B lymphocyte-derived acetylcholine limits steady-state and emergency hematopoiesis.

Autonomic nerves control organ function through the sympathetic and parasympathetic branches, which have opposite effects. In the bone marrow, sympathetic (adrenergic) nerves promote hematopoiesis; however, how parasympathetic (cholinergic) signals modulate hematopoiesis is unclear. Here, we show that B lymphocytes are an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system, which reduced hematopoiesis. Single-cell RNA sequencing identified nine clusters of cells that expressed the cholinergic α7 nicotinic receptor (Chrna7) in the bone marrow stem cell niche, including endothelial and mesenchymal stromal cells (MSCs). Deletion of B cell-derived acetylcholine resulted in the differential expression of various genes, including Cxcl12 in leptin receptor+ (LepR+) stromal cells. Pharmacologic inhibition of acetylcholine signaling increased the systemic supply of inflammatory myeloid cells in mice and humans with cardiovascular disease.

Training-Induced Deactivation of the AT1 Receptor Pathway Drives Autonomic Control and Heart Remodeling During the Transition From the Pre- to Hypertensive Phase in Spontaneously Hypertensive Rats.

BACKGROUND: The effects of hypertension and exercise training (T) on the sequential interplay between renin-angiotensin system (RAS), autonomic control and heart remodeling during the development of hypertension in spontaneously hypertensive rats (SHR), was evaluated.Methods and Results:Time course changes of these parameters were recorded in 4-week-old SHR submitted to a T or sedentary (S) protocol. Wistar Kyoto rats served as controls. Hemodynamic recordings were obtained in conscious rats at experimental weeks 0, 1, 2, 4, and 8. The left ventricle (LV) was collected to evaluate RAS gene and protein expression, cardiomyocytes' hypertrophy and collagen accumulation. Pre-hypertensive SHR exhibited augmented AT1R gene expression; at 5 weeks, they presented with elevated pressure, increased LV angiotensinogen and ACE mRNA expression, followed by sympathoexcitation (from the 8thweek onwards). Marked AT1R protein content, myocytes's hypertrophy, collagen deposition and increased pressure variability were observed in 12-week-old sedentary SHR. In addition to attenuating all these effects, T activated Mas receptor expression augmented parasympathetic modulation of the heart, and delayed the onset and reduced the magnitude, but did not block the development of genetic hypertension. CONCLUSIONS: The close temporal relationship between changes in the LV ACE-Ang II-AT1R axis, autonomic control and cardiac remodeling at both the establishment of hypertension and during exercise training reveals the essential role played by the AT1R pathway in driving cardiac remodeling and autonomic modulation during the transition from the pre- to hypertensive phase.

Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells.

A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creERT2; Leprfl/fl mice reveals that leptin's effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.

Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration.

Innate immune cells recruited to inflammatory sites have short life spans and originate from the marrow, which is distributed throughout the long and flat bones. While bone marrow production and release of leukocyte increases after stroke, it is currently unknown whether its activity rises homogeneously throughout the entire hematopoietic system. To address this question, we employed spectrally resolved in vivo cell labeling in the murine skull and tibia. We show that in murine models of stroke and aseptic meningitis, skull bone marrow-derived neutrophils are more likely to migrate to the adjacent brain tissue than cells that reside in the tibia. Confocal microscopy of the skull-dura interface revealed myeloid cell migration through microscopic vascular channels crossing the inner skull cortex. These observations point to a direct local interaction between the brain and the skull bone marrow through the meninges.

Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion.

RATIONALE: Superficial erosion currently causes up to a third of acute coronary syndromes; yet, we lack understanding of its mechanisms. Thrombi because of superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation. OBJECTIVE: This study tested in vivo the involvement of disturbed flow and of neutrophils, hyaluronan, and Toll-like receptor 2 ligation in superficial intimal injury, a process implicated in superficial erosion. METHODS AND RESULTS: In mouse carotid arteries with established intimal lesions tailored to resemble the substrate of human eroded plaques, acute flow perturbation promoted downstream endothelial cell activation, neutrophil accumulation, endothelial cell death and desquamation, and mural thrombosis. Neutrophil loss-of-function limited these findings. Toll-like receptor 2 agonism activated luminal endothelial cells, and deficiency of this innate immune receptor decreased intimal neutrophil adherence in regions of local flow disturbance, reducing endothelial cell injury and local thrombosis (P<0.05). CONCLUSIONS: These results implicate flow disturbance, neutrophils, and Toll-like receptor 2 signaling as mechanisms that contribute to superficial erosion, a cause of acute coronary syndrome of likely growing importance in the statin era.

