scholarly journals T cell-derived extracellular vesicles are elevated in essential HTN

2020 ◽  
Vol 319 (5) ◽  
pp. F868-F875
Author(s):  
Sabrina La Salvia ◽  
Luca Musante ◽  
Joanne Lannigan ◽  
Joseph Christopher Gigliotti ◽  
Thu H. Le ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cell ◽  
Extracellular Vesicles ◽  
Immune Cell ◽  
Kidney Tissue ◽  
Cell Communication ◽  
Organ Damage ◽  
In Vivo Model ◽  
Ang Ii

Extracellular vesicles (EVs) are novel mediators of cell-to-cell communication and appear to mediate the pathogenesis of hypertension (HTN). However, the mechanisms underlying the involvement of EVs in HTN remain unclear. The adaptive and innate immune systems play an important role affecting the kidney and vasculature in animal models of HTN. Evolving evidence shows that immune cell-derived EVs can modulate the immune system in a paracrine fashion and therefore may mediate the effects of inflammation in the pathogenesis of HTN. Therefore, we aimed to understand if specific subtypes of leukocyte/immune cell-derived EVs are altered in essential HTN using an in vivo model of angiotensin II (ANG II)-induced HTN. After 4 wk of ANG II treatment, EVs were isolated from the blood and kidney. EV origin and counts were characterized with Imaging Flow Cytometry, antibody panels targeting platelets, endothelial cells, and leukocytes including B and T cells, monocytes, and neutrophils. Leukocyte-derived EVs (CD45+) were elevated in the circulation and kidney tissue in ANG II-induced HTN. Subgroup analysis depicted T cell-derived EVs (CD3+) to be significantly elevated in ANG II-induced HTN (3.50 e+5 particles/mL) compared with control groups (9.16 e+4 particles/mL, P = 0.0106). T cell-derived EVs also significantly correlated with systolic blood pressure levels ( r2 = 0.898, P = 0.0012). In summary, leukocyte-derived EVs, and more specifically T cell-derived EVs (CD3+), are elevated in ANG II-induced HTN in the circulation and kidney tissue and correlate well with blood pressure severity. EVs from the circulation and kidney may be sensitive biomarkers for HTN and end-organ damage and may lead to new mechanistic insights in this silent disease.

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

Hypertension ◽  
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.

Angiotensin II-induced hypertrophy is potentiated in mice overexpressing p22phox in vascular smooth muscle

2005 ◽  
Vol 288 (1) ◽  
pp. H37-H42 ◽  
Author(s):  
David S. Weber ◽  
Petra Rocic ◽  
Adamantios M. Mellis ◽  
Karine Laude ◽  
Alicia N. Lyle ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
In Vivo Model ◽  
Ros Generation ◽  
Ang Ii ◽  
Vascular Hypertrophy ◽  
Wall Area

Increased reactive oxygen species (ROS) are implicated in several vascular pathologies associated with vascular smooth muscle hypertrophy. In the current studies, we utilized transgenic (Tg) mice (Tg p22smc) that overexpress the p22 phox subunit of NAD(P)H oxidase selectively in smooth muscle. These mice have a twofold increase in aortic p22 phox expression and H2O2 production and thus provide an excellent in vivo model in which to assess the effects of increased ROS generation on vascular smooth muscle cell (VSMC) function. We tested the hypothesis that overexpression of VSMC p22 phox potentiates angiotensin II (ANG II)-induced vascular hypertrophy. Male Tg p22smc mice and negative littermate controls were infused with either ANG II or saline for 13 days. Baseline blood pressure was not different between control and Tg p22smc mice. ANG II significantly increased blood pressure in both groups, with this increase being slightly exacerbated in the Tg p22smc mice. Baseline aortic wall thickness and cross-sectional wall area were not different between control and Tg p22smc mice. Importantly, the ANG II-induced increase in both parameters was significantly greater in the Tg p22smc mice compared with control mice. To confirm that this potentiation of vascular hypertrophy was due to increased ROS levels, additional groups of mice were coinfused with ebselen. This treatment prevented the exacerbation of hypertrophy in Tg p22smc mice receiving ANG II. These data suggest that although increased availability of NAD(P)H oxidase-derived ROS is not a sufficient stimulus for hypertrophy, it does potentiate ANG II-induced vascular hypertrophy, making ROS an excellent target for intervention aimed at reducing medial thickening in vivo.

