hyp.76.suppl_1.p033 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Ana Paula O Leite ◽

Xiao C Li ◽

Dulce E Casarini ◽

Jia L Zhuo

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Pressor Response ◽

Proximal Tubules ◽

Ang Ii ◽

Wild Type ◽

Tubulointerstitial Injury ◽

Male And Female ◽

Arterial Blood ◽

Induced Hypertension

Dysregulation of intrarenal renin-angiotensin system is one of the key factors of human hypertension, but the mechanisms involved remain incompletely understood. To determine the roles of AT 1a receptors in the proximal tubules of the kidney, we infused angiotensin II (Ang II) for 2 weeks (40 ng / min, i.p.) in adult male and female wild-type C57BL/6J and mutant mice with deletion of AT 1a receptors in the proximal tubules (PT- Agtr1a -/- ), and treated with or without the AT 1 receptor blocker losartan (20 mg/kg/day, p.o.) (n=8 per group). The pressor response, 24 h urinary Na + excretion, glomerular and tubulointerstitial injury were compared between male and female wild-type and PT- Agtr1a -/- mice. Basal systolic, diastolic, and mean arterial blood pressure were about 13 ± 3 mmHg lower in male and female PT- Agtr1a -/- mice ( P <0.01), but no differences were observed between male and female wild-type or PT- Agtr1a -/- mice. In response to Ang II, both male and female wild-type and PT- Agtr1a -/- mice developed hypertension ( P <0.01), and the net pressor response were similar in male and female wild-type and PT- Agtr1a -/- mice (n.s.). However, absolute blood pressure was about 12 ± 3 mmHg lower in male and female PT- Agtr1a -/- mice ( P <0.01 vs. wild-type). Ang II-induced hypertension increased the natriuretic response in both male and female wild-type and PT- Agtr1a -/- mice ( P <0.01), but there were no significant differences between male and female wild-type and PT- Agtr1a -/- mice (n.s). Losartan did not increase the natriuretic responses further in all animals. Furthermore, Ang II-induced hypertension was associated with significant increases in glomerular and tubulointerstitial injury in male and female wild-type mice ( P <0.01), which were attenuated in male and female PT- Agtr1a -/- mice ( P <0.01). LOS treatment attenuated Ang II-induced hypertension and decreased Ang II-induced glomerular and tubulointerstitial injury in male and female wild-type and PT- Agtr1a -/- mice ( P <0.01). Taken together, we demonstrated that intratubular AT 1 (AT 1a ) receptors in the proximal tubules of the kidney plays a key role in maintaining basal blood pressure homeostasis and overall body salt and fluid balance, and the development of Ang II-induced hypertension and kidney injury.

Download Full-text

Proximal Tubule-Specific Deletion of Angiotensin II Type 1a Receptors in the Kidney Attenuates Circulating and Intratubular Angiotensin II–Induced Hypertension in PT- Agtr1a −/− Mice

Hypertension ◽

10.1161/hypertensionaha.120.16336 ◽

2021 ◽

Author(s):

Xiao Chun Li ◽

Ana Paula Oliveira Leite ◽

Xiaowen Zheng ◽

Chunling Zhao ◽

Xu Chen ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Fusion Protein ◽

Proximal Tubule ◽

Proximal Tubules ◽

Normal Blood ◽

Ang Ii ◽

Normal Blood Pressure ◽

Wild Type ◽

Induced Hypertension

The present study used a novel mouse model with proximal tubule-specific knockout of AT 1a receptors in the kidney, PT- Agtr1a −/− , to test the hypothesis that intratubular Ang II (angiotensin II) and AT 1a receptors in the proximal tubules are required for maintaining normal blood pressure and the development of Ang II–induced hypertension. Twenty-six groups (n=6–15 per group) of adult male wild-type, global Agtr1a −/− , and PT- Agtr1a −/− mice were infused with Ang II (1.5 mg/kg per day, IP), or overexpressed an intracellular Ang II fusion protein in the proximal tubules for 2 weeks. Basal telemetry blood pressure were ≈15±3 mm Hg lower in PT- Agtr1a −/− than wild-type mice and ≈13±3 mm Hg higher than Agtr1a −/− mice ( P <0.01). Basal glomerular filtration was ≈23.9% higher ( P <0.01), whereas fractional proximal tubule Na + reabsorption was lower in PT- Agtr1a −/− mice ( P <0.01). Deletion of AT 1a receptors in the proximal tubules augmented the pressure-natriuresis response ( P <0.01) and natriuretic responses to salt loading or Ang III infusion ( P <0.01). Ang II induced hypertension in wild-type, PT- Agtr1a −/− and PT- Nhe3 −/− mice, but the pressor response was ≈16±2 mm Hg lower in PT- Agtr1a −/− and PT- Nhe3 −/− mice ( P <0.01). Deletion of AT 1a receptors or NHE3 (Na + /H + exchanger 3) in the proximal tubules attenuated ≈50% of Ang II–induced hypertension in wild-type mice ( P <0.01), but blocked intracellular Ang II fusion protein-induced hypertension in PT- Agtr1a −/− mice ( P <0.01). Taken together, the results of the present study provide new insights into the critical role of intratubular Ang II/AT 1 (AT 1a )/NHE3 pathways in the proximal tubules in normal blood pressure control and the development of Ang II–induced hypertension.

