Spinal projecting neurons in rostral ventromedial medulla co-regulate motor and sympathetic tone.

Many behaviors require the coordinated actions of somatic and autonomic functions. However, the underlying mechanisms remain elusive. By opto-stimulating different populations of descending spinal projecting neurons (SPNs) in anesthetized mice, we show that stimulation of excitatory SPNs in the rostral ventromedial medulla (rVMM) resulted in a simultaneous increase in somatomotor and sympathetic activities. Conversely, opto-stimulation of rVMM inhibitory SPNs decreased both activities. Anatomically, these SPNs innervate both sympathetic preganglionic neurons and motor-related regions in the spinal cord. Fiber-photometry recording indicated that the activities of rVMM SPNs correlate with different levels of muscle and sympathetic tone during distinct arousal states. Inhibiting rVMM excitatory SPNs reduced basal muscle and sympathetic tone, impairing locomotion initiation and high-speed performance. In contrast, silencing the inhibitory population abolished muscle atonia and sympathetic hypoactivity during rapid eye movement (REM) sleep. Together, these results identify rVMM SPNs as descending spinal projecting pathways controlling the tone of both the somatomotor and sympathetic systems.

Nitric oxide signaling in health and disease.

The surprising discovery that the diatomic gas nitric oxide (NO) is generated by mammalian cells and serves to regulate a multitude of physiological processes has continued to fascinate biologists for almost four decades. The biochemistry of NO is complex, and novel insights into the control of NO biosynthesis and mechanisms of signal transduction are continuously emerging. NO is a key regulator of cardiovascular function, metabolism, neurotransmission, immunity, and more, and aberrant NO signaling is a central feature of many major disorders including cardiovascular disease, diabetes, and cancer. Here, we discuss the basics of NO biology emphasizing recent advances in the field including novel means of increasing NO bioactivity with therapeutic and nutritional implications.

Sex differences in blood pressure regulation and hypertension: renal, hemodynamic, and hormonal mechanisms.

The teleology of sex differences has been argued since at least as early as Aristotle's controversial Generation of Animals more than 300 years BC, which reflects the sex bias of the time to contemporary readers. Although the question "why are the sexes different" remains a topic of debate in the present day in metaphysics, the recent emphasis on sex comparison in research studies has led to the question "how are the sexes different" being addressed in health science through numerous observational studies in both health and disease susceptibility, including blood pressure regulation and hypertension. These efforts have resulted in better understanding of differences in males and females at the molecular level that partially explain their differences in vascular function and renal sodium handling and hence blood pressure and the consequential cardiovascular and kidney disease risks in hypertension. This review focuses on clinical studies comparing differences between men and women in blood pressure over the life span and response to dietary sodium and highlights experimental models investigating sexual dimorphism in the renin-angiotensin-aldosterone, vascular, sympathetic nervous, and immune systems, endothelin, the major renal sodium transporters/exchangers/channels, and the impact of sex hormones on these systems in blood pressure homeostasis. Understanding the mechanisms governing sex differences in blood pressure regulation could guide novel therapeutic approaches in a sex-specific manner to lower cardiovascular risks in hypertension and advance personalized medicine.

The Renal Physiology of Pendrin-Positive Intercalated Cells.

Intercalated cells (ICs) are found in the connecting tubule and the collecting duct. Of the three IC subtypes identified, type B intercalated cells are one of the best characterized and known to mediate Cl- absorption and HCO3- secretion, largely through the anion exchanger pendrin. This exchanger is thought to act in tandem with the Na+-dependent Cl-/HCO3- exchanger, NDCBE, to mediate net NaCl absorption. Pendrin is stimulated by angiotensin II and aldosterone administration via the angiotensin type 1a and the mineralocorticoid receptors, respectively. It is also stimulated in models of metabolic alkalosis, such as with NaHCO3 administration. In some rodent models, pendrin-mediated HCO3- secretion modulates acid-base balance. However, of probably more physiological or clinical significance is the role of these pendrin-positive ICs in blood pressure regulation, which occurs, at least in part, through pendrin-mediated renal Cl- absorption, as well as their effect on the epithelial Na+ channel, ENaC. Aldosterone stimulates ENaC directly through principal cell mineralocorticoid hormone receptor (ligand) binding and also indirectly through its effect on pendrin expression and function. In so doing, pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. In addition to its role in Na+ and Cl- balance, pendrin affects the balance of other ions, such as K+ and I-. This review describes how aldosterone and angiotensin II-induced signaling regulate pendrin and the contribution of pendrin-positive ICs in the kidney to distal nephron function and blood pressure.

