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Cerebrovascular reactivity (CVR) decreases with advancing age, contributing to increased risk of cognitive impairment; however, the mechanisms underlying the age-related decrease in CVR are incompletely understood. Age-related changes to T cells, such as impaired mitochondrial respiration, increased inflammation, likely contribute to peripheral and cerebrovascular dysfunction in animals. However, whether T-cell mitochondrial respiration is related to cerebrovascular function in humans is not known. Therefore, we hypothesized that peripheral T-cell mitochondrial respiration would be positively associated with CVR and that T-cell glycolytic metabolism would be negatively associated with CVR. Twenty middle-aged adults (58 ± 5 yr) were recruited for this study. T cells were separated from peripheral blood mononuclear cells. Cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR, a marker of glycolytic activity) were measured using extracellular flux analysis. CVR was quantified using the breath-hold index (BHI), which reflects the change in blood velocity in the middle-cerebral artery (MCAv) during a 30-s breath-hold. In contrast to our hypothesis, we found that basal OCR in CD8+ T cells (β = −0.59, R² = 0.27, P = 0.019) was negatively associated with BHI. However, in accordance with our hypothesis, we found that basal ECAR (β = −2.20, R² = 0.29, P = 0.015) and maximum ECAR (β = −50, R² = 0.24, P = 0.029) were negatively associated with BHI in CD8+ T cells. There were no associations observed in CD4+ T cells. These associations appeared to be primarily mediated by an association with the pressor response to the breath-hold test. Overall, our findings suggest that CD8+ T-cell respiration and glycolytic activity may influence CVR in humans. NEW & NOTEWORTHY Peripheral T-cell metabolism is related to in vivo cerebrovascular reactivity in humans. Higher glycolytic metabolism in CD8+ T cells was associated with lower cerebrovascular reactivity to a breath-hold in middle-aged adults, which is possibly reflective of a more proinflammatory state in midlife. [ABSTRACT FROM AUTHOR]

Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. Here, we have described a pathway in which hypertensive stimuli promote dendritic cell (DC) activation of T cells, ultimately leading to hypertension. Using multiple murine models of hypertension, we determined that proteins oxidatively modified by highly reactive γ-ketoaldehydes (isoketals) are formed in hypertension and accumulate in DCs. Isoketal accumulation was associated with DC production of IL-6, IL-1β, and IL-23 and an increase in costimulatory proteins CD80 and CD86. These activated DCs promoted T cell, particularly [CD8.sup.+] T cell, proliferation; production of IFN-γ and IL-17A; and hypertension. Moreover, isoketal scavengers prevented these hypertension-associated events. Plasma F2-isoprostanes, which are formed in concert with isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also markedly elevated in circulating monocytes and DCs from humans with hypertension. Our data reveal that hypertension activates DCs, in large part by promoting the formation of isoketals, and suggest that reducing isoketals has potential as a treatment strategy for this disease., Introduction It is well established that inflammation is involved in the genesis of hypertension (1). T cells and macrophages accumulate in the kidneys and vasculature of animals with experimental hypertension [...]

Inhibition of mammalian target of rapamycin, mTOR, extends lifespan and reduces age-related disease. It is not known what role mTOR plays in the arterial aging phenotype or if mTOR inhibition by dietary rapamycin ameliorates age-related arterial dysfunction. To explore this, young (3.8 ± 0.6 months) and old (30.3 ± 0.2 months) male B6D2F1 mice were fed a rapamycin supplemented or control diet for 6-8 weeks. Although there were few other notable changes in animal characteristics after rapamycin treatment, we found that glucose tolerance improved in old mice, but was impaired in young mice, after rapamycin supplementation (both P < 0.05). Aging increased mTOR activation in arteries evidenced by elevated S6K phosphorylation ( P < 0.01), and this was reversed after rapamycin treatment in old mice ( P < 0.05). Aging was also associated with impaired endothelium-dependent dilation ( EDD) in the carotid artery ( P < 0.05). Rapamycin improved EDD in old mice ( P < 0.05). Superoxide production and NADPH oxidase expression were higher in arteries from old compared to young mice ( P < 0.05), and rapamycin normalized these ( P < 0.05) to levels not different from young mice. Scavenging superoxide improved carotid artery EDD in untreated ( P < 0.05), but not rapamycin-treated, old mice. While aging increased large artery stiffness evidenced by increased aortic pulse-wave velocity ( PWV) ( P < 0.01), rapamycin treatment reduced aortic PWV ( P < 0.05) and collagen content ( P < 0.05) in old mice. Aortic adenosine monophosphate-activated protein kinase ( AMPK) phosphorylation and expression of the cell cycle-related proteins PTEN and p27kip were increased with rapamycin treatment in old mice (all P < 0.05). Lastly, aging resulted in augmentation of the arterial senescence marker, p19 ( P < 0.05), and this was ameliorated by rapamycin treatment ( P < 0.05). These results demonstrate beneficial effects of rapamycin treatment on arterial function in old mice and suggest these improvements are associated with reduced oxidative stress, AMPK activation and increased expression of proteins involved in the control of the cell cycle. [ABSTRACT FROM AUTHOR]