Download Full-text

Abstract 7: Angiotensin II Type 2 Receptor Deficiency Increases Renal ACE/ACE2 Ratio-Ang II-AT1R Expression In Male but not in Female Mice

Hypertension ◽

10.1161/hyp.60.suppl_1.a7 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Quaisar Ali ◽

Yonnie Wu ◽

Tadashi Inagami ◽

Tahir Hussain

Keyword(s):

Blood Pressure ◽

Renal Function ◽

Angiotensin Ii ◽

Renin Activity ◽

Ang Ii ◽

Male And Female ◽

Female Mice ◽

Gender Specific

Angiotensin II acting via Angiotensin II type 2 receptors (AT2Rs) is believed to be protective against blood pressure increase and affects renal function under pathophysiological condition. Recently we have observed that stimulation of AT2Rs in male obese Zucker rats has shifted the two opposing arms of renin angiotensin system (RAS) i.e. ACE-Ang II-AT1 vs ACE2/Ang-(1-7)-Mas. Evidence suggests that estrogen regulates RAS, including AT2R in female mice. We hypothesized that AT2R has a gender specific regulation of RAS. In the present study, we investigated the role of AT2Rs in regulating RAS components in male and female mice. Kidney cortex from AT2R knockout (AT2RKO) male and female mice and wild type (WT) with similar background (C57BL/6) of 20 weeks of age were used in the study. The cortical ACE expression (ng ACE/μg tissue) was significantly increased in AT2RKO mice (3±0.02) compared to WT males (1.9±0.02). LC/MS analysis of cortical tissue revealed that Ang II was also significantly increased in AT2RKO mice (WT: 31±3, AT2RKO: 47±3 fmoles/mg tissue). Deletion of AT2R significantly increased AT1R (204%, 204 of 100) expression and had no effect on renin activity compared to WT males. The cortical expression of ACE2 activity (WT: 113±8, AT2RKO: 40±11, RFU/min), Ang-(1-7) levels (WT: 7.3±1.4, AT2RKO: 3±0.8 fmoles/mg tissue) and Mas receptor (AT2RKO: 54±15, % of WT) was significantly decreased in AT2RKO males compared to WT. The cortical expression of the AT2R and MasR was 2-fold greater in WT females compared to WT male. The renin activity (WT: 32±2, AT2RKO: 21±0.3, RFU/min) and MasR expression (WT: 187.5±55, AT2KO: 47±9) was significantly decreased in AT2RKO females compared to the female WT. Interestingly, Ang-(1-7) level (WT: 5.7±0.7, AT2RKO 2.6±0.7 fmoles/mg tissue) was decreased but no changes in ACE or ACE2 activity was observed in AT2KO females compared to their WT, suggesting a role of non-ACE2 pathway. This study suggests that AT2R regulates ACE/ACE2 ratio-Ang II-AT1R expression negatively only in males, whereas in females, it regulates Ang-(1-7) potentially via non-ACE2 pathway. Such changes indicate a gender specific mechanisms potentially associated with AT2R-mediated regulation of renal function and blood pressure control.

Download Full-text

The α2-isoform of Na-K-ATPase mediates ouabain-induced hypertension in mice and increased vascular contractility in vitro

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00083.2004 ◽

2005 ◽

Vol 288 (2) ◽

pp. H477-H485 ◽

Cited By ~ 114

Author(s):

Iva Dostanic ◽

Richard J. Paul ◽

John N. Lorenz ◽

Steven Theriault ◽

James W. Van Huysse ◽

...