A new test for trait mean and variance detects unreported loci for blood-pressure variation.

Variability in quantitative traits has clinical, ecological, and evolutionary significance. Most genetic variants identified for complex quantitative traits have only a detectable effect on the mean of trait. We have developed the mean-variance test (MVtest) to simultaneously model the mean and log-variance of a quantitative trait as functions of genotypes and covariates by using estimating equations. The advantages of MVtest include the facts that it can detect effect modification, that multiple testing can follow conventional thresholds, that it is robust to non-normal outcomes, and that association statistics can be meta-analyzed. In simulations, we show control of type I error of MVtest over several alternatives. We identified 51 and 37 previously unreported associations for effects on blood-pressure variance and mean, respectively, in the UK Biobank. Transcriptome-wide association studies revealed 633 significant unique gene associations with blood-pressure mean variance. MVtest is broadly applicable to studies of complex quantitative traits and provides an important opportunity to detect novel loci.

Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension.

Genome-wide association studies of blood pressure (BP) have identified >1,000 loci, but the effector genes and biological pathways at these loci are mostly unknown. Using published association summary statistics, we conducted annotation-informed fine-mapping incorporating tissue-specific chromatin segmentation and colocalization to identify causal variants and candidate effector genes for systolic BP, diastolic BP, and pulse pressure. We observed 532 distinct signals associated with ≥2 BP traits and 84 with all three. For >20% of signals, a single variant accounted for >75% posterior probability, 65 were missense variants in known (SLC39A8, ADRB2, and DBH) and previously unreported BP candidate genes (NRIP1 and MMP14). In disease-relevant tissues, we colocalized >80 and >400 distinct signals for each BP trait with cis-eQTLs and regulatory regions from promoter capture Hi-C, respectively. Integrating mouse, human disorder, gene expression and tissue abundance data, and literature review, we provide consolidated evidence for 436 BP candidate genes for future functional validation and discover several potential drug targets.

LRP1 Repression by SNAIL Results in ECM Remodeling in Genetic Risk for Vascular Diseases.

BACKGROUND: Genome-wide association studies implicate common genetic variations in the LRP1 (low-density lipoprotein receptor-related protein 1) locus at risk for multiple vascular diseases and traits. However, the underlying biological mechanisms are unknown. METHODS: Fine mapping analyses included Bayesian colocalization to identify the most likely causal variant. Human induced pluripotent stem cells were genome-edited using CRISPR-Cas9 to delete or modify candidate enhancer regions and generate LRP1 knockout cell lines. Cells were differentiated into smooth muscle cells through a mesodermal lineage. Transcription regulation was assessed using luciferase reporter assay, transcription factor knockdown, and chromatin immunoprecipitation. Phenotype changes in cells were conducted using cellular assays, bulk RNA sequencing, and mass spectrometry. RESULTS: Multitrait colocalization analyses pointed at rs11172113 as the most likely causal variant in LRP1 for fibromuscular dysplasia, migraine, pulse pressure, and pulmonary function trait. We found the rs11172113-T allele to associate with higher LRP1 expression. Genomic deletion in induced pluripotent stem cell-derived smooth muscle cells supported rs11172113 to locate in an enhancer region regulating LRP1 expression. We found transcription factors MECP2 (methyl CpG binding protein 2) and SNAIL to repress LRP1 expression through an allele-specific mechanism, involving SNAIL interaction with disease risk allele. LRP1 knockout decreased induced pluripotent stem cell-derived smooth muscle cell proliferation and migration. Differentially expressed genes were enriched for collagen-containing extracellular matrix, connective tissue development, and lung development. LRP1 knockout and deletion of rs11172113 enhancer showed potentiated canonical TGF-ß (transforming growth factor beta) signaling through enhanced phosphorylation of SMAD2/3. Analyses of the protein content of decellularized extracts indicated partial extracellular matrix remodeling involving enhanced secretion of CYR61, a known LRP1 ligand involved in vascular integrity and TIMP3, implicated in extracellular matrix maintenance and also known to interact with LRP1. CONCLUSIONS: Our findings support allele-specific LRP1 gene repression by the endothelial-to-mesenchymal transition regulator SNAIL. We propose decreased LRP1 expression in smooth muscle cells to remodel the extracellular matrix enhanced by TGF-ß as a potential mechanism of this pleiotropic locus for vascular diseases.