Abstract P159: Scavengers of Isolevuglandins as Novel Therapeutic Approaches for Treating Hypertension & Associated Inflammation

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Wei Chen ◽  
Liang Xiao ◽  
Annet Kirabo ◽  
Danielle L Michell ◽  
Sean S Davies ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Lymphocytes ◽  
Antihypertensive Drugs ◽  
Study Drug ◽  
Organ Damage ◽  
Blue Staining ◽  
Ang Ii ◽  
Subsequent Activation ◽  
Oxidatively Modified

Adaptive immunity and especially T lymphocytes play a crucial role in the development of hypertension. Proteins that are oxidatively modified by highly reactive isolevuglandins (isoLGs) accumulate in dendritic cells & lead to subsequent activation of T lymphocytes. This process can be prevented by compounds known to scavenge isoLGs, such as 2-hydroxybenzylamine (2-HOBA). The overall goal of current study is to develop novel antihypertensive drugs based on this isoLG scavenging strategy, that will not only prevent but will also reverse hypertension and its associated inflammatory end-organ damage. Initially, the preventative effects of 10 putative isoLG scavengers were tested. C57Bl/6 mice received angiotensin (Ang) II (490 ng/kg/min) infusion for 14 days. Each compound was administered in the drinking water (1mg/ml) at the onset of Ang II infusion for 7 days to a half of the mice & for entire 14 day period to another half of the animals. Blood pressure was measured by tail cuff method. Among 10 compounds, we found that 2-HOBA, methyl 2HOBA (Me2HOBA) & 3-methoxy2-HOBA (3-Mo2HOBA) were most effective in lowering blood pressure. Interestingly, the pyridoxamine analogs were not effectively lowered blood pressure. We further examined the efficacy of our 3 most effective compounds in reversing established hypertension. Mice received Ang II infusion for 6 weeks and received each study drug (2 mg/ml) during the last 4 weeks. We employed radiotelemetry to monitor blood pressure. Compared with untreated mice, Me2-HOBA, 3-Mo2-HOBA & 2-HOBA were equally effective in lowering blood pressure by 20 mmHg (all p < 0.05 vs no drug). Six weeks of Ang II infusion caused 2- to 4-fold increases in renal T cell (CD3 + ) & monocyte/macrophage (F4/80 + ) infiltration as measured by immunohistochemistry & all three compounds markedly reduced these by 50%. These treatments also reduced aortic fibrosis as measured by Masson’s Trichrome blue staining. We conclude that these isoLG scavengers can be potentially used as new effective therapy for lowering blood pressure & attenuating hypertensive renal & vascular damage. Variability of in vivo effectiveness for the different scavengers likely reflects differences in bioavailability due to structure & lypophilicity.

scholarly journals Endothelial-Derived Extracellular Vesicles Induce Cerebrovascular Dysfunction in Inflammation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1525
Author(s):  
David Roig-Carles ◽  
Eduard Willms ◽  
Ruud D. Fontijn ◽  
Sarai Martinez-Pacheco ◽  
Imre Mäger ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
T Cell ◽  
Extracellular Vesicles ◽  
Lipid Membrane ◽  
Immune Cell ◽  
Leukocyte Adhesion ◽  
Cell Communication ◽  
Adhesion Assay ◽  
Cerebrovascular Dysfunction ◽  
T Cell Adhesion

Blood–brain barrier (BBB) dysfunction is a key hallmark in the pathology of many neuroinflammatory disorders. Extracellular vesicles (EVs) are lipid membrane-enclosed carriers of molecular cargo that are involved in cell-to-cell communication. Circulating endothelial EVs are increased in the plasma of patients with neurological disorders, and immune cell-derived EVs are known to modulate cerebrovascular functions. However, little is known about whether brain endothelial cell (BEC)-derived EVs themselves contribute to BBB dysfunction. Human cerebral microvascular cells (hCMEC/D3) were treated with TNFα and IFNy, and the EVs were isolated and characterised. The effect of EVs on BBB transendothelial resistance (TEER) and leukocyte adhesion in hCMEC/D3 cells was measured by electric substrate cell-substrate impedance sensing and the flow-based T-cell adhesion assay. EV-induced molecular changes in recipient hCMEC/D3 cells were analysed by RT-qPCR and Western blotting. A stimulation of naïve hCMEC/D3 cells with small EVs (sEVs) reduced the TEER and increased the shear-resistant T-cell adhesion. The levels of microRNA-155, VCAM1 and ICAM1 were increased in sEV-treated hCMEC/D3 cells. Blocking the expression of VCAM1, but not of ICAM1, prevented sEV-mediated T-cell adhesion to brain endothelia. These results suggest that sEVs derived from inflamed BECs promote cerebrovascular dysfunction. These findings may provide new insights into the mechanisms involving neuroinflammatory disorders.