Effect of continuous and interval aerobic exercise training on baroreflex sensitivity in heart failure.

INTRODUCTION: The ability of continuous aerobic exercise training (AET) to increase baroreflex control and cardiac function in heart failure (HF) has been well described, but the comparison between continuous and interval AET on these functions is inconclusive. OBJECTIVES: To compare the effects of continuous and interval AET on cardiac function and baroreflex sensitivity (BrS) in an experimental model of HF. METHODS: Rats were divided into the following groups: continuous training (HF-CT), intense interval training (HF-IIT), moderate interval training (HF-MIT), sedentary group (HF-SED), and sham sedentary (SHAM-SED). Animals underwent surgery to induce HF by ligation of the interventricular coronary artery. Six weeks after surgery, AET was started (8weeks, 3sessions/week). Echocardiography studies to assess cardiac function were performed before and after AET. At the end of the training protocols, the BrS index was assessed by stepwise intravenous infusions of sodium nitroprusside and phenylephrine. RESULTS: All methods of exercise prevented the HF-induced increase in left ventricular diameter in diastole observed in the HF-SED rats (0.88±0.09 vs. 1.03±0.09cm; P<0.05), but only the HF-CT (28.5±6.3 vs. 39.2±12.7%; P<0.05) and HF-MIT (31.0±8.5 vs. 42.0±10.3%; P<0.05) groups exhibited an increase in ejection fraction. Nevertheless, the HF-CT group was the only group that showed a tachycardia reflex higher than that of the HF-SED group (0.87±0.34 vs. 0.20±0.05bpm/mmHg; P<0.05) and similar to that of the SHAM-SED group (1.04±0.11bpm/mmHg). CONCLUSIONS: These results suggest that continuous and moderate interval training induced similar improvements in cardiac function but that only continuous training induced higher BrS in HF rats.

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR.

Exercise training (ExT) is recommended to treat hypertension along with pharmaceutical antihypertensive therapies. Effects of ExT in hypothalamic content of high mobility box 1 (HMGB1) and microglial activation remain unknown. We examined whether ExT would decrease autonomic and cardiovascular abnormalities in spontaneously hypertensive rats (SHR), and whether these effects were associated with decreased HMGB1 content, microglial activation, and inflammation in the hypothalamic paraventricular nucleus (PVN). Normotensive Wistar-Kyoto (WKY) rats and SHR underwent moderate-intensity ExT for 2 wk. After ExT, cardiovascular (heart rate and arterial pressure) and autonomic parameters (arterial pressure and heart rate variability, peripheral sympathetic activity, cardiac vagal activity, and baroreflex function) were measured in conscious and freely-moving rats through chronic arterial and venous catheterization. Cerebrospinal fluid, plasma, and brain were collected for molecular and immunohistochemistry analyses of the PVN. In addition to reduced heart rate variability, decreased vagal cardiac activity and increased mean arterial pressure, heart rate, arterial pressure variability, cardiac, and vasomotor sympathetic activity, SHR had higher HMGB1 protein expression, IκB-α phosphorylation, TNF-α and IL-6 protein expression, and microglia activation in the PVN. These changes were accompanied by higher plasma and cerebrospinal fluid levels of HMGB1. The ExT + SHR group had decreased expression of HMGB1, CXCR4, SDF-1, and phosphorylation of p42/44 and IκB-α. ExT reduced microglial activation and proinflammatory cytokines content in the PVN, and improved autonomic control as well. Data suggest that training-induced downregulation of activated HMGB1/CXCR4/microglia/proinflammatory cytokines axis in the PVN of SHR is a prompt neural adaptation to counterbalance the deleterious effects of inflammation on autonomic control.