Transportation Noise Pollution and Cardiovascular Health.

Epidemiological studies have found that transportation noise increases the risk for cardiovascular morbidity and mortality, with solid evidence for ischemic heart disease, heart failure, and stroke. According to the World Health Organization, at least 1.6 million healthy life years are lost annually from traffic-related noise in Western Europe. Traffic noise at night causes fragmentation and shortening of sleep, elevation of stress hormone levels, and increased oxidative stress in the vasculature and the brain. These factors can promote vascular (endothelial) dysfunction, inflammation, and arterial hypertension, thus elevating cardiovascular risk. The present review focusses on the indirect, nonauditory cardiovascular health effects of noise. We provide an updated overview of epidemiological research on the effects of transportation noise on cardiovascular risk factors and disease, and mechanistic insights based on the latest clinical and experimental studies and propose new risk markers to address noise-induced cardiovascular effects in the general population. We will discuss the potential effects of noise on vascular dysfunction, oxidative stress, and inflammation in humans and animals. We will elaborately explain the underlying pathomechanisms by alterations of gene networks, epigenetic pathways, circadian rhythm, signal transduction along the neuronal-cardiovascular axis, and metabolism. We will describe current and future noise mitigation strategies. Finally, we will conduct an overall evaluation of the status of the current evidence of noise as a significant cardiovascular risk factor.

GLI1+ Cells Contribute to Vascular Remodeling in Pulmonary Hypertension.

BACKGROUND: The precise origin of newly formed ACTA2+ (alpha smooth muscle actin-positive) cells appearing in nonmuscularized vessels in the context of pulmonary hypertension is still debatable although it is believed that they predominantly derive from preexisting vascular smooth muscle cells (VSMCs). METHODS: Gli1Cre-ERT2; tdTomatoflox mice were used to lineage trace GLI1+ (glioma-associated oncogene homolog 1-positive) cells in the context of pulmonary hypertension using 2 independent models of vascular remodeling and reverse remodeling: hypoxia and cigarette smoke exposure. Hemodynamic measurements, right ventricular hypertrophy assessment, flow cytometry, and histological analysis of thick lung sections followed by state-of-the-art 3-dimensional reconstruction and quantification using Imaris software were used to investigate the contribution of GLI1+ cells to neomuscularization of the pulmonary vasculature. RESULTS: The data show that GLI1+ cells are abundant around distal, nonmuscularized vessels during steady state, and this lineage contributes to around 50% of newly formed ACTA2+ cells around these normally nonmuscularized vessels. During reverse remodeling, cells derived from the GLI1+ lineage are largely cleared in parallel to the reversal of muscularization. Partial ablation of GLI1+ cells greatly prevented vascular remodeling in response to hypoxia and attenuated the increase in right ventricular systolic pressure and right heart hypertrophy. Single-cell RNA sequencing on sorted lineage-labeled GLI1+ cells revealed an Acta2high fraction of cells with pathways in cancer and MAPK (mitogen-activated protein kinase) signaling as potential players in reprogramming these cells during vascular remodeling. Analysis of human lung-derived material suggests that GLI1 signaling is overactivated in both group 1 and group 3 pulmonary hypertension and can promote proliferation and myogenic differentiation. CONCLUSIONS: Our data highlight GLI1+ cells as an alternative cellular source of VSMCs in pulmonary hypertension and suggest that these cells and the associated signaling pathways represent an important therapeutic target for further studies.

Mitochondrial CypD Acetylation Promotes Endothelial Dysfunction and Hypertension.