Abstract 04: Growth Arrest Specific 6 And Axl Signaling Coordinate Endothelial Cell And Immune Cell Activation To Promote Inflammation And Hypertension.

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Justin P Van Beusecum ◽  
Natalia Barbaro ◽  
Charles D Smart ◽  
Mingfang Ao ◽  
David M Patrick ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Flow Cytometry ◽  
Endothelial Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Growth Arrest ◽  
Positive Association ◽  
Marrow Transplant ◽  
Ang Ii

Endothelial cells (ECs) activated by hypertensive (10%) cyclical stretch releases factors including IL-6 and hydrogen peroxide that stimulate the conversion of human monocytes to an intermediate inflammatory phenotype. A novel subset of DCs in humans has been identified that express Axl and Sigelc-6 + (AS DCs) which drive T cells proliferation and produce inflammatory cytokines. The interplay between ECs and AS DCs in hypertension is unkown. We assessed AS DCs by flow cytometry in normotensive (n=23) and hypertensive (n=11) subjects and found a significant increase in AS DCs in hypertensive compared to normotensive subjects (297 ± 73 vs. 108 ± 26/ml; p =0.0304). When moncoytes were exposed to human aortic endothelial cells (HAECs) undergoing 10% stretch, the formation of AS DCs was markedly enhanced compared to 5%. The ligand for Axl is growth arrest specific 6 (GAS6), and we found that 10% HAEC stretch caused a 50% increase in the release of GAS6 by ECs comapred to 5%. We knocked down either EC GAS6 or Axl using siRNA and either of these abrogated the ability of ECs to promote AS DC formation. Using flow cytometry to analyze venous ECs that had been harvested from 23 volunteers to quantify EC activation and GAS6 secretion in vivo, we found a positive association between GAS6 and ICAM-1 (R 2 =0.39, p =0.0012). We found a positive association between pulse pressure and plasma GAS6 (R 2 =0.25, p =0.0079) ands systolic blood pressure and GAS6 (R 2 =0.19, p=0.0025) in volunteers. We found that plasma GAS6 is increased in Ang II hypertension and that either genetic deletion or pharmacological inhibition of Axl lowered blood pressure in reposne to Ang II and reduced renal inflammation. To investigate the role of immunological vs. stromal Axl in vivo, we perfomed bone marrow transplant studies and found that both Axl WT/WT ->Axl -/- and Axl -/- ->Axl W/WT had a significant reduction in blood pressure by 20 mmHg compared to the Axl WT/WT -> Axl WT/WT control. These data show that both immunological and stromal Axl contribute to hypertension and inflammation and GAS6/Axl signlaing may be a novel therapeutic target in this disease.

scholarly journals Cd40-Independent Pathways of T Cell Help for Priming of Cd8+ Cytotoxic T Lymphocytes

2000 ◽  
Vol 191 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Zhengbin Lu ◽  
Lingxian Yuan ◽  
Xianzheng Zhou ◽  
Eduardo Sotomayor ◽  
Hyam I. Levitsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Communication ◽  
Cd8 T Cell ◽  
Cd4 Help ◽  
T Cell Help

In many cases, induction of CD8+ CTL responses requires CD4+ T cell help. Recently, it has been shown that a dominant pathway of CD4+ help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4+ T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide–specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4+ T helper cells, respectively. We found that CD4+ T cells can provide potent help for DCs to activate CD8+ T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4+ help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4+–CD8+ T cell communication via lymphokines. Therefore, we conclude that CD4+ help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4+–CD8+ T cell communication.

Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat

2007 ◽  
Vol 292 (2) ◽  
pp. F861-F867 ◽  
Author(s):  
Melvin R. Hayden ◽  
Nazif A. Chowdhury ◽  
Shawna A. Cooper ◽  
Adam Whaley-Connell ◽  
Javad Habibi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Proximal Tubule ◽  
Structural Damage ◽  
Kidney Tissue ◽  
Proximal Tubule Cell ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, with subsequent elevated tissue ANG II, hypertension, and nephropathy. The proximal tubule cell (PTC) is responsible for the reabsorption of 5–8 g of glomerular filtered albumin each day. Excess filtered albumin may contribute to PTC damage and tubulointerstitial disease. This investigation examined the role of ANG II-induced oxidative stress in PTC structural remodeling: whether such changes could be modified with in vivo treatment with ANG type 1 receptor (AT1R) blockade (valsartan) or SOD/catalase mimetic (tempol). Male Ren2 (6–7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk. Systolic blood pressure, albuminuria, N-acetyl-β-d-glucosaminidase, and kidney tissue malondialdehyde (MDA) were measured, and ×60,000 transmission electron microscopy images were used to assess PTC microvilli structure. There were significant differences in systolic blood pressure, albuminuria, lipid peroxidation (MDA and nitrotyrosine staining), and PTC structure in Ren2 vs. Sprague-Dawley rats (each P < 0.05). Increased mean diameter of PTC microvilli in the placebo-treated Ren2 rats ( P < 0.05) correlated strongly with albuminuria ( r2 = 0.83) and moderately with MDA ( r2 = 0.49), and there was an increase in the ratio of abnormal forms of microvilli in placebo-treated Ren2 rats compared with Sprague-Dawley control rats ( P < 0.05). AT1R blockade, but not tempol treatment, abrogated albuminuria and N-acetyl-β-d-glucosaminidase; both therapies corrected abnormalities in oxidative stress and PTC microvilli remodeling. These data indicate that PTC structural damage in the Ren2 rat is related to the oxidative stress response to ANG II and/or albuminuria.

Abstract 14: An Anti-inflammatory Proton Sensing-receptor Contributes To Cardiovascular Protection Of Gut Microbiota-derived Metabolites

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Liang Xie ◽  
Rikeish R Muralitharan ◽  
Evany Dinakis ◽  
Michael E Nakai ◽  
Hamdi Jama ◽  
...  
Keyword(s):  
T Cell ◽  
Gut Microbiota ◽  
Dietary Fibre ◽  
Dietary Intervention ◽  
Immune Cell ◽  
Ang Ii ◽  
Direct Role ◽  
Cardiovascular Protection ◽  
Anti Inflammatory ◽  
The Impact

High fibre (HF) diet protects against hypertension via the production of acidic metabolites, e.g. short-chain fatty acids, by the gut microbiota. While these metabolites have a direct role in blood pressure (BP) regulation, their acidic nature may activate proton-sensing receptors, which have anti-inflammatory functions. G-protein coupled receptor 65 (GPR65) is a proton-sensing receptor activated around pH 6.5 and is critical for gut homeostasis. We hypothesized that GPR65 is involved in the cardiovascular protection by dietary fibre. We first measured cecal pH of C57BL/6 (WT) mice after a 7-day dietary intervention with either HF or low fibre (LF) diets (n=6/group). HF diet lowered cecal pH to a level where GPR65 is highly activated, compared to the LF diet (6.5±0.1 vs 7.6±0.1, P<0.001). The impact of pH and GPR65 on T cell production of IFNγ, a pro-inflammatory cytokine, in vitro was measured by flow cytometry. Acidic pH inhibited the production of IFNγ by CD8+ T cells (pH 6.5 vs pH 7.5, P<0.001). Cells lacking GPR65 had higher IFNγ at both pH (P<0.001). To determine if GPR65 is involved in BP regulation by dietary fibre, WT and GPR65 knockout ( Gpr65 -/- ) mice were implanted with minipumps containing angiotensin II (Ang II, 0.5mg/kg/day, 28 days, n=8-9/group) and fed with HF diet. BP, cardiorenal function and immune cell infiltration were measured. Gpr65 -/- mice had higher BP compared to WT mice after 2 weeks (mean arterial pressure ± SEM; WT 79.8±2.4 vs Gpr65 -/- 95.8±1.6mmHg, P<0.001) and 4 weeks of Ang II infusion (WT 92.3±2.4 vs Gpr65 -/- 99.5±1.3, P=0.062). Gpr65 -/- mice developed cardiac (P=0.035) and renal (P=0.025) hypertrophy, and impaired renal natriuretic (P=0.054) and diuretic (P=0.056) function compared to WT mice. This was accompanied by higher macrophage (P=0.009) and γδ T cell (P=0.014) infiltration in the kidneys. In conclusion, our data suggest that pH-sensing by GPR65 contributes to the protection against hypertension by dietary fibre via inflammatory mechanisms. This is a novel mechanism that contributes to BP regulation via the gut microbiota.