Keyword(s):

Blood Pressure ◽

Left Ventricular ◽

Genetically Engineered ◽

Wild Type ◽

Vascular Contractility ◽

Genetically Engineered Mice ◽

Basal Tone ◽

Induced Hypertension ◽

Spontaneous Contractions

Although ouabain is known to induce hypertension, the mechanism of how this cardiac glycoside affects blood pressure is uncertain. The present study demonstrates that the α2-isoform of the Na-K-ATPase mediates the pressor effects of ouabain in mice. To accomplish this, we analyzed the effect of ouabain on blood pressure in wild-type mice, where the α2-isoform is sensitive to ouabain, and genetically engineered mice expressing a ouabain-insensitive α2-isoform of the Na-K-ATPase. Thus differences in the response to ouabain between these two genotypes can only be attributed to the α2-isoform of Na-K-ATPase. As the α1-isoform is naturally resistant to ouabain in rodents, it will not be inhibited by ouabain in either genotype. Whereas prolonged administration of ouabain increased levels of ouabain in serum from both wild-type and targeted animals, hypertension developed only in wild-type mice. In addition, bolus intravenous infusion of ouabain increased the systolic, mean arterial, and left ventricular blood pressure in only wild-type anesthetized mice. In vitro, ouabain increased vascular tone and thereby phenylephrine-induced contraction of the aorta in intact and endothelium-denuded wild-type mice but in α2-resistant mice. Ouabain also increased the magnitude of the spontaneous contractions of portal vein and the basal tone of the intact aorta from only wild-type mice. The increase in aortic basal tone was dependent on the presence of endothelium. Our studies also demonstrate that the α2-isoform of Na-K-ATPase mediates the ouabain-induced increase in vascular contractility. This could play a role in the development and maintenance of ouabain-induced hypertension.

Download Full-text

Sex Differences in Angiotensin II-Induced Hypertension and Kidney Injury: Role of AT1a Receptors in The Proximal Tubule of The Kidney

Clinical Science ◽

10.1042/cs20201574 ◽

2021 ◽

Author(s):

Ana Paula Oliverio Leite ◽

Xiao Chun Li ◽

Ruman Hassan ◽

Xiaowen Zheng ◽

Barbara T Alexander ◽

...

Keyword(s):

Sex Differences ◽

Angiotensin Ii ◽

Proximal Tubule ◽

Kidney Injury ◽

Proximal Tubules ◽

Ang Ii ◽

Wild Type ◽

Male And Female ◽

Induced Hypertension ◽

Different Strains

In the present study, we tested the hypothesis that there are significant sex differences in angiotensin II (Ang II)-induced hypertension and kidney injury using male and female wild-type and proximal tubule-specific AT1a receptor knockout mice (PT-Agtr1a-/-). Twelve groups (n=8-12 per group) of adult male and female wild-type and PT-Agtr1a-/- mice were infused with a pressor dose of Ang II via osmotic pump for 2 weeks (1.5 mg/kg/day, i.p.) and simultaneously treated with or without losartan (20 mg/kg/day, p.o.) to determine the respective roles of AT1a receptors in the proximal tubules versus systemic tissues. Basal systolic, diastolic, and mean arterial pressure were approximately 13 ± 3 mmHg lower (P<0.01), while basal 24 h urinary Na+, K+, and Cl- excretion were significantly higher in both male and female PT-Agtr1a-/- mice than wild-type controls (P<0.01) without significant sex differences between different strains. Both male and female wild-type and PT-Agtr1a-/- mice developed hypertension (P<0.01), and the magnitudes of the pressor responses to Ang II were similar between male and female wild-type and PT-Agtr1a-/- mice (n.s.). Likewise, Ang II-induced hypertension was significantly attenuated in both male and female PT-Agtr1a-/- mice (P<0.01). Furthermore, losartan attenuated the hypertensive responses to Ang II to similar extents in both male and female wild-type and PT-Agtr1a-/- mice. Finally, Ang II-induced kidney injury was attenuated in PT-Agtr1a-/- mice (P<0.01). In conclusion, the present study demonstrates that deletion of AT1a receptors in the proximal tubules of the kidney attenuates Ang II-induced hypertension and kidney injury without revealing significant sex differences.

Download Full-text

Abstract 101: Cardiac Deleterious Role of Galectin-3 in Chronic Angiotensin-II Induced Hypertension

Hypertension ◽

10.1161/hyp.62.suppl_1.a101 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Germán E González ◽

Nour-Eddine Rhaleb ◽

Xiao- P Yang ◽

Oscar A Carretero

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Cardiac Fibrosis ◽

Systolic Dysfunction ◽

Left Ventricular ◽

Carbohydrate Binding ◽

Ang Ii ◽

Induced Hypertension ◽

Galectin 3

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.