BACKGROUND: Nearly half of adults have hypertension, a major risk factor for cardiovascular disease. Mitochondrial hyperacetylation is linked to hypertension, but the role of acetylation of specific proteins is not clear. We hypothesized that acetylation of mitochondrial CypD (cyclophilin D) at K166 contributes to endothelial dysfunction and hypertension. METHODS: To test this hypothesis, we studied CypD acetylation in patients with essential hypertension, defined a pathogenic role of CypD acetylation in deacetylation mimetic CypD-K166R mutant mice and endothelial-specific GCN5L1 (general control of amino acid synthesis 5 like 1)-deficient mice using an Ang II (angiotensin II) model of hypertension. RESULTS: Arterioles from hypertensive patients had 280% higher CypD acetylation coupled with reduced Sirt3 (sirtuin 3) and increased GCN5L1 levels. GCN5L1 regulates mitochondrial protein acetylation and promotes CypD acetylation, which is counteracted by mitochondrial deacetylase Sirt3. In human aortic endothelial cells, GCN5L1 depletion prevents superoxide overproduction. Deacetylation mimetic CypD-K166R mice were protected from vascular oxidative stress, endothelial dysfunction, and Ang II-induced hypertension. Ang II-induced hypertension increased mitochondrial GCN5L1 and reduced Sirt3 levels resulting in a 250% increase in GCN5L1/Sirt3 ratio promoting CypD acetylation. Treatment with mitochondria-targeted scavenger of cytotoxic isolevuglandins (mito2HOBA) normalized GCN5L1/Sirt3 ratio, reduced CypD acetylation, and attenuated hypertension. The role of mitochondrial acetyltransferase GCN5L1 in the endothelial function was tested in endothelial-specific GCN5L1 knockout mice. Depletion of endothelial GCN5L1 prevented Ang II-induced mitochondrial oxidative stress, reduced the maladaptive switch of vascular metabolism to glycolysis, prevented inactivation of endothelial nitric oxide, preserved endothelial-dependent relaxation, and attenuated hypertension. CONCLUSIONS: These data support the pathogenic role of CypD acetylation in endothelial dysfunction and hypertension. We suggest that targeting cytotoxic mitochondrial isolevuglandins and GCN5L1 reduces CypD acetylation, which may be beneficial in cardiovascular disease.

Circadian Rhythms in Cardiovascular Metabolism.

Energetic demand and nutrient supply fluctuate as a function of time-of-day, in alignment with sleep-wake and fasting-feeding cycles. These daily rhythms are mirrored by 24-hour oscillations in numerous cardiovascular functional parameters, including blood pressure, heart rate, and myocardial contractility. It is, therefore, not surprising that metabolic processes also fluctuate over the course of the day, to ensure temporal needs for ATP, building blocks, and metabolism-based signaling molecules are met. What has become increasingly clear is that in addition to classic signal-response coupling (termed reactionary mechanisms), cardiovascular-relevant cells use autonomous circadian clocks to temporally orchestrate metabolic pathways in preparation for predicted stimuli/stresses (termed anticipatory mechanisms). Here, we review current knowledge regarding circadian regulation of metabolism, how metabolic rhythms are synchronized with cardiovascular function, and whether circadian misalignment/disruption of metabolic processes contribute toward the pathogenesis of cardiovascular disease.

Hypertension: Causes and Consequences of Circadian Rhythms in Blood Pressure.

Hypertension is extremely common, affecting approximately 1 in every 2 adults globally. Chronic hypertension is the leading modifiable risk factor for cardiovascular disease and premature mortality worldwide. Despite considerable efforts to define mechanisms that underlie hypertension, a potentially major component of the disease, the role of circadian biology has been relatively overlooked in both preclinical models and humans. Although the presence of daily and circadian patterns has been observed from the level of the genome to the whole organism, the functional and structural impact of biological rhythms, including mechanisms such as circadian misalignment, remains relatively poorly defined. Here, we review the impact of daily rhythms and circadian systems in regulating blood pressure and the onset, progression, and consequences of hypertension. There is an emphasis on the impact of circadian biology in relation to vascular disease and end-organ effects that, individually or in combination, contribute to complex phenotypes such as cognitive decline and the loss of cardiac and brain health. Despite effective treatment options for some individuals, control of blood pressure remains inadequate in a substantial portion of the hypertensive population. Greater insight into circadian biology may form a foundation for novel and more widely effective molecular therapies or interventions to help in the prevention, treatment, and management of hypertension and its related pathophysiology.