scholarly journals Platelets Disseminate Extracellular Vesicles in Lymph in Rheumatoid Arthritis

2020 ◽  
Vol 40 (4) ◽  
pp. 929-942 ◽  
Author(s):  
Nicolas Tessandier ◽  
Imene Melki ◽  
Nathalie Cloutier ◽  
Isabelle Allaeys ◽  
Adam Miszta ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Extracellular Vesicles ◽  
Lymphatic System ◽  
Circulatory System ◽  
Donor Cell ◽  
Vascular Leakage ◽  
In Vivo Model ◽  
Interstitial Tissue ◽  
Tissue Fluid

Objective: The lymphatic system is a circulatory system that unidirectionally drains the interstitial tissue fluid back to blood circulation. Although lymph is utilized by leukocytes for immune surveillance, it remains inaccessible to platelets and erythrocytes. Activated cells release submicron extracellular vesicles (EV) that transport molecules from the donor cell. In rheumatoid arthritis, EV accumulate in the joint where they can interact with numerous cellular lineages. However, whether EV can exit the inflamed tissue to recirculate is unknown. Here, we investigated whether vascular leakage that occurs during inflammation could favor EV access to the lymphatic system. Approach and Results: Using an in vivo model of autoimmune inflammatory arthritis, we show that there is an influx of platelet EV, but not EV from erythrocytes or leukocytes, in joint-draining lymph. In contrast to blood platelet EV, lymph platelet EV lacked mitochondrial organelles and failed to promote coagulation. Platelet EV influx in lymph was consistent with joint vascular leakage and implicated the fibrinogen receptor α2bβ 3 and platelet-derived serotonin. Conclusions: These findings show that platelets can disseminate their EV in fluid that is inaccessible to platelets and beyond the joint in this disease.

Abstract P617: Angiotensin II-induced Hypertension And Vascular Injury Is Mediated By Gamma/delta T Cells

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Antoine Caillon ◽  
Muhammad Oneeb Rehman Mian ◽  
Tlili Barhoumi ◽  
Pierre Paradis ◽  
Ernesto L. Schiffrin
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
T Cell ◽  
Vascular Injury ◽  
Mesenteric Artery ◽  
Gamma Delta T Cells ◽  
Ang Ii ◽  
Wild Type ◽  
Gamma Delta ◽  
Adaptive Immune

Objective: Both innate antigen presenting cells and the adaptive immune system have been shown to play a role in the development of hypertension. Nevertheless, the T cell subset involved in the pathophysiology of hypertension remains unclear. There is a small subset of “innate-like” T cells expressing gamma/delta T cell receptor (TCR) rather than the alpha/beta TCR that could play a role in bridging between the innate and adaptive immune systems. However, it is unknown whether gamma/delta T cells contribute to development of hypertension. Method/Results: Thirteen to 15 week-old male C57BL/6 wild-type and Tcrd-/- mice, which are devoid of gamma/delta T cells, were infused or not with angiotensin (Ang) II (490 ng/kg/min, SC) for 7 or 14 days (n=4-9). Telemetric blood pressure, mesenteric artery endothelial function and vascular remodeling by pressurized myography and spleen T cell profile by flow cytometry were evaluated. Fourteen days of Ang II increased systolic blood pressure (167±4 vs 125±2 mmHg, P≤0.01) in wild-type compared to control mice. The frequency of gamma/delta T cells (6±1% vs 3±1%, P≤0.05) and activated (CD69+) gamma/delta T cells (11±1% vs 7±1%) was increased after 7 days of Ang II, and 7 days later were respectively unchanged or further increased (24±2% vs 10±1%) in wild-type compared to control mice. Ang II decreased mesenteric artery relaxation responses to acetylcholine (51±5% vs 88±3%, P≤0.01) and increased media/lumen (5±1 vs 3±0%, P≤0.01) in wild-type mice compare to controls. No gamma/delta T cells were detected in Tcrd-/- treated or not with Ang II. All the above Ang II effects were abrogated in Tcrd-/- mice. Conclusion: These data suggest that gamma/delta T cells mediate Ang II-induced blood pressure rise and vascular injury. Gamma/delta T cells could be key immune cells bridging innate and adaptive immune responses during the development of hypertension.

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