Recent studies have emphasized a role of adaptive immunity, and particularly T cells, in the genesis of hypertension. We sought to determine the T-cell subtypes that contribute to hypertension and renal inflammation in angiotensin II-induced hypertension. Using T-cell receptor spectratyping to examine T-cell receptor usage, we demonstrated that CD8(+) cells, but not CD4(+) cells, in the kidney exhibited altered T-cell receptor transcript lengths in Vβ3, 8.1, and 17 families in response to angiotensin II-induced hypertension. Clonality was not observed in other organs. The hypertension caused by angiotensin II in CD4(-/-) and MHCII(-/-) mice was similar to that observed in wild-type mice, whereas CD8(-/-) mice and OT1xRAG-1(-/-) mice, which have only 1 T-cell receptor, exhibited a blunted hypertensive response to angiotensin II. Adoptive transfer of pan T cells and CD8(+) T cells but not CD4(+)/CD25(-) cells conferred hypertension to RAG-1(-/-) mice. In contrast, transfer of CD4(+)/CD25(+) cells to wild-type mice receiving angiotensin II decreased blood pressure. Mice treated with angiotensin II exhibited increased numbers of kidney CD4(+) and CD8(+) T cells. In response to a sodium/volume challenge, wild-type and CD4(-/-) mice infused with angiotensin II retained water and sodium, whereas CD8(-/-) mice did not. CD8(-/-) mice were also protected against angiotensin-induced endothelial dysfunction and vascular remodeling in the kidney. These data suggest that in the development of hypertension, an oligoclonal population of CD8(+) cells accumulates in the kidney and likely contributes to hypertension by contributing to sodium and volume retention and vascular rarefaction. [ABSTRACT FROM AUTHOR]

Recent studies have emphasized a role of adaptive immunity, and particularly T cells, in the genesis o f hypertension. We sought to determine the T-cell subtypes that contribute to hypertension and renal inflammation in angiotensin II-induced hypertension. Using T-cell receptor spectratyping to examine T-cell receptor usage, we demonstrated that CD8+ cells, but not CD4+ cells, in the kidney exhibited altered T-cell receptor transcript lengths in Vβ3, 8.1, and 17 families in response to angiotensin II-induced hypertension. Clonality was not observed in other organs. The hypertension caused by angiotensin II in CD4-/- and MHCII-/- mice was similar to that observed in wild-type mice, whereas CD8-/- mice and OT1xRAG-1-/- mice, which have only 1 T-cell receptor, exhibited a blunted hypertensive response to angiotensin II. Adoptive transfer of pan T cells and CD8+ T cells but not CD4+/CD25- cells conferred hypertension to RAG-1-/- mice. In contrast, transfer of CD4+/CD25+ cells to wild-type mice receiving angiotensin II decreased blood pressure. Mice treated with angiotensin II exhibited increased numbers of kidney CD4+ and CD8+ T cells. In response to a sodium/volume challenge, wild-type and CD4-/- mice infused with angiotensin II retained water and sodium, whereas CD8-/- mice did not. CD8-/- mice were also protected against angiotensin-induced endothelial dysfunction and vascular remodeling in the kidney. These data suggest that in the development of hypertension, an oligoclonal population of CD8+ cells accumulates in the kidney and likely contributes to hypertension by contributing to sodium and volume retention and vascular rarefaction. [ABSTRACT FROM AUTHOR]