Myeloid-Specific JAK2 Contributes to Inflammation and Salt Sensitivity of Blood Pressure.

BACKGROUND: Salt sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen-presenting cells (APCs), resulting in high blood pressure, but the mechanisms are unknown. Here, we hypothesized that APC-specific JAK2 (Janus kinase 2) through STAT3 (signal transducer and activator of transcription 3) and SMAD3 (small mothers against decapentaplegic homolog 3) contributes to SSBP. METHOD: We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP. We also used a myeloid cell-specific CD11c+ JAK2 knockout mouse model and measured blood pressure with radiotelemetry after N-omega-nitro-L-arginine-methyl ester and a high salt diet treatment. We used flow cytometry for immunophenotyping and measuring cytokine levels. Fluorescence in situ hybridization and immunohistochemistry were performed to spatially visualize the kidney's immune cells and cytokine levels. Echocardiography was performed to assess cardiac function. RESULTS: We found that high salt treatment upregulates gene expression of the JAK/STAT/SMAD pathway while downregulating inhibitors of this pathway, such as suppression of cytokine signaling and cytokine-inducible SH2, in human monocytes. Expression of the JAK2 pathway genes mirrored changes in blood pressure after salt loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11c+ APCs, attenuated salt-induced hypertension in mice with SSBP. Mechanistically, we found that SMAD3 acted downstream of JAK2 and STAT3, leading to increased production of highly reactive isolevuglandins and proinflammatory cytokine IL (interleukin)-6 in renal APCs, which activate T cells and increase production of IL-17A, IL-6, and TNF-α (tumor necrosis factor-alpha). CONCLUSIONS: Our findings reveal the APC JAK2 signaling pathway as a potential target for the diagnosis and treatment of SSBP in humans.

Salt Sensitivity of Blood Pressure.

The year 2024 marks the centennial of the initiation of the American Heart Association. Over the past 100 years, the American Heart Association has led groundbreaking discoveries in cardiovascular disease including salt sensitivity of blood pressure, which has been studied since the mid-1900s. Salt sensitivity of blood pressure is an important risk factor for cardiovascular events, but the phenotype remains unclear because of insufficient understanding of the underlying mechanisms and lack of feasible diagnostic tools. In honor of this centennial, we commemorate the initial discovery of salt sensitivity of blood pressure and chronicle the subsequent scientific discoveries and efforts to mitigate salt-induced cardiovascular disease with American Heart Association leading the way. We also highlight determinants of the pathophysiology of salt sensitivity of blood pressure in humans and recent developments in diagnostic methods and future prospects.

o8G Site-Specifically Modified tRF-1-AspGTC: A Novel Therapeutic Target and Biomarker for Pulmonary Hypertension.

BACKGROUND: Hypoxia and oxidative stress contribute to the development of pulmonary hypertension (PH). tRNA-derived fragments play important roles in RNA interference and cell proliferation, but their epitranscriptional roles in PH development have not been investigated. We aimed to gain insight into the mechanistic contribution of oxidative stress-induced 8-oxoguanine in pulmonary vascular remodeling. METHODS: Through small RNA modification array analysis and quantitative polymerase chain reaction, a significant upregulation of the 8-oxoguanine -modified tRF-1-AspGTC was found in the lung tissues and the serum of patients with PH. RESULTS: This modification occurs at the position 5 of the tRF-1-AspGTC (5o8G tRF). Inhibition of the 5o8G tRF reversed hypoxia-induced proliferation and apoptosis resistance in pulmonary artery smooth muscle cells. Further investigation unveiled that the 5o8G tRF retargeted mRNA of WNT5A (Wingless-type MMTV integration site family, member 5A) and CASP3 (Caspase3) and inhibited their expression. Ultimately, BMPR2 (Bone morphogenetic protein receptor 2) -reactive oxygen species/5o8G tRF/WNT5A signaling pathway exacerbated the progression of PH. CONCLUSIONS: Our study highlights the role of site-specific 8-oxoguanine-modified tRF in promoting the development of PH. Our findings present a promising therapeutic avenue for managing PH and propose 5o8G tRF as a potential innovative marker for diagnosing this disease.

