Current knowledge suggests that hypertension is in part mediated by immune mechanisms. Both IL-23 and IL-17 are upregulated in several experimental hypertensive rodent models, as well as in hypertensive humans in observational studies. Recent preclinical studies have shown that either IL-23 or IL-17A treatment induce blood pressure elevation. However, the IL-23/IL-17 axis has not been a major therapeutic target in hypertension, unlike in other autoimmune diseases. In this review, we summarize current knowledge on the role of these cytokines in immune mechanisms contributing to hypertension, and discuss the potential of IL-23/IL-17-targeted therapy for treatment of hypertension.
<b><i>Background:</i></b> Pressurized myography is useful for the assessment of small artery structures and function. However, this procedure requires technical expertise for sample preparation and effort to choose an appropriate sized artery. In this study, we developed an automatic artery/vein differentiation and a size measurement system utilizing machine learning algorithms. <b><i>Methods and Results:</i></b> We used 654 independent mouse mesenteric artery images for model training. The model yielded an Intersection-over-Union of 0.744 ± 0.031 and a Dice coefficient of 0.881 ± 0.016. The vessel size and lumen size calculated from the predicted vessel contours demonstrated a strong linear correlation with manually determined vessel sizes (<i>R</i> = 0.722 ± 0.048, <i>p</i> < 0.001 for vessel size and <i>R</i> = 0.908 ± 0.027, <i>p</i> < 0.001 for lumen size). Last, we assessed the relation between the vessel size before and after dissection using a pressurized myography system. We observed a strong positive correlation between the wall/lumen ratio before dissection and the lumen expansion ratio (<i>R</i> = 0.832, <i>p</i> < 0.01). Using multivariate binary logistic regression, 2 models estimating whether the vessel met the size criteria (lumen size of 160–240 μm) were generated with an area under the receiver operating characteristic curve of 0.761 for the upper limit and 0.747 for the lower limit. <b><i>Conclusion:</i></b> The U-Net-based image analysis method could streamline the experimental approach.
Objective: We previously demonstrated that a small subpopulation of T cells considered (innate-like), expressing the γδ T-cell receptor (TCR) plays a key role in hypertension and vascular injury. γδ T cells can be subdivided according to the TCR variant (V) subtype that is generally specific for a tissue. A subpopulation of lungs and skin γδ T cells that are Vγ6+ and produce interleukin (IL)-17A was shown to respond promptly to pneumococcal infection and skin inflammation. However, γδ T cell Vγ subtypes involved in hypertension are still unknown. We hypothesized that the Vγ6+ γδ T cell may play a role in angiotensin (Ang) II-induced hypertension and vascular injury. Design and method: Eleven- to 13-week-old C57BL/6J male mice were infused or not with Ang II (490 ng/kg/min, SC) for 14 days, (n = 5–14). The γδ T cell Vγ subtypes were profiled and markers of activation of Vγ6+ γδ T cells were determined by flow cytometry. Results: In spleen and mesenteric lymph nodes (MLNs) the most abundant γδ T cells Vγ were Vγ1/2+ and Vγ4+ followed by Vγ6+,Vγ5+ and Vγ7+. In thoracic aortic (TA) perivascular adipose tissue (PVAT), the most abundant γδ T cell Vγ was Vγ6+ followed by Vγ4+, Vγ1/2+, Vγ5+ and Vγ7+. In mesenteric artery (MA) PVAT, the most abundant γδ T cell Vγ subtype was Vγ6+ followed by Vγ4+, Vγ7+, Vγ5+ and Vγ1/2+. Ang II increased the frequency of Vγ6+ γδ T cells in the spleen (1.5-fold, P < 0.01) and TA PVAT (1.6-fold, P < 0.01), whereas it only tended to increase them in MA PVAT. The frequency of IL-17 producing effector memory (CCR6 + CXCR3–CD44 + CD69 + ) Vγ6+ γδ T cells were increased in spleen (1.7-fold, P < 0.01) and trended to be elevated in mesenteric PVAT in Ang II-infused mice compared to control mice. Conclusions: Vγ6+ γδ T cells were the most abundant Vγ subtype in PVAT. IL-17 producing effector memory Vγ6+ γδ T cells may play a role in Ang II-induced hypertension. Targeting a γδ T cell variant subtype could be a therapeutic approach to reduce inflammation in hypertension.