The purpose of this investigation was to determine if endogenous T cell receptors (TCR) are required for the development of hypertension. Our laboratory has preliminary data suggesting that hypertension is associated with an oligoclonal TCR expansion of CD8+ T cells in mouse kidney. To determine whether mice with an altered TCR phenotype are protected against hypertension, OT1 mice, which express a transgenic TCR specific for ovalbumin on CD8+ cells, and OT1xRag-1-/- mice were infused with angiotensin II (490ng/min/kg) or vehicle. Blood pressure was measured by telemetery. After 2 weeks OT1 mice infused with angiotensin II exhibited increased blood pressure (171 ± 10 systolic, 113 ± 16 diastolic, mean ± S.E.M. mmHg) compared to controls (117 ± 15 systolic, 83 ± 7 diastolic). The hypertensive response was blunted in OT1xRag-1-/- mice that received angiotensin II (142 ± 12 systolic, 85 ± 13 diastolic). Analysis of kidney resident CD8+ TCR by flow cytometery revealed that 6.8 ± 2.9% and 5.2 ± 1.7% in sham and angiotensin II treated OT1 mice respectively were non-transgenic whereas 0.3 ± 0.2% and 0.5 ± 0.1% in sham and angiotensin II treated OT1xRag-1-/- mice respectively were non-transgenic. These data together with the finding that hypertension promotes an oligoclonal TCR expansion in kidney suggest that endogenous TCR are required to respond to neoantigens and mediate the development of overt hypertension. [ABSTRACT FROM AUTHOR]

T cells have been implicated in the genesis of hypertension however the mechanisms and subtype of T cells involved are still poorly understood. Moreover, the manner by which T cells of various subtypes affect renal function remains poorly defined. Recently, we found that CD8+ T cells play a critical role in the blood pressure elevation caused by angiotensin II. We sought to determine if CD8+ T cells have a role in the renal responses to angiotensin II. In metabolic chamber studies, we found that wild-type mice excrete 80% of a saline load (10% of body weight) in 4 hours, and that this is decreased in response to angiotensin II to 60 ± 5% (p < 0.05) in WT mice but not in CD8-/- mice. In contrast, CD4-/- mice demonstrate a markedly exaggerated anti-natriuretic and anti-diuretic response to angiotensin II (p < 0.001). We also found that chronic angiotensin II infusion increases superoxide production in the renal cortex of WT and CD4-/- mice, but not in CD8-/- mice. In addition, we found that angiotensin II infusion caused significant hypertrophy of the renal arterioles (< 25 μm diameter) as reflected by an increase in the media/lumen ratio in wild type and CD4-/- mice, (1.5 to 4.5 and 2.9 to 5.3 respectively, p < 0.05 for each), but to a lesser extent in CD8-/- mice (1.8 to 3.3). We also observed that the number of arterioles 0-25 micron in diameter decreased from 16.5 and 15.5 to 11.8 and to 11.4/mm2 in wild type and CD4-/- mice respectively in response to angiotensin II, but was not changed in CD8-/- mice. Our study therefore shows a previously unrecognized role for CD8+ T cells in modulating renal sodium and volume retention, renal cortical superoxide production, vascular hypertrophy and rarefaction. Thus, CD8+ T cells are an important intermediate in the actions of angiotensin II on the kidney, and a potential therapeutic target. [ABSTRACT FROM AUTHOR]

We have previously shown that T cells play a critical role in the genesis of hypertension, and that activated T cells infiltrate the vasculature and the kidney to promote vasoconstriction and sodium retention. Stimulation of the T cell receptor (TCR) with a specific antigen leads to clonal expansion of cells with identical TCRs. In contrast, if multiple antigens are presented, T cells with multiple TCRs proliferate. We sought to determine if hypertension promotes a mono- or polyclonal T cell response. TCR Vβ chain gene transcript length can be used to examine T cell clonality. We produced hypertension in C57Bl/6 mice by chronic (2 week, 490 ng/kg/min) infusion of angiotensin II and used vehicle infused mice as controls. PCR was employed to amplify the 24 TCR Vβ chain subfamilies in the kidney and mesenteric vasculature. PCR products were subjected to high-resolution capillary electrophoresis fragment analysis to determine TCR Vβ chain transcript length. Eleven of the 24 Vβ length profiles exhibited greater than 20% skewing with angiotensin II infusion in kidney and 6 of 24 exhibited greater than 20% skewing in mesentery. Dominant transcript lengths were present with angiotensin II infusion for Vβ 1 (30 ± 5 vs. 51 ± 7), 3 (29 ± 3 vs. 51 ± 12) and 20 (0 ± 0 vs. 41 ± 18) in kidney and 1 (30 ± 2 vs. 43 ± 4), 4 (27 ± 4 vs. 45 ± 3) and 20 (15 ± 3 vs. 46 ± 6) in mesentery (data are expressed as % ± S.E.M. of TCR transcripts of a given length within each Vβ family, sham vs. angiotensin II, n = 5 per group). These results suggest that hypertension results in oligoclonal T cell expansion in the kidney and mesentery. Alterations in Vβ 1 and 20 in both kidney and mesentery suggest a common TCR response between tissues. [ABSTRACT FROM AUTHOR]

Vascular dysfunction has emerged as a significant risk factor for the development of cardio- and cerebrovascular diseases (CVDs), which are currently the leading cause of morbidity and mortality worldwide. T-lymphocytes (T-cells) have been shown to be important modulators of vascular function in primary aging and CVDs, likely by producing inflammatory cytokines and reactive oxygen species that influence vasoprotective molecules. This review summarizes the role of T-cells on vascular function in aging, hypertension, and atherosclerosis in animals and humans, and discusses potential T-cell targeted therapeutics to prevent, delay, or reverse vascular dysfunction.

