Loss of Angiotensin II Type 2 Receptor Improves Blood Pressure in Elastin Insufficiency

There is ample evidence supporting a role for angiotensin II type 2 receptor (AT2R) in counterbalancing the effects of angiotensin II (ang II) through the angiotensin II type 1 receptor by promoting vasodilation and having anti-inflammatory effects. Elastin insufficiency in both humans and mice results in large artery stiffness and systolic hypertension. Unexpectedly, mesenteric arteries from elastin insufficient (Eln+/−) mice were shown to have significant vasoconstriction to AT2R agonism in vitro suggesting that AT2R may have vasoconstrictor effects in elastin insufficiency. Given the potential promise for the use of AT2R agonists clinically, the goal of this study was to determine whether AT2R has vasoconstrictive effects in elastin insufficiency in vivo. To avoid off-target effects of agonists and antagonists, mice lacking AT2R (Agtr2−/Y) were bred to Eln+/− mice and cardiovascular parameters were assessed in wild-type (WT), Agtr2−/Y, Eln+/−, and Agtr2−/Y;Eln+/− littermates. As previously published, Agtr2−/Y mice were normotensive at baseline and had no large artery stiffness, while Eln+/− mice exhibited systolic hypertension and large artery stiffness. Loss of AT2R in Eln+/− mice did not affect large artery stiffness or arterial structure but resulted in significant reduction of both systolic and diastolic blood pressure. These data support a potential vasocontractile role for AT2R in elastin insufficiency. Careful consideration and investigation are necessary to determine the patient population that might benefit from the use of AT2R agonists.

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Abstract MP03: ROCK2 Specific Inhibition Attenuates Angiotensin II-induced Hypertension In Mice

Hypertension ◽

10.1161/hyp.78.suppl_1.mp03 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Daniel J Fehrenbach ◽

Meena S Madhur

Keyword(s):

Blood Pressure ◽

T Cell ◽

Angiotensin Ii ◽

Repeated Measures ◽

Flow Cytometric Analysis ◽

Coiled Coil ◽

Ang Ii ◽

Induced Hypertension

Hypertension, or an elevated blood pressure, is the primary modifiable risk factor for cardiovascular disease, the number one cause of mortality worldwide. We previously demonstrated that Th17 activation and interleukin 17A (IL-17A)/IL-21 production is integral for the full development of a hypertensive phenotype as well as the renal and vascular damage associated with hypertension. Rho-associated coiled-coil containing protein Kinase 2 (ROCK2) serves as a molecular switch upregulating Th17 and inhibiting regulatory T cell (Treg) differentiation. We hypothesize that hypertension is characterized by excessive T cell ROCK2 activation leading to increased Th17/Treg ratios and ultimately end-organ damage. We first showed in vitro that KD025, an experimental orally bioavailable ROCK2 inhibitor inhibits Th17 cell proliferation and IL-17A/IL-21 production. To determine if hypertensive stimuli such as endothelial stretch increases T cell ROCK2 expression, we cultured human aortic endothelial cells exposed to 5% (normotensive) or 10% (hypertensive) stretch with circulating human T cells and HLA-DR+ antigen presenting cells. Hypertensive stretch increased T cell ROCK2 expression 2-fold. We then tested the effect of ROCK2 inhibition with KD025 (50mg/kg i.p. daily) in vivo on angiotensin II (Ang II)-induced hypertension. Treatment with KD025 significantly attenuated the hypertensive response within 1 week of Ang II treatment (systolic blood pressure: 139± 8 vs 108±7mmHg) and this persisted for the duration of the 4 week study reaching blood pressures 20 mmHg lower (135±13mmHg) than vehicle treated mice (158±4mmHg p<0.05 effect of treatment 2-way Repeated Measures ANOVA). Flow cytometric analysis of tissue infiltrating leukocytes revealed that KD025 treatment increased Treg/Th17 ratios in the kidney (0.61±0.03 vs 0.79±0.08, p<0.05 student’s t-test). Thus, T cell ROCK2 may be a novel therapeutic target for the treatment of hypertension.