Introduction: The innate-like γδ T cells play a role in angiotensin II (AngII)-induced hypertension, vascular injury and T cell activation in perivascular adipose tissue (PVAT). Hypothesis: We hypothesized that single cell RNA sequencing (scRNA-seq) will reveal γδ T cell subpopulations in PVAT involved in hypertension, vascular injury and T cell activation. Methods: Male C57BL/6J mice were infused SC or not with 490 ng/kg/min AngII for 14 days (n=3). Hypertension was confirmed by tail cuff blood pressure measurement. Mesenteric vessels (MV) with PVAT were collected, lymph nodes removed, single cell suspension obtained and labeled with hashtag antibodies, T cells isolated by fluorescence-activated cell sorting, the 6 samples pooled in one tube, and scRNA libraries prepared with a Chromium Next GEM Single Cell 3’ Reagent Kit. Sequencing was done on an Illumina Novaseq 6000, and data analysed using Cell Ranger pipeline and Seurat tools. Cell subpopulations were validated by flow cytometry. Results: ScRNA-seq yielded 5,030 cells with 137,990 reads/cell and identified 11 T cell clusters. Subclustering of T cells expressing the T cell receptor (TCR) δ constant chain revealed 3 δ natural killer T (δNKT) (δNKT0, δNKT1 and activated δNKT cells) and 3 γδ T cell subpopulations ( Trgc1 low effector memory, TCR δ variable 4 + and apoptotic γδ T cells). AngII increased >2-fold the frequency of activated δNKT cells, and decreased by 74% δNKT0 cells. Gene expression profiling revealed that activated δNKT and δNKT0 cells could be identified using unique markers, Cd28 and Sell , respectively. Flow cytometry showed that TCRδ + CD28 + Sell - T cells were increased (393±57.2 vs 227±44.4 cells/MV-PVAT) and TCRδ + CD28 - Sell + T cells decreased (21.6±4.1 vs 45.3±4.10 cells/MV-PVAT) in MV-PVAT of AngII vs sham-treated mice. Conclusion: This study identified an activated δNKT cell subpopulation in MV-PVAT that may play a role in AngII-induced hypertension, vascular injury and T cell activation.
Background: The mechanisms of blood pressure (BP) regulation by endothelin (ET)-1 produced by endothelial cells (ECs) are complex and remain unclear. Transgenic mice with tamoxifen-inducible EC-restricted human ET-1 overexpression (ieET-1) exhibited BP elevation 3 months after induction. ET-1 has been shown to stimulate the release of aldosterone from adrenal cortex (AC). Whether aldosterone plays a role in EC ET-1 overexpression-induced BP elevation and vascular injury is still unknown. Methods and results: Nine to 12-week-old male ieET-1 mice and control ieCre mice expressing a tamoxifen-inducible Cre recombinase under the control of EC-specific Tie2 promoter were treated with tamoxifen (1 mg/kg/day, SC) for 5 days and studied 3 months later. Plasma aldosterone levels measured by ELISA was increased in ieET-1 vs. ieCre mice (1.21±0.14 vs. 0.70±0.09 ng/mL, P <0.05). Reverse transcription-quantitative PCR (RT-qPCR) showed that aldosterone synthase ( Cyp11b2 ) was decreased in AC of ieET-1 vs. ieCre mice (fold change: 0.52±0.06 vs. 1.00±0.16, P <0.01). CYP11B2 protein levels measured by Western Blotting was unchanged. Treatment with mineralocorticoid receptor antagonist eplerenone (100 mg/kg/day) during the last 2 weeks decreased daytime systolic BP determined by telemetry in ieET-1 vs. ieCre mice (Systolic after 14 days [mm Hg]: 128±1.6 vs. 137±1.8, P <0.01). The EC50 concentration for norepinephrine-induced MA contraction was reduced in ieET-1 vs. ieCre mice (EC50 [mol/L]: 5x10 -7 ±6x10 -8 vs. 4x10 -6 ±7x10 -7 , P <0.05), which was reversed by elplerenone (EC50 [mol/L]: 8x10 -6 ±5x10 -6 , P <0.05). The MA relaxation response to acetylcholine was decreased in ieET-1 vs. ieCre mice (32.2±5.3% vs. 70.5±5.9%), effect that was reduced by eplerenone (43.1±5.5%). The MA endothelium-independent relaxation response to sodium nitroprusside (SNP) was similar in ieET-1 and ieCre mice. Eplerenone enhanced sensitivity to SNP in iET-1 mice (EC50 [mol/L]: 3x10 -8 ±1x10 -8 vs. 1x10 -7 ±2x10 -8 , P <0.05). Conclusions: Increased aldosterone production contributes to EC human ET-1 overexpression-induced daytime SBP elevation, enhanced contractile response to norepinephrine and endothelial dysfunction.
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