Circadian and Diurnal Regulation of Cerebral Blood Flow.

Circadian and diurnal variation in cerebral blood flow directly contributes to the diurnal variation in the risk of stroke, either through factors that trigger stroke or due to impaired compensatory mechanisms. Cerebral blood flow results from the integration of systemic hemodynamics, including heart rate, cardiac output, and blood pressure, with cerebrovascular regulatory mechanisms, including cerebrovascular reactivity, autoregulation, and neurovascular coupling. We review the evidence for the circadian and diurnal variation in each of these mechanisms and their integration, from the detailed evidence for mechanisms underlying the nocturnal nadir and morning surge in blood pressure to identifying limited available evidence for circadian and diurnal variation in cerebrovascular compensatory mechanisms. We, thus, identify key systemic hemodynamic factors related to the diurnal variation in the risk of stroke but particularly identify the need for further research focused on cerebrovascular regulatory mechanisms.

Orphan GPCR GPRC5C Facilitates Angiotensin II-Induced Smooth Muscle Contraction.

BACKGROUND: GPCRs (G-protein-coupled receptors) play a central role in the regulation of smooth muscle cell (SMC) contractility, but the function of SMC-expressed orphan GPCR class C group 5 member C (GPRC5C) is unclear. The aim of this project is to define the role of GPRC5C in SMC in vitro and in vivo. METHODS: We studied the role of GPRC5C in the regulation of SMC contractility and differentiation in human and murine SMC in vitro, as well as in tamoxifen-inducible, SMC-specific GPRC5C knockout mice under basal conditions and in vascular disease in vivo. RESULTS: Mesenteric arteries from tamoxifen-inducible, SMC-specific GPRC5C knockout mice showed ex vivo significantly reduced angiotensin II (Ang II)-dependent calcium mobilization and contraction, whereas responses to other relaxant or contractile factors were normal. In vitro, the knockdown of GPRC5C in human aortic SMC resulted in diminished Ang II-dependent inositol phosphate production and lower myosin light chain phosphorylation. In line with this, tamoxifen-inducible, SMC-specific GPRC5C knockout mice showed reduced Ang II-induced arterial hypertension, and acute inactivation of GPRC5C was able to ameliorate established arterial hypertension. Mechanistically, we show that GPRC5C and the Ang II receptor AT1 dimerize, and knockdown of GPRC5C resulted in reduced binding of Ang II to AT1 receptors in HEK293 cells, human and murine SMC, and arteries from tamoxifen-inducible, SMC-specific GPRC5C knockout mice. CONCLUSIONS: Our data show that GPRC5C regulates Ang II-dependent vascular contraction by facilitating AT1 receptor-ligand binding and signaling.

Alleviating Hypertension by Selectively Targeting Angiotensin Receptor-Expressing Vagal Sensory Neurons.

Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors that apprise the brain of blood volume and pressure. Here, we test whether neurons within the nodose ganglia that express angiotensin type-1a receptors (referred to as NGAT1aR) serve as baroreceptors that differentially influence blood pressure (BP) in male and female mice. Using Agtr1a-Cre mice and Cre-dependent AAVs to direct tdTomato to NGAT1aR, neuroanatomical studies revealed that NGAT1aR receive input from the aortic arch, project to the caudal nucleus of the solitary tract (NTS), and synthesize mechanosensitive ion channels, Piezo1/2 To evaluate the functionality of NGAT1aR, we directed the fluorescent calcium indicator (GCaMP6s) or the light-sensitive channelrhodopsin-2 (ChR2) to Agtr1a-containing neurons. Two-photon intravital imaging in Agtr1a-GCaMP6s mice revealed that NGAT1aR couple their firing to elevated BP, induced by phenylephrine (i.v.). Furthermore, optical excitation of NGAT1aR at their soma or axon terminals within the caudal NTS of Agtr1a-ChR2 mice elicited robust frequency-dependent decreases in BP and heart rate, indicating that NGAT1aR are sufficient to elicit appropriate compensatory responses to vascular mechanosensation. Optical excitation also elicited hypotensive and bradycardic responses in ChR2-expressing mice that were subjected to deoxycorticosterone acetate (DOCA)-salt hypertension; however, the duration of these effects was altered, suggestive of hypertension-induced impairment of the baroreflex. Similarly, increased GCaMP6s fluorescence observed after administration of phenylephrine was delayed in mice subjected to DOCA-salt or chronic delivery of angiotensin II. Collectively, these results reveal the structure and function of NGAT1aR and suggest that such neurons may be exploited to discern and relieve hypertension.