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In vitro and in vivo inhibition of renin by fatty acids.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1978.234.6.e593 ◽

1978 ◽

Vol 234 (6) ◽

pp. E593 ◽

Cited By ~ 1

Author(s):

T A Kotchen ◽

W J Welch ◽

R T Talwalkar

Keyword(s):

Blood Pressure ◽

Fatty Acids ◽

Linoleic Acid ◽

Angiotensin Ii ◽

Neutral Lipids ◽

Pressor Response ◽

Arterial Blood ◽

Arachidonic Acids

Circulating neutral lipids inhibit the in vitro renin reaction. To identify the inhibitor(s), free fatty acids were added to human renin and homologous substrate. Capric, lauric, palmitoleic, linoleic, and arachidonic acids each inhibited the rate of angiotensin I production in vitro (P less than 0.01). Inhibition by polysaturated fatty acids (linoleic and arachidonic) was less (P less than 0.01) after catalytic hydrogenation of the double bonds. To evaluate an in vivo effect of renin inhibition intra-arterial blood pressure responses to infusions of renin and angiotensin II (5.0 microgram) were measured in anephric rats (n = 6) before and after infusion of linoleic acid (10 mg iv). Mean increase of blood pressure to angiotensin II before (75 mmHg +/- 9) and after (90 +/- 12) linoleic acid did not differ (P greater than 0.05). However, the pressor response to renin after linoleic acid (18 +/- 3) was less (P less than 0.00)) than that before (102 +/- 13). In summary, several fatty acids inhibit the in vitro renin reaction, and in part inhibition is dependent on unsaturation. Linoleic acid also inhibits the in vivo pressor response to renin. These results suggest that fatty acids may modify the measurement of plasma renin activity and may also affect angiotensin production in vivo.

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Autophagy inhibition by chloroquine prevents increase in blood pressure and preserves endothelial functions

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i4.16 ◽

2020 ◽

Vol 19 (4) ◽

pp. 789-796

Author(s):

Moon Jain ◽

Hina Iqbal ◽

Pankaj Yadav ◽

Himalaya Singh ◽

Debabrata Chanda ◽

...

Keyword(s):

Blood Pressure ◽

Cell Migration ◽

Endothelial Cell ◽

Angiotensin Ii ◽

Ang Ii ◽

Hypertensive Rats ◽

Autophagy Flux ◽

Endothelial Functions

Purpose: To determine the effects of lysosomal inhibition of autophagy by chloroquine (CHQ) onhypertension-associated changes in the endothelial functions. Method: Angiotensin II (Ang II)-treated human endothelial cell line EA.hy926 and renovascularhypertensive rats were subjected to CHQ treatment (in vitro: 0.5, 1, and 2.5 μM; in vivo: 50 mg/kg/dayfor three weeks). Changes in the protein expressions of LC3b II (autophagosome formation marker) andp62 (autophagy flux marker) were assessed using immunoblotting. Cell migration assay, tubuleformation assay (in vitro), and organ bath studies (in vivo) were performed to evaluate the endothelialfunctions. Hemodynamic parameters were measured as well. Results: A higher expression of LC3b II and a reduced expression of p62 observed in the Ang II-treatedendothelial cells, as well as in the aorta of the hypertensive rats, indicated enhanced autophagy.Treatment with CHQ resulted in reduced autophagy flux (in vitro as well as in vivo) and suppressed AngII-induced endothelial cell migration and angiogenesis (in vitro). The treatment with CHQ was alsoobserved to prevent increase in blood pressure in hypertensive rats and preserved acetylcholineinducedrelaxation in phenylephrine-contracted aorta from the hypertensive rats. In addition, chloroquineattenuated Ang II-induced contractions in the aorta of normotensive as well as hypertensive rats. Conclusion: These observations indicated that CHQ lowers the blood pressure and preserves thevascular endothelial function during hypertension. Keywords: Angiotensin II, Autophagy, Chloroquine, Endothelial function, Hypertension, Vasculardysfunction

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Comparative Pharmacology of New Specific Angiotensin Antagonists

Clinical Science ◽

10.1042/cs048019s ◽

1974 ◽

Vol 48 (s2) ◽

pp. 19s-21s

Author(s):

B. A. Schoelkens

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Blood Pressure Response ◽

Renal Hypertension ◽

Antagonistic Activity ◽

Conscious Rats ◽

Blood Pressures ◽

Colon Ascendens

1. The angiotensin II antagonism by newly synthesized 8-C-phenylglycine analogues of [5-isoleucine]angiotensin II in different preparations was investigated in vitro and in vivo. 2. All analogues competitively inhibited the myotropic effect of angiotensin II on the isolated colon ascendens of the guinea-pig and the stomach of the rat. 3. In normotensive dogs, cats, rabbits, guinea-pigs and rats the blood pressure response to infused angiotensin II was inhibited by the antagonists. The angiotensin II-induced fall in renal blood flow in the dog was blocked during infusion of the analogues. Acute renal hypertension in rats was significantly decreased. Of conscious rats variously with normal blood pressures, spontaneous hypertension and chronic renal hypertension, only in the last group could a marked uniform fall in blood pressure be demonstrated. The central pressor effect of angiotensin II was also inhibited in conscious rats. 4. 8-C-Phenylglycine analogues of [5-isoleucine]-angiotensin II exhibit a specific antagonistic activity to endogenous and exogenous angiotensin II.