Cerebrovascular reactivity (CVR) decreases with advancing age, contributing to increased risk of cognitive impairment; however, the mechanisms underlying the age-related decrease in CVR are incompletely understood. Age-related changes to T cells, such as impaired mitochondrial respiration, increased inflammation, likely contribute to peripheral and cerebrovascular dysfunction in animals. However, whether T-cell mitochondrial respiration is related to cerebrovascular function in humans is not known. Therefore, we hypothesized that peripheral T-cell mitochondrial respiration would be positively associated with CVR and that T-cell glycolytic metabolism would be negatively associated with CVR. Twenty middle-aged adults (58 ± 5 yr) were recruited for this study. T cells were separated from peripheral blood mononuclear cells. Cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR, a marker of glycolytic activity) were measured using extracellular flux analysis. CVR was quantified using the breath-hold index (BHI), which reflects the change in blood velocity in the middle-cerebral artery (MCAv) during a 30-s breath-hold. In contrast to our hypothesis, we found that basal OCR in CD8 + T cells (β = -0.59, R 2  = 0.27, P = 0.019) was negatively associated with BHI. However, in accordance with our hypothesis, we found that basal ECAR (β = -2.20, R 2  = 0.29, P = 0.015) and maximum ECAR (β = -50, R 2  = 0.24, P = 0.029) were negatively associated with BHI in CD8 + T cells. There were no associations observed in CD4 + T cells. These associations appeared to be primarily mediated by an association with the pressor response to the breath-hold test. Overall, our findings suggest that CD8 + T-cell respiration and glycolytic activity may influence CVR in humans. NEW & NOTEWORTHY Peripheral T-cell metabolism is related to in vivo cerebrovascular reactivity in humans. Higher glycolytic metabolism in CD8 + T cells was associated with lower cerebrovascular reactivity to a breath-hold in middle-aged adults, which is possibly reflective of a more proinflammatory state in midlife.

The prevalence of major depressive disorder (MDD) is highest in young adulthood, an effect that has been magnified by the COVID-19 pandemic. Importantly, individuals with MDD are at a greater risk of developing cardiovascular disease (CVD). Accumulating evidence supports immune system dysregulation as a major contributor to the elevated CVD risk in older adults with MDD; however, whether this is present in young adults with MDD without comorbid disease remains unclear. Interestingly, recent data suggest augmented T-cell mitochondrial reactive oxygen species (T-cell mitoROS) as a potent driver of immune dysregulation in animal models of psychiatric disease. With this background in mind, we tested the hypothesis that young adults with MDD would have augmented T-cell mitoROS and circulating proinflammatory cytokines compared with healthy young adults without MDD (HA). Whole blood was drawn from 14 young adults with MDD (age: 23 ± 2 yr) and 11 HA (age: 22 ± 1 yr). T-cell mitoROS (MitoSOX red; total: CD3 + , T-helper: CD4 + , T cytotoxic: CD8 + ) and serum cytokines were assessed by flow cytometry. Total T-cell mitoROS was significantly greater in adults with MDD compared with HA [median: 14,089 arbitrary units (AU); median: 1,362 AU, P = 0.01]. Likewise, both T-helper and T-cytotoxic cell mitoROS were significantly greater in adults with MDD compared with HA (both: P < 0.05). There were no differences in circulating cytokines between groups (all cytokines: P > 0.05). Collectively, these findings suggest that elevated T-cell mitoROS may represent an early marker of immune system dysregulation in young, otherwise healthy, adults with MDD. NEW & NOTEWORTHY To our knowledge, we provide the first evidence of augmented T-cell mitochondrial reactive oxygen species (T-cell mitoROS) in young, otherwise healthy adults with MDD. Although the elevated T-cell mitoROS did not correspond to a proinflammatory profile, these findings suggest that elevated T-cell mitoROS may be an early marker of immune system dysregulation in young adults with MDD.