Atividade nervosa simpática e desenvolvimento de lesões de órgãos-alvo na hipertensão arterial: benefícios autonômicos induzidos pelo treinamento aeróbio / Sympathetic nerve activity and development of end-organ injury in hypertension: autonomic benefits induced by aerobic training

A disfunção autonômica encontra-se estreitamente associada ao estabe- lecimento da hipertensão arterial, sendo caracterizada por aumento da atividade simpática, redução do tônus vagal e disfunção barorreflexa, contribuindo para a instalação da insuficiência cardíaca, do infarto do miocárdio, do acidente vascular cerebral, entre outras comorbidades. Remodelamento hipertrófico de arteríolas cerebrais, ativação de quimiorreceptores, anormalidades na barreira hematoencefálica e aumento da atividade neuronal determinam a geração de espécies reativas de oxigênio e citocinas pró-inflamatórias em áreas de controle cardiovascular, as quais, em associação com a hiperativação do sistema renina-angiotensina, perpetuam a disfunção autonôrnica e favorecem a manutenção da hipertensão arterial crônica. Além disto, a disfunção barorreflexa aumenta a variabilidade da pressão arterial, predispondo à rarefação capilar e determinando a progressão de lesões de órgãos-alvo. Por sua vez, a maior disponibilidade de angiotensina li nos diferentes tecidos é um importante estímulo para a inflamação tecidual e hipertrofia de artérias/arteríolas periféricas, potencializando os efeitos deletérios desencadeados pela hiperatividade simpática e disfunção barorreflexa. A hipertensão, uma vez estabelecida, é uma doença crônica que exige tratamento continuado, o qual pode reduzir os níveis pressóricos, mas não curá-Ia. Um importante avanço no controle da hipertensão foi a constatação de que o treinamento aeróbio, mesmo não normalizando a pressão arterial, reduz acentuadamente o estresse oxidativo e a in- flamação em áreas autonômicas, corrigindo prontamente a disfunção barorreflexa, aumentando o tônus vaga I e reduzindo a atividade simpá- tica. Estas adaptações autonôrnicas, em associação com a reversão do remodelamento hipertrófico arteriolar em tecidos exercitados, reduzem a resistência vascular periférica e a pressão arterial.

Autononic dysfunction is closely related to the development of hypertension, being characterized by increased sympathetic activity, decreased vagal tonus and baroreflex dysfunction. These autonornic adaptations contribute to heart failure, myocardial infarction and stroke as well. Hypertrophic remodeling ofbrain arterioles, chemoreceptors activation, blood-brain barrier abnormalities determine reactive oxygen species and pro-inflammatory cytokines production and increased neuronal activity within autonornic brain areas controlling the cardiovascular system. These responses associated with hyperactivation ofthe renin-angiotensin system allow the maintenance of chronic hypertension. Furthermore, baroreflex dysfunction increases arterial pressure variability that causes capillary rarefaction and end-organs injuries. On several tissues, increased Angiotensin li production is an important stimulus for tissue inflammation and arteries/arterioles hypertrophy, thus potentiating the deleterious effects of sympathetic hyperactivity and baroreflex dysfunction. Once established, hypertension is a chronic disease that needs continuous treatment. Chronic pharmacological interventions are able to decrease arterial pressure, but not cure it. An important advance on hypertension control was our recent finding that aerobic training, even not normalizing arterial pressure, sharply decreases oxidative stress and inflammation into autonornic control areas and promptly corrects baro- reflex dysfunction and cardiac vagal activity. Theses training-induced autonomic adaptations associated with reversion ofhypertrophic arteriole remodeling contribute to decrease peripheraJ vascular resistance and arterial pressure in hypertensive subjects.

Exercicio Aerobio Intervalado Induz Maior Reducao na Sobrecarga Cardiaca na Recuperacao em Ratos / Aerobic Interval Exercise Training Induces Greater Reduction in Cardiac Workload in the Recovery Period in Rats