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Altered vascular contractility in adult female rats with hypertension programmed by prenatal glucocorticoid exposure

Journal of Endocrinology ◽

10.1677/joe.1.06506 ◽

2006 ◽

Vol 188 (3) ◽

pp. 435-442 ◽

Cited By ~ 31

Author(s):

P W F Hadoke ◽

R S Lindsay ◽

J R Seckl ◽

B R Walker ◽

C J Kenyon

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Adult Female ◽

Vascular Function ◽

Mesenteric Arteries ◽

Female Rats ◽

Control Group ◽

Pregnant Rats ◽

Vascular Contractility

Excessive exposure to glucocorticoids during gestation reduces birth weight and induces permanent hypertension in adulthood. The mechanisms underlying this programmed elevation of blood pressure have not been established. We hypothesised that prenatal glucocorticoid exposure may lead to vascular dysfunction in adulthood. Pregnant rats received dexamethasone (Dex) (100 μg/kg, s.c.) or vehicle (control) daily throughout pregnancy. Blood pressure was elevated (students t-test, unpaired; P < 0.05) in adult female offspring (aged 12–16 weeks) of Dex-treated mothers (148.0 ± 3.6 mmHg, n=10) compared with the control group (138.0 ± 2.5 mmHg, n=8). Vascular responsiveness in aortae and mesenteric arteries was differentially affected by prenatal Dex: aortae were less responsive to angiotensin II, whereas mesenteric arteries were more responsive to norepinephrine, vasopressin and potassium (mesenteric arteries respond poorly to angiotensin II in vitro). Acetylcholine-mediated, endothelium-dependent relaxation was similar in both groups. Prenatal exposure to Dex had no effect on blood pressure or aldosterone response to acute (15 min, i.v.) infusion of angiotensin II (75 ng/kg per min). In contrast, chronic (2-week, s.c.) infusion of angiotensin II (100 ng/kg per min) produced a greater elevation (P < 0.05) of blood pressure in Dex-treated rats (150.0 ± 3.6 mmHg) than in controls (135.3 ± 5.4 mmHg), and aldosterone levels were higher in Dex-treated animals. There was no angiotensin II-induced medial hypertrophy/hyperplasia in mesenteric arteries from Dex-treated rats. These results indicate that vascular function is altered in a region-specific manner in rats with glucocorticoid-programmed hypertension. Despite a striking increase in mesenteric artery contraction in Dex-treated rats, in vivo studies suggest that abnormalities of the renin-angiotensin-aldosterone system, rather than enhanced vascular contractility, may be responsible for the elevation of blood pressure in these animals.

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Exploiting AT2R to Improve CD117 Stem Cell Function In Vitro and In Vivo - Perspectives for Cardiac Stem Cell Therapy

Cellular Physiology and Biochemistry ◽

10.1159/000430335 ◽

2015 ◽

Vol 37 (1) ◽

pp. 77-93 ◽

Cited By ~ 2

Author(s):

Marion Ludwig ◽

Anita Tölk ◽

Anna Skorska ◽

Christian Maschmeier ◽

Ralf Gaebel ◽

...

Keyword(s):

Stem Cell ◽

Angiotensin Ii ◽

Cell Function ◽

Therapeutic Option ◽

Stimulation Protocol ◽

Promising Tool ◽

Positive Effect

Background/Aims: CD117+ stem cell (SC) based therapy is considered an alternative therapeutic option for terminal heart disease. However, controversies exist on the effects of CD117+ SC implantation. In particular, the link between CD117+ SC function and angiotensin-II-type-2 receptor (AT2R) after MI is continuously discussed. We therefore asked whether 1) AT2R stimulation influences CD117+ SC properties in vitro and, 2) which effects can be ascribed to AT2R stimulation in vivo. Methods: We approached AT2R stimulation with Angiotensin II while simultaneously blocking its opponent receptor AT1 with Losartan. CD117 effects were dissected using a 2D-Matrigel assay and HL-1 co-culture in vitro. A model of myocardial infarction, in which we implanted EGFP+ CD117 SC, was further applied. Results: While we found indications for AT2R driven vasculogenesis in vitro, co-culture experiments revealed that CD117+ SC improve vitality of cardiomyocytes independently of AT2R function. Likewise, untreated CD117+ SC had a positive effect on cardiac function and acted cardioprotective in vivo. Conclusions: Therefore, our data show that transient AT2R stimulation does not significantly add to the beneficial actions of CD117+ SC in vivo. Yet, exploiting AT2R driven vasculogenis via an optimized AT2R stimulation protocol may become a promising tool for cardiac SC therapy.

