Activation of angiotensin type 2 receptor attenuates testosterone-induced hypertension and uterine vascular resistance in pregnant rats

Enos Protein ◽

Abstract Preeclampsia is a pregnancy-related hypertensive disorder with unclear mechanisms. While hypersensitivity to angiotensin II via vasoconstrictive angiotensin type-1 receptor (AT1R) is observed in preeclampsia, the importance of vasodilatory angiotensin type-2 receptor (AT2R) in the control of vascular dysfunction is less clear. We assessed whether AT1R, AT2R and eNOS expression is altered in placental vessels of preeclamptic women and tested if ex vivo incubation with AT2R agonist Compound 21 (C21; 1 μM) could restore AT1R, AT2R and eNOS balance. Further, using a rat model of gestational hypertension induced by elevated testosterone, we examined whether C21 (1 μg·kg−1·day−1, oral) could preserve AT1R and AT2R balance and improve blood pressure, uterine artery blood flow, and vascular function. Western blots revealed that AT1R protein level was higher while AT2R and eNOS protein were reduced in preeclamptic placental vessels, and AT2R agonist C21 decreased AT1R and increased AT2R and eNOS protein levels in preeclamptic vessels. In testosterone-dams, blood pressure was higher, and uterine artery blood flow was reduced, and C21 treatment reversed these levels similar to those in controls dams. C21 attenuated the exaggerated Ang II contraction and improved endothelium-dependent vasorelaxation in uterine arteries of testosterone-dams. These C21-mediated vascular effects were associated with decreased AT1R and increased AT2R and eNOS protein levels. C21 also increased serum nitrate/nitrite and bradykinin production in testosterone-dams and attenuated the feto-placental growth restriction. Thus, AT1R upregulation and AT2R downregulation is observed in preeclampsia and testosterone-model, and increasing AT2R activity could help restore AT1R and AT2R balance and improve gestational vascular function.

Abstract 081: Reporter Mouse Strain Provides a Novel Look at Angiotensin Type-2 Receptor Distribution in Central Nervous System Cardiovascular Control Centers

Hypertension ◽

10.1161/hyp.64.suppl_1.081 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Annette D de Kloet ◽

Lei Wang ◽

Jacob A Ludin ◽

Helmut Hiller ◽

Justin A Smith ◽

...

Keyword(s):

Blood Pressure ◽

Fluid Balance ◽

Hypothalamic Nucleus ◽

Reporter Mouse ◽

Arterial Blood ◽

Egfp Reporter ◽

The Brain ◽

It is established that angiotensin-II acts at its type-1 receptor (AT1R) in the brain to increase sympathetic outflow and blood pressure, and modulate fluid balance. However, the role of the angiotensin type-2 receptor (AT2R) in the neural control of these processes has received far less attention, largely because of an inability to effectively localize these receptors at a cellular level in the brain. The present studies combine the use of a bacterial artificial chromosome transgenic AT2R-eGFP reporter mouse with recent advances in in situ hybridization (ISH) to circumvent this obstacle. Dual IHC/ ISH studies validated the AT2R-eGFP reporter mice by determining that eGFP and AT2R mRNA were highly co-localized within the nucleus of the solitary tract (NTS; 98.0 ± 0.18 %; 125 ± 3.6 of 127 ± 3.9 cells; n = 4). Analysis of eGFP immunoreactivity in the brain revealed localization to neurons within nuclei that regulate blood pressure and fluid balance (e.g., NTS and median preoptic nucleus [MnPO]). Additional IHC/ISH studies uncovered the phenotype of specific AT2R-eGFP cells. For example, within the NTS, AT2R-eGFP neurons primarily express glutamic acid decarboxylase-67 (GABAergic; 80 ± 2.8 %; 225 ± 12.5 of 280 ± 8.4 cells; n = 4), while only a subset express vesicular glutamate transporter-2 (glutamatergic; 18.2 ± 2.9 %; 50.8 ± 7.7 of 280 ± 8.4 cells) or AT1R (8.7 ± 1.0 %; 22 ± 2.2 of 256 ± 11.7 cells). No co-localization was observed with tyrosine hydroxylase in the NTS. Although AT2R-eGFP neurons were not observed within the paraventricular hypothalamic nucleus (PVN), eGFP was localized to efferents terminating in the PVN and to GABAergic neurons surrounding this nucleus. Retrograde neuronal tract tracing studies revealed that many eGFP-positive efferents to the PVN arise from neurons in the MnPO. Based on these neuroanatomical results, we hypothesized that activation of central AT2R would decrease blood pressure. Consistent with this hypothesis, chronic administration of the selective AT2R agonist, compound 21 (7.5 ng/h into the lateral cerebral ventricle) reduced baseline mean arterial blood pressure relative to control mice (103 ± 1.65 v. 110 ± 1.70 mmHg; n = 16; p = 0.02). These studies demonstrate that central AT2R are positioned to regulate blood pressure.