Fundamento: O treinamento aeróbio intervalado produz maior benefício na função cardiovascular comparado ao treinamento aeróbio contínuo. Objetivo: O presente estudo teve como objetivo analisar os efeitos de ambas as modalidades nas respostas hemodinâmicas de ratos sadios. Métodos: Ratos machos foram distribuídos aleatoriamente em três grupos: exercício contínuo (EC, n = 10); exercício intervalado (EI, n = 10); e controle (C, n = 10). A sessão do grupo EC consistiu em 30 min à intensidade de 50% da velocidade máxima (Vel Máx). O grupo EI realizou 30 min, incluindo três períodos de 4 min a 60% da Vel Máx intercalados com 4 min de recuperação a 40% da Vel Máx. Frequência Cardíaca (FC), Pressão Arterial (PA) e Duplo Produto (DP) foram medidos antes, durante e após o exercício. Resultados: Os grupos EC e EI apresentaram aumento da PA sistólica e DP durante o exercício em comparação ao repouso. Após o término do exercício, o grupo EC mostrou menor resposta da PA sistólica e do DP em relação ao repouso, enquanto o grupo EI apresentou menor PA sistólica e PA média. No entanto, somente no grupo EI a FC e o DP apresentaram menor resposta na recuperação. Conclusão: Uma sessão de exercício intervalado em ratos sadios induziu respostas hemodinâmicas similares durante o exercício às obtidas em exercício contínuo. Na recuperação, o exercício intervalado promoveu maiores reduções no esforço cardíaco do que em sessões contínuas de exercício. .

Background: Aerobic interval exercise training has greater benefits on cardiovascular function as compared with aerobic continuous exercise training. Objective: The present study aimed at analyzing the effects of both exercise modalities on acute and subacute hemodynamic responses of healthy rats. Methods: Thirty male rats were randomly assigned into three groups as follows: continuous exercise (CE, n = 10); interval exercise (IE, n = 10); and control (C, n = 10). Both IE and CE groups performed a 30-minute exercise session. The IE group session consisted of three successive 4-minute periods at 60% of maximal velocity (Max Vel), with 4-minute recovery intervals at 40% of Max Vel. The CE group ran continuously at 50% of Max Vel. Heart rate (HR), blood pressure(BP), and rate pressure product (RPP) were measured before, during and after the exercise session. Results: The CE and IE groups showed an increase in systolic BP and RPP during exercise as compared with the baseline values. After the end of exercise, the CE group showed a lower response of systolic BP and RPP as compared with the baseline values, while the IE group showed lower systolic BP and mean BP values. However, only the IE group had a lower response of HR and RPP during recovery. Conclusion: In healthy rats, one interval exercise session, as compared with continuous exercise, induced similar hemodynamic responses during exercise. However, during recovery, the interval exercise caused greater reductions in cardiac workload than the continuous exercise. .

Aerobic interval exercise training induces greater reduction in cardiac workload in the recovery period in rats.

BACKGROUND: Aerobic interval exercise training has greater benefits on cardiovascular function as compared with aerobic continuous exercise training. OBJECTIVE: The present study aimed at analyzing the effects of both exercise modalities on acute and subacute hemodynamic responses of healthy rats. METHODS: Thirty male rats were randomly assigned into three groups as follows: continuous exercise (CE, n = 10); interval exercise (IE, n = 10); and control (C, n = 10). Both IE and CE groups performed a 30-minute exercise session. The IE group session consisted of three successive 4-minute periods at 60% of maximal velocity (Max Vel), with 4-minute recovery intervals at 40% of Max Vel. The CE group ran continuously at 50% of Max Vel. Heart rate (HR), blood pressure(BP), and rate pressure product (RPP) were measured before, during and after the exercise session. RESULTS: The CE and IE groups showed an increase in systolic BP and RPP during exercise as compared with the baseline values. After the end of exercise, the CE group showed a lower response of systolic BP and RPP as compared with the baseline values, while the IE group showed lower systolic BP and mean BP values. However, only the IE group had a lower response of HR and RPP during recovery. CONCLUSION: In healthy rats, one interval exercise session, as compared with continuous exercise, induced similar hemodynamic responses during exercise. However, during recovery, the interval exercise caused greater reductions in cardiac workload than the continuous exercise.

