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

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

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.782138 ◽

2021 ◽

Vol 8 ◽

Author(s):

Michelle Lin ◽

Robyn A. Roth ◽

Beth A. Kozel ◽

Robert P. Mecham ◽

Carmen M. Halabi

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Systolic Hypertension ◽

Mesenteric Arteries ◽

Large Artery ◽

Ample Evidence ◽

Artery Stiffness

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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Enhanced in vivo IgE production and T cell polarization toward the type 2 phenotype in association with indoor exposure to VOC: results of the LARS study

International Journal of Hygiene and Environmental Health ◽

10.1078/1438-4639-00100 ◽

2001 ◽

Vol 204 (4) ◽

pp. 211-221 ◽

Cited By ~ 80

Author(s):

Irina Lehmann ◽

Martina Rehwagen ◽

Ulrike Diez ◽

Annett Seiffart ◽

Ulrike Rolle-Kampczyk ◽

...

Keyword(s):

T Cell ◽

Cell Polarization ◽

Indoor Exposure ◽

T Cell Polarization

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Expression of Cell Cycle Proteins P21 waf1/Cip1 , P27 kip1 , Cyclin D1 and CDK4 in Blood Vessels of Angiotensin II-Infused Rats. Role of AT 1 Receptors.

Hypertension ◽

10.1161/hyp.36.suppl_1.707-b ◽

2000 ◽

Vol 36 (suppl_1) ◽

pp. 707-707

Author(s):

Quy N Diep ◽

Mohammed El Mabrouk ◽

Rhian M Touyz ◽

Ernesto L Schiffrin

Keyword(s):

Cell Cycle ◽

Angiotensin Ii ◽

Dna Synthesis ◽

Cyclin D1 ◽

Blood Vessels ◽

Thymidine Incorporation ◽

Mesenteric Arteries ◽

Ang Ii

P79 Angiotensin II (Ang II) is an important modulator of cell growth via AT 1 receptors, as demonstrated both in vivo and in vitro . Here, we investigated the role of different proteins involved in the cell cycle, including cyclin D1, cyclin-dependent kinase 4 (cdk4) and cdk inhibitors p21 and p27 in blood vessels of Ang II-infused rats and the effect therein of the AT 1 receptor antagonist losartan. Male Sprague Dawley rats were infused for 7 days with Ang II (120 ng/kg/min s.c.) and/or treated with losartan (10 mg/kg/day orally). DNA synthesis in mesenteric arteries was evaluated by radiolabeled 3 H-thymidine incorporation. The expression of p21, p27, cyclin D1, cdk4 and E2F, which play critical roles during G1-phase of the cell cycle process, was examined by Western blot analysis. Tail cuff systolic blood pressure (mmHg) was elevated (p<0.05, n=9) in Ang II-infused rats (161.3±8.2) vs. controls (110.1±5.3) and normalized by losartan (104.4±3.2). Radiolabeled 3 H-thymidine incorporation (cpm/100 μg DNA) showed that Ang II-infusion significantly increased DNA synthesis (152±5 vs. 102±6, p<0.05). Expression of p21 and p27 was significantly decreased in the Ang II group to 23.2±10.4% and 10.3±5.3% of controls, respectively, whereas expression of cyclin D1 and cdk4 was significantly increased in the Ang II group to 213.7±8% and 263.6±37% of controls, respectively. These effects induced by Ang II infusion was normalized in the presence of losartan. Ang II had no effect on the expression of E2F. Thus, when AT 1 receptors are stimulated in vivo , DNA synthesis is enhanced in blood vessels by activation of cyclin D1 and cdk4. Reduction in cell cycle kinase inhibitors p21 and p27 may contribute to activation of growth induced by in vivo AT 1 receptor stimulation.