Download Full-text

Effect of sacubitril valsartan on cardiac function and endothelial function in patients with chronic heart failure with reduced ejection fraction

Clinical Hemorheology and Microcirculation ◽

10.3233/ch-201032 ◽

2020 ◽

pp. 1-9

Author(s):

Bao-Hua Li ◽

Kuai-Fa Fang ◽

Pei-Huan Lin ◽

Yi-Hui Zhang ◽

Yong-Xiang Huang ◽

...

Keyword(s):

Ejection Fraction ◽

Endothelial Function ◽

Cardiac Function ◽

Conventional Treatment ◽

Left Ventricular ◽

Control Group ◽

Observation Group ◽

Ang Ii ◽

Reduced Ejection Fraction ◽

The Difference

OBJECTIVE: The aim of the present study was to observe the effect of sacubitril valsartan on cardiac function and vascular endothelial function in patients with chronic heart failure with reduced ejection fraction (HFrEF). METHODS: A total of 80 patients with HFrEF were randomly divided into an observation group and a control group, with 40 patients in each group. Sacubitril valsartan was added to the conventional treatment in the observation group, and perindopril was added to the conventional treatment in the control group. Both groups were treated continuously for 12 weeks. The left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), flow-mediated vasodilatory function (FMD) of the brachial artery, and levels of plasma Ang II, endothelin 1 (ET-1), and calcitonin gene-related peptide (CGRP), together with the serum nitric oxide (NO) and NO synthase (NOS) were compared before and after treatment in the groups. RESULTS: Before the treatment, the levels of LVEF, LVEDD, FMD, Ang II, ET-1, CGRP, NO, and NOS in the observation group were not significantly different from those in the control group (P > 0.05). However, the levels of LVEF, FMD, CGRP, NO, and NOS in both groups were significantly higher after the treatment than those before the treatment (P < 0.05) and significantly higher in the observation group than those in the control group. The difference was statistically significant (P < 0.05). Meanwhile, the levels of LVEDD, Ang II, and ET-1 in both groups decreased significantly after the treatment (P < 0.05) and were significantly lower in the observation group than those in the control group. The difference was statistically significant (P < 0.05). CONCLUSION: Sacubitril valsartan might improve endothelial function while increasing cardiac function in HFrEF patients.

Download Full-text

Sex and the G Protein–Coupled Estrogen Receptor Impact Vascular Stiffness

Hypertension ◽

10.1161/hypertensionaha.120.16915 ◽

2021 ◽

Author(s):

Benard O. Ogola ◽

Gabrielle L. Clark ◽

Caleb M. Abshire ◽

Nicholas R. Harris ◽

Kaylee L. Gentry ◽

...

Keyword(s):

Blood Pressure ◽

Estrogen Receptor ◽

Sex Differences ◽

G Protein ◽

Wall Thickness ◽

Left Ventricular ◽

Axial Stiffness ◽

Ang Ii ◽

Wild Type ◽

G Protein Coupled

Because arterial stiffness increases following menopause, estrogen may be a protective factor. Our previous work indicates that the GPER (G protein–coupled estrogen receptor) mediates estrogen’s vascular actions. In the current study, we assessed arterial stiffening using pulse wave velocity (PWV), a clinically relevant measurement that independently predicts cardiovascular mortality. We hypothesized that genetic deletion of GPER would attenuate sex differences in PWV and would be associated with changes in passive vascular mechanics. Control and Ang II (angiotensin II)–infused male and female wild-type and GPER knockout mice were assessed for blood pressure, intracarotid PWV, cardiac function, passive biaxial mechanics, constitutive modeling, and histology. Sex differences in PWV and left ventricular mass were detected in wild-type mice but absent in GPER knockout and Ang II–infused mice, regardless of genotype. Despite lower PWV, the material stiffness of female wild-type carotids was greater than males in control conditions and was maintained in response to Ang II due to increased wall thickness. PWV positively correlated with unloaded thickness as well as circumferential and axial stiffness only in females. In contrast, blood pressure positively associated with circumferential and axial stiffness in males. Taken together, we found that female wild-type mice were unique in their vascular adaptation to hypertension by increasing wall thickness to maintain stiffness. Given that carotid arteries are easily accessible clinically, systematic assessment of intracarotid PWV in women may provide insight into vascular damage that cannot be assumed from blood pressure measurements alone.

Download Full-text