Efeito de diferentes metodologias de treinamento físico na função cardíaca e no controle barorreflexo cardíaco em modelo experimental de cardiopatia dilatada isquêmica / Effect of different methods of physical training on cardiac function and cardiac baroreflex control in an experimental model of ischemic dilated cardiomyopathy

Introdução: O treinamento físico contínuo (Cont) é tradicionalmente empregado como estratégia terapêutica não-farmacológica da IC. Contudo outros métodos de treinamento vêem sendo crescentemente utilizadas. Objetivo: Avaliar o efeito de diferentes metodologias de treinamentos físico sobre a função cardíaca e sensibilidade barorreflexa em modelo experimental de IC. Metodologia: Dividimos 43 ratos Wistar Kyoto, machos e com massa corporal entre 250 e 350g em: IC e sham. O grupo IC foi subdivido em: Cont (IC Cont), Intervalado moderado (IC IAer), Intervalado intenso (IC IAna) e Sedentário (Ic Sed). A IC foi introduzida atavés da ligadura da artéria coronária interventricular. Após 6 semanas do procedimento e ao final do treinamento, foi avaliada a função cardíaca através do ecocardiograma. A medida da fração de ejeção e dos diâmetros ventriculares e atriais foi efetuada pelo método de Simpson e módulo M, respectivamente. No ínicio, na quarta semana e ao final do treinamento, os ratos foram submetidos ao teste de esforço máximo (TE) em esteira rolante. Após 48 horas do terceiro TE, as variáveis hemodinâmicas (pressão arterial, frequência cardíaca e duplo produto) e o controle barorreflexo cardíaco foram determinados. O índice de sensibilidade barorreflexa foi obtido pela razão da variação da FC e da PA sistólica antes e após cada infusão. O treinamento físico foi caracterizado por um período de 8 semanas, com uma frequência semanal de 3 sessões, onde cada treino durou 30 minutos. O IC Cont consistiu na manutenção de 70por cento da velocidade máxima obtida no TE, já o IC IAna foi marcado pela alternância de segmento de 1 min a 90por cento e 50por cento da velocidade máxima no TE. Por outro lado, o IC IAer se caracterizou pela alternância de períodos de 5 min a 80por cento e 60por cento da velocidade máxima no TE. Resultados: Constatamos aumento significativo da fração de ejeção no Ic Cont (28,48 mais ou menos 5por cento vs 39,2 mais ou menos 11por cento) e IC IAer (31,03 mais ou menos 7por cento vs 42 mais ou menos 9por cento). Sobre os diâmetros ventriculares e atriais não observamos modificações significativa nos grupos treinados. Entretanto, o IC Sed demonstrou aumento do diâmetro do ventrículo esquerdo em diástole (0,89 mais ou menos 0,1cm vs 1 mais ou menos 0,1cm). A respeito do índice de controle barorreflexo cardíaco, apenas o IC Cont apresentou um maior índice do que o IC Sed (1,65 mais ou menos 1 bpm/mmHg vs 0,82 mais ou menos 0,4 bpm/mmHg). Conclusão: A partir dos resultados obtidos, podemos sugerir que o IC Cont e IC IAer parecem ser os métodos mais adequados para a melhoria da função cardíaca e da disfunção barorreflexa na IC.

Influência da terapia com exercícios supervisionados na pressão arterial de pacientes com doenças cardiovasculares / Influence of supervised exercise therapy on blood pressure of patients with cardiovascular diseases

Objetivo: Comparar o comportamento da pressão arterial em pacientes com doenças cardiovasculares, durante sessões de exercícios físicos supervisionados. Métodos: Coorte de 62 pacientes, divididos em: Grupo I - portadores de doença coronariana e hipertensão (DACHAS; n igual a 38); Grupo II - portadores de insuficiência cardíaca (IC; n igual a 13); Grupo III - portadores de hipertensão (HAS; n igual a 11). Os pacientes foram submetidos a sessões de exercícios, predominantemente aeróbicos. A pressão arterial foi verificado no início, no meio e ao final dos exercícios. A análise estatística foi feita através dos testes t de Student, qui-quadrado e ANOVA, considerando significativo menor que 0,05. Resultados: Observou-se redução da pressão arterial entre o início e o final das sessões, em todos os grupos, porém demonstrando desempenho diferenciado. Em relação à pressão arterial sistólica, os pacientes do Grupo I apresentaram diminuição de 125,17 maior ou menor que 14,36mmHg para 116,20 maior ou menor que 13,57mmHg (p igual a 0,001); do Grupo II de 112,57 maior ou menor que 20,67mmHg para 107,23 maior ou menor que 16,76mmHg (p igual a 0,003); e do Grupo III de 126,85 maior ou menor que 12,76mmHg para 115,64 maior ou menor que 9,78mmHg (p igual a 0,001). Também foi constatada redução da pressão arterial diastólica...