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Proapoptotic and Growth-Inhibitory Role of Angiotensin II Type 2 Receptor in Vascular Smooth Muscle Cells of Spontaneously Hypertensive Rats In Vivo

Hypertension ◽

10.1161/01.hyp.35.5.1069 ◽

2000 ◽

Vol 35 (5) ◽

pp. 1069-1073 ◽

Cited By ~ 60

Author(s):

Bun-Seng Tea ◽

Shant Der Sarkissian ◽

Rhian M. Touyz ◽

Pavel Hamet ◽

Denis deBlois

Keyword(s):

Smooth Muscle ◽

Angiotensin Ii ◽

Vascular Smooth Muscle Cells ◽

Spontaneously Hypertensive Rats ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Growth Inhibitory

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Upregulation of angiotensin II type 2 receptor expression in estrogen-induced pituitary hyperplasia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00477.2003 ◽

2004 ◽

Vol 286 (5) ◽

pp. E786-E794 ◽

Cited By ~ 10

Author(s):

Cecilia Suarez ◽

Graciela Díaz-Torga ◽

Arturo González-Iglesias ◽

Carolina Cristina ◽

Damasia Becu-Villalobos

Keyword(s):

Angiotensin Ii ◽

Receptor Expression ◽

Receptor Subtype ◽

At2 Receptor ◽

Ang Ii ◽

Pituitary Hyperplasia ◽

Releasing Effect ◽

At2 Receptors

Recent evidence shows that reexpression and upregulation of angiotensin II (ANG II) type 2 (AT2) receptor in adult tissues occur during pathological conditions such as tissue hyperplasia, inflammation, and remodeling. In particular, expression of functional AT2 receptors in the pituitary and their physiological significance and regulation have not been described. In this study, we demonstrate that chronic in vivo estrogen treatment, which induces pituitary hyperplasia, enhances local AT2 expression (measured by Western blot and RT-PCR) concomitantly with downregulation of ANG II type 1 (AT1) receptors. In vivo progesterone treatment of estrogen-induced pituitary hyperplasia did not modify either the ANG II receptor subtype expression pattern or octapeptide-induced and AT1-mediated calcium signaling. Nevertheless, an unexpected potentiation of the ANG II prolactin-releasing effect was observed in this group, and this response was sensitive to both AT1 and AT2 receptor antagonists. These data are the first to document that ANG II can act at the pituitary level through the AT2 receptor subtype and that estrogens display a differential regulation of AT1 and AT2 receptors at this level.

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Group 2 Innate Lymphoid Cells Exhibit Tissue-Specific Dynamic Behaviour During Type 2 Immune Responses

Frontiers in Immunology ◽

10.3389/fimmu.2021.711907 ◽

2021 ◽

Vol 12 ◽

Author(s):

Laurence S. C. Lok ◽

Jennifer A. Walker ◽

Helen E. Jolin ◽

Seth T. Scanlon ◽

Masaru Ishii ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Intestinal Mucosa ◽

Dynamic Behaviour ◽

Helminth Infection ◽

Lymphoid Cells ◽

Group 2

Group 2 innate lymphoid cells (ILC2s) are early effectors of mucosal type 2 immunity, producing cytokines such as interleukin (IL)-13 to mediate responses to helminth infection and allergen-induced inflammation. ILC2s are also present in lymph nodes (LNs) and can express molecules required for antigen presentation, but to date there are limited data on their dynamic behaviour. We used a CD2/IL-13 dual fluorescent reporter mouse for in vivo imaging of ILC2s and Th2 T cells in real time following a type 2 priming helminth infection or egg injection. After helminth challenge, we found that ILC2s were the main source of IL-13 in lymphoid organs (Peyer’s patches and peripheral LNs), and were located in T cell areas. Intravital imaging demonstrated an increase in IL-13+ ILC2 size and movement following helminth infection, but reduced duration of interactions with T cells compared with those in homeostasis. In contrast, in the intestinal mucosa, we observed an increase in ILC2-T cell interactions post-infection, including some of prolonged duration, as well as increased IL-13+ ILC2 movement. These data suggest that ILC2 activation enhances cell motility, with the potential to increase the area of distribution of cytokines to optimise the early generation of type 2 responses. The prolonged ILC2 interactions with T cells within the intestinal mucosa are consistent with the conclusion that contact-based T cell activation may occur within inflamed tissues rather than lymphoid organs. Our findings have important implications for our understanding of the in vivo biology of ILC2s and the way in which these cells facilitate adaptive immune responses.

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