Effects of Angiotensin Type 2 Receptor Overexpression in the Rostral Ventrolateral Medulla on Blood Pressure and Urine Excretion in Normal Rats

Hypertension ◽

10.1161/hypertensionaha.107.101717 ◽

2008 ◽

Vol 51 (2) ◽

pp. 521-527 ◽

Cited By ~ 58

Author(s):

Lie Gao ◽

Weizhong Wang ◽

Wei Wang ◽

Hongwei Li ◽

Colin Sumners ◽

...

Keyword(s):

Blood Pressure ◽

Rostral Ventrolateral Medulla ◽

Ventrolateral Medulla ◽

Urine Excretion ◽

PP058. The additive effect of plasma levels of sFlt-1/PLGF ratio following the risk classification using both blood pressure levels and uterine artery blood flow impedance in the second trimester on the later occurrence of preeclampsia

Pregnancy Hypertension ◽

10.1016/j.preghy.2012.04.169 ◽

2012 ◽

Vol 2 (3) ◽

pp. 273

Author(s):

A. Ohkuchi ◽

C. Hirashima ◽

K. Takahashi ◽

S. Matsubara ◽

M. Suzuki

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Plasma Levels ◽

Uterine Artery ◽

Risk Classification ◽

Additive Effect ◽

Artery Blood Flow ◽

Second Trimester ◽

Flow Impedance ◽

Plgf Ratio

Selective Inhibition of the Renal Angiotensin Type 2 Receptor Increases Blood Pressure in Conscious Rats

Hypertension ◽

10.1161/01.hyp.37.5.1285 ◽

2001 ◽

Vol 37 (5) ◽

pp. 1285-1291 ◽

Cited By ~ 31

Author(s):

Allan F. Moore ◽

Nicolas T. Heiderstadt ◽

Esther Huang ◽

Nancy L. Howell ◽

Zhi-Qin Wang ◽

...

Keyword(s):

Blood Pressure ◽

Selective Inhibition ◽

Conscious Rats ◽

Relaxin attenuates organ fibrosis via an angiotensin-type 2 receptor mechanism in aged hypertensive female rats

Kidney360 ◽

10.34067/kid.0002722021 ◽

2021 ◽

pp. 10.34067/KID.0002722021

Author(s):

Giannie Barsha ◽

Sarah L Walton ◽

Edmund Kwok ◽

Katrina M Mirabito Colafella ◽

Anita P Pinar ◽

...

Keyword(s):

Vascular Function ◽

Cardiac Fibrosis ◽

Female Rats ◽

Therapeutic Effects ◽

Protective Effects ◽

Spontaneously Hypertensive ◽

Models Of Disease ◽

Background: The anti-fibrotic effects of recombinant human relaxin (RLX) in the kidney are dependent on an interaction between its cognate receptor (RXFP1) and the angiotensin type 2 receptor (AT2R) in male models of disease. Whether RLX has therapeutic effects, which are also mediated via the AT2R, in hypertensive adult and aged/reproductively senescent females is unknown. Thus, we determined whether treatment with RLX provides cardiorenal protection, via an AT2R-dependent mechanism, in adult and aged female stroke prone-spontaneously hypertensive rats (SHRSP). Methods: In 6- (6MO) and 15-month-old (15MO; reproductively senescent) female SHRSP, systolic blood pressure (SBP), glomerular filtration rate (GFR) and proteinuria were measured before and after 4 weeks treatment with vehicle (Veh), RLX (0.5 mg/kg/day s.c.) or RLX+PD123319 (AT2R antagonist; 3 mg/kg/day s.c.). Aortic endothelium-dependent relaxation and fibrosis of the kidney, heart and aorta were assessed. Results: In 6MO SHRSP, RLX significantly enhanced GFR by ~25% (P=0.001) and reduced cardiac fibrosis (P=0.01) as compared to vehicle-treated counterparts. These effects were abolished or blunted by PD123319 co-administration. In 15MO females, RLX reduced interstitial renal (P=0.02) and aortic (P=0.003) fibrosis, and lowered SBP (13±3 mmHg; P=0.04) relative to controls. These effects were also blocked by PD123319 co-treatment (all p<0.05 versus RLX treatment alone). RLX also markedly improved vascular function by ~40% (P<0.0001) in 15MO SHRSP, but this was not modulated by PD123319 co-treatment. Conclusion: The anti-fibrotic and organ-protective effects of RLX, when administered to a severe model of hypertension, conferred cardiorenal protection in adult and reproductively senescent female rats, to a great extent via an AT2R-mediated mechanism.