GLP-1 in the Hypothalamic Paraventricular Nucleus Promotes Sympathetic Activation and Hypertension.

Glucagon-like peptide-1 (GLP-1) and its analogs are widely used for diabetes treatment. The paraventricular nucleus (PVN) is crucial for regulating cardiovascular activity. This study aims to determine the roles of GLP-1 and its receptors (GLP-1R) in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male normotensive rats and spontaneously hypertensive rats (SHR). Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. GLP-1 and GLP-1R expressions were present in the PVN. PVN microinjection of GLP-1R agonist recombinant human GLP-1 (rhGLP-1) or EX-4 increased RSNA and MAP, which were prevented by GLP-1R antagonist exendin 9-39 (EX9-39) or GLP-1R antagonist 1, superoxide scavenger tempol, antioxidant N-acetylcysteine, NADPH oxidase (NOX) inhibitor apocynin, adenylyl cyclase (AC) inhibitor SQ22536 or protein kinase A (PKA) inhibitor H89. PVN microinjection of rhGLP-1 increased superoxide production, NADPH oxidase activity, cAMP level, AC, and PKA activity, which were prevented by SQ22536 or H89. GLP-1 and GLP-1R were upregulated in the PVN of SHR. PVN microinjection of GLP-1 agonist increased RSNA and MAP in both WKY and SHR, but GLP-1 antagonists caused greater effects in reducing RSNA and MAP in SHR than in WKY. The increased superoxide production and NADPH oxidase activity in the PVN of SHR were augmented by GLP-1R agonists but attenuated by GLP-1R antagonists. These results indicate that activation of GLP-1R in the PVN increased sympathetic outflow and blood pressure via cAMP-PKA-mediated NADPH oxidase activation and subsequent superoxide production. GLP-1 and GLP-1R upregulation in the PVN partially contributes to sympathetic overactivity and hypertension.

Effects of zinc in podocytes and cortical collecting duct in vitro and Dahl Salt-Sensitive rats in vivo.

Zinc is one of the essential divalent cations in the human body and a fundamental microelement involved in the regulation of many cellular and subcellular functions. Experimental studies reported that zinc deficiency is associated with renal damage and could increase blood pressure. It was proposed that zinc dietary supplementation plays a renoprotective role. Our study aimed to investigate the effects of zinc on intracellular signaling in renal cells and explore the correlation between dietary zinc and the progression of salt-induced hypertension. The impact of extracellular zinc concentrations on two different kidney epithelial cell types - podocytes and principal cells of the cortical collecting duct (CCD), was tested. In podocytes, a rise in extracellular zinc promotes TRPC6 channel-mediated calcium entry but not altered intracellular zinc levels. However, we observe the opposite effect in CCD cells with no alteration in calcium levels and steady-state elevation in intracellular zinc. Moreover, prolonged extracellular zinc exposure leads to cytotoxic insults in CCD cells but not in podocytes, characterized by increased cell death and disrupted cytoskeletal organization. Next, we tested if dietary zinc plays a role in the development of hypertension in Dahl salt-sensitive rats. Neither zinc-rich nor deficient diets impact the regular development of salt-sensitive hypertension. These results suggest specialized roles for zinc in renal function, implicating its involvement in proliferation and apoptosis in CCD cells and calcium signaling and cytoskeletal dynamics modulation in podocytes. Further research is required to elucidate the detailed mechanisms of zinc action and its implications in renal health and disease.