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Estrogens and the Angiotensin II Type 2 Receptor Control Flow-Mediated Outward Remodeling in the Female Mouse Mesenteric Artery

Journal of Vascular Research ◽

10.1159/000511799 ◽

2020 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Emilie Vessieres ◽

Anne-Laure Guihot ◽

Linda Grimaud ◽

Jordan Rivron ◽

Jean-François Arnal ◽

...

Keyword(s):

T Cell ◽

Angiotensin Ii ◽

Control Flow ◽

Mesenteric Arteries ◽

Expansion Phase ◽

Inflammatory Phase ◽

Collateral Pathways ◽

Feed Arteries

Flow-mediated outward remodeling (FMR) is involved in postischemic revascularization. Angiotensin II type 2 receptor (AT2R), through activation of T-cell-mediated IL-17 production, and estrogens are involved in FMR. Thus, we investigated the interplay between estrogens and AT2R in FMR using a model of ligation of feed arteries supplying collateral pathways in mouse mesenteric arteries in vivo. Arteries were collected after 2 (inflammatory phase), 4 (diameter expansion phase), and 7 days (remodeling completed). We used AT2R+/+ and AT2R−/− ovariectomized (OVX) female mice treated or not with 17-beta-estradiol (E2). Seven days after ligation, arterial diameter was larger in high flow (HF) compared to normal flow (NF) arteries. FMR was absent in OVX mice and restored by E2. AT2R gene expression was higher in HF than in NF arteries only in E2-treated OVX AT2R+/+ mice. CD11b and TNF alpha levels (inflammatory phase), MMP2 and TIMP1 (extracellular matrix digestion), and NOS3 (diameter expansion phase) expression levels were higher in HF than in NF arteries only in E2-treated AT2R+/+ mice, not in the other groups. Thus, E2 is necessary for AT2R-dependent diameter expansion, possibly through activation of T-cell AT2R, in arteries submitted chronically to high blood flow.

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The Angiotensin II Type 2 Receptor, a Target for Protection and Regeneration of the Peripheral Nervous System?

Pharmaceuticals ◽

10.3390/ph14030175 ◽

2021 ◽

Vol 14 (3) ◽

pp. 175

Author(s):

Aurore Danigo ◽

Amandine Rovini ◽

Flavien Bessaguet ◽

Hichem Bouchenaki ◽

Amandine Bernard ◽

...

Keyword(s):

Nervous System ◽

Angiotensin Ii ◽

Peripheral Nervous System ◽

Neuroprotective Effects ◽

Pharmacological Studies ◽

The Central Nervous System ◽

G Protein Coupled

Preclinical evidence, accumulated over the past decade, indicates that the angiotensin II type 2 receptor (AT2R) stimulation exerts significant neuroprotective effects in various animal models of neuronal injury, notably in the central nervous system. While the atypical G protein-coupled receptor superfamily nature of AT2R and its related signaling are still under investigation, pharmacological studies have shown that stimulation of AT2R leads to neuritogenesis in vitro and in vivo. In this review, we focus on the potential neuroprotective and neuroregenerative roles of AT2R specifically in the peripheral nervous system (PNS). The first section describes the evidence for AT2R expression in the PNS and highlights current controversies concerning the cellular distribution of the receptor. The second section focuses on AT2R signaling implicated in neuronal survival and in neurite outgrowth. The following sections review the relatively few preclinical studies highlighting the putative neuroprotective and neuroregenerative effects of AT2R stimulation in the context of peripheral neuropathy.

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Pressor Response to Angiotensin I and Angiotensin II: The Site of Conversion of Angiotensin I

Clinical Science ◽

10.1042/cs0430839 ◽

1972 ◽

Vol 43 (6) ◽

pp. 839-849 ◽

Cited By ~ 7

Author(s):

E. C. Osborn ◽

G. Tildesley ◽

P. T. Pickens

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Pressor Response ◽

Left Ventricular ◽

Angiotensin I ◽

Intravenous Injections ◽

Pressor Responses ◽

The Difference

1. The pressor responses to angiotensin I were compared with those to angiotensin II after injections into the left ventricle and jugular vein in the sheep, dog and pig. 2. The ability of angiotensin I to raise the blood pressure was less than that of angiotensin II with both routes of injection, a difference which was more marked after ventricular injection. 3. When equipressor doses of the hormones were given there was a delay of 1–3 s in the onset of the pressor response to angiotensin I compared with angiotensin II after left-ventricular injections; the difference in the delay in onset was less apparent with intravenous injections. 4. The development of the pressor responses was similar with both hormones when equipressor doses were used but the rises in blood pressure were more prolonged with angiotensin I, especially when given by the left-ventricular route. 5. The in vitro rate of activation of angiotensin I by blood was much slower than the apparent in vivo formation of angiotensin II.

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