Impact of resveratrol mediated increased uterine artery blood flow on fetal haemodynamics, blood pressure, and oxygenation in sheep

Experimental Physiology ◽

10.1113/ep089237 ◽

2021 ◽

Author(s):

Tanroop Aujla ◽

Jack R. T. Darby ◽

Brahmdeep S. Saini ◽

Mitchell C. Lock ◽

Stacey L. Holman ◽

...

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Uterine Artery ◽

Artery Blood Flow

Aldosterone Receptor Antagonism Normalizes Vascular Function in 11β-Hydroxysteroid Dehydrogenase Deficient Hypertension

Hypertension ◽

10.1161/hyp.36.suppl_1.691-d ◽

2000 ◽

Vol 36 (suppl_1) ◽

pp. 691-691

Author(s):

Thomas Quaschning ◽

Frank T Ruschitzka ◽

Carolyn Mb Lunt ◽

Bernhard Niggli ◽

Sidney Shaw ◽

...

Keyword(s):

Blood Pressure ◽

Protein Content ◽

Vascular Function ◽

Hydroxysteroid Dehydrogenase ◽

Receptor Antagonism ◽

Tissue Levels ◽

Protein Levels ◽

Aldosterone Receptor ◽

Endothelium Dependent Relaxation ◽

Enos Protein

76 Background: The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolising glucocorticoids to their receptor inactive 11-dehydro derivatives. The present study investigated the effect of the aldosterone receptor antagonist spironolactone on endothelial function in liquorrhice induced hypertension. Methods: Glycyrrhizic acid (GA), a recognised inhibitor of 11β-HSD2 was supplemented to the drinking water (3g/L) of Wistar Kyoto rats over a period of 21 days. From day 8 to 21 spirolonoactone (5.8±0.6 mg/kg/d) or placebo was added to chow (n=7/group). Endothelium-dependent and -independent vascular function was assessed as relaxation of preconstricted aortic rings to acetylcholine (10 -10 -10 -5 mol/L) or sodium nitroprusside (10 -10 -10 -5 mol/L). Furthermore aortic eNOS protein content, nitrate tissue levels, endothelin-1 (ET-1) protein levels were determined. Results: GA application increased SBP to 185±9 mmHg vs 142±8 mmHg in control animals, p<0.01). In the GA group endothelium-dependent relaxation was impaired as compared to controls (73±6% vs 99±5% of norepinephrine 3x10 -7 mol/L), whereas endothelium independent relaxation remained unchanged. In the aorta of 11β-HSD2 deficient rats, eNOS protein content and nitrate tissue levels (1114±128 vs 518±77μg/g protein, p<0.05) decreased. In contrast, aortic endothelin-1 (ET-1) protein levels were enhanced by GA. (308±38 vs 497±47 pg/mg tissue, p<0.05). Treatment with spironolactone normalized blood pressure in animals on GA (142±9 mmHg vs 189±8 mmHg in the placebo group; p<0.01) and restored endothelium-dependent relaxation (96±3%, p<0.01 vs placebo). Spironolactone furthermore blunted the decrease in vascular eNOS protein content and nitrate tissue levels as well as the elevation of ET-1 protein levels. Conclusion: In 11β-HSD2-deficient hypertension, aldosterone receptor antagonism normalizes blood pressure, prevents up-regulation of vascular ET-1 and restores NO-mediated endothelial dysfunction and therefore may advance as a novel therapeutic approach.