Background Understanding the temporal trend of the disease burden of stroke and its attributable risk factors in China, especially at provincial levels, is important for effective prevention strategies and improvement. The aim of this analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) is to investigate the disease burden of stroke and its risk factors at national and provincial levels in China from 1990 to 2019. MethodsFollowing the methodology in the GBD 2019, the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) of stroke cases in the Chinese population were estimated by sex, age, year, stroke subtypes (ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage), and across 33 provincial administrative units in China from 1990 to 2019. Attributable mortality and DALYs of underlying risk factors were calculated by a comparative risk assessment. Findings In 2019, there were 3•94 million (95% uncertainty interval 3•43-4•58) new stroke cases in China. The incidence rate of stroke increased by 86•0% (73•2-99•0) from 1990, reaching 276•7 (241•3-322•0) per 100 000 population in 2019. The age-standardised incidence rate declined by 9•3% (3•3-15•5) from 1990 to 2019. Among 28•76 million (25•60-32•21) prevalent cases of stroke in 2019, 24•18 million (20•80-27•87) were ischaemic stroke, 4•36 million (3•69-5•05) were intracerebral haemorrhage, and 1•58 million (1•32-1•91) were subarachnoid haemorrhage. The prevalence rate increased by 106•0% (93•7-118•8) and age-standardised prevalence rate increased by 13•2% (7•7-19•1) from 1990 to 2019. In 2019, there were 2•19 million (1•89-2•51) deaths and 45•9 million (39•8-52•3) DALYs due to stroke. The mortality rate increased by 32•3% (8•6-59•0) from 1990 to 2019. Over the same period, the age-standardised mortality rate decreased by 39•8% (28•6-50•7) and the DALY rate decreased by 41•6% (30•7-50•9). High systolic blood pressure, ambient particulate matter pollution exposure, smoking, and diet high in sodium were four major risk factors for stroke burden in 2019. Moreover, we found marked differences of stroke burden and attributable risk factors across provinces in China from 1990 to 2019.Interpretation The disease burden of stroke is still severe in China, although the age-standardised incidence and mortality rates have decreased since 1990. The stroke burden in China might be reduced through blood pressure management, lifestyle interventions, and air pollution control. Moreover, because substantial heterogeneity of stroke burden existed in different provinces, improved health care is needed in provinces with heavy stroke burden.

Ischemic stroke (IS) is a detrimental neurological disease with limited treatments options. It has been challenging to define the roles of brain cell subsets in IS onset and progression due to cellular heterogeneity in the CNS. Here, we employed single-cell RNA sequencing (scRNA-seq) to comprehensively map the cell populations in the mouse model of MCAO (middle cerebral artery occlusion). We identified 17 principal brain clusters with cell-type specific gene expression patterns as well as specific cell subpopulations and their functions in various pathways. The CNS inflammation triggered upregulation of key cell type-specific genes unpublished before. Notably, microglia displayed a cell differentiation diversity after stroke among its five distinct subtypes. Importantly, we found the potential trajectory branches of the monocytes/macrophage’s subsets. Finally, we also identified distinct subclusters among brain vasculature cells, ependymal cells and other glia cells. Overall, scRNA-seq revealed the precise transcriptional changes during neuroinflammation at the single-cell level, opening up a new field for exploration of the disease mechanisms and drug discovery in stroke based on the cell-subtype specific molecules.

Objective-Elevated levels of C-reactive protein (CRP), a proinflammatory marker, are associated with reduced systemic endothelium-dependent NO-mediated dilation in patients with coronary artery disease; however, the direct effect of CRP on coronary microvascular reactivity remains unknown. Herein, we examined whether CRP can modulate endothelium-dependent NO-mediated dilation of coronary arterioles and whether proinflammatory signaling pathways such as stress-activated protein kinases (p38 and c-Jun N-terminal kinase [JNK]) and oxidative stress are involved in the CRP-mediated effect. Methods and Results-Porcine coronary arterioles were isolated and pressurized without flow for in vitro study.Intraluminal treatment with a clinically relevant concentration of CRP (7 g/mL; 1 hour) significantly attenuated the NO release and vasodilation to serotonin. Further incubation with the NO precursor L-arginine (3 mmol/L) partially restored serotonin-induced vasodilation. In the presence of superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), NAD(P)H oxidase inhibitor apocynin, or p38 kinase (an upstream activator of NAD(P)H oxidase) inhibitor SB203850, but not xanthine oxidase inhibitor allopurinol or JNK inhibitor SP600125, the detrimental effect of CRP on serotonin-induced dilation was prevented. Dihydroethidium staining showed that CRP produced SB203850-and TEMPOL-sensitive superoxide production in the arteriolar endothelium. CRP treatment of coronary arterioles significantly increased NAD(P)H oxidase activity. Conclusions-CRP inhibits endothelium-dependent NO-mediated dilation in coronary arterioles by producing superoxide from NAD(P)H oxidase via p38 kinase activation. By impairing endothelium-dependent NO-mediated vasoreactivity, CRP could facilitate the initiation of numerous cardiovascular diseases. Key Words: C-reactive protein Ⅲ nitric oxide Ⅲ free radicals Ⅲ coronary artery disease A growing wealth of evidence supports the paradigm that inflammation plays a pivotal role in the development and progression of atherosclerosis. 1 C-reactive protein (CRP) is an acute-phase inflammatory marker that has been shown in several prospective studies to be an independent risk factor for cardiovascular events such as stroke, myocardial infarction, and coronary artery disease. 2-4 Recent evidence suggests that CRP may not only be a marker but also a mediator of inflammation and atherogenesis via direct effects on leukocytes and vascular cells. For example, CRP promotes monocyte chemotaxis 5 and facilitates low-density lipoprotein uptake by macrophages in vitro. 6 In vascular smooth muscle cells, CRP has been shown to increase angiotensin type 1 receptor number and angiotensin type 1 receptor-mediated reactive oxygen species formation, 7 as well as activation of stress-activated protein kinases p38 kinase and c-Jun N-terminal kinase (JNK). 8 In endothelial cells, CRP facilitated the release of plasminogen activator inhibitor-1 9 and endothelin-1, 10 increased the expression of cell adhesion molecules, 1...

It has been reported that sensitivity to angiotensin II (Ang II) is higher in efferent (Ef) than afferent (Af) arterioles (Arts). We tested the hypothesis that this is due to arteriolar differences in the interaction between Ang II and endothelium-derived relaxing factor/nitric oxide (EDNO). Rabbit Af-Arts with glomerulus intact were microperfused in vitro at a constant pressure. Ef-Arts were perfused from the distal end of either the Af-Art (orthograde perfusion) or the Ef-Art (retrograde perfusion) to eliminate influences of the Af-Art or glomerulus, respectively. Ang II did not alter Af-Art luminal diameter until the concentration reached 10-9 M, which decreased the diameter by 11±2.6% (n = 11; P < 0.002). In contrast, Ef-Arts became significantly constricted at concentrations as low as 10-11 M with either perfusion. Surprisingly, the decrease in Ef-Art diameter at 10-10, 10-', and 10-8 M was significantly greater with retrograde perfusion (44±6.9%, 70±5.6%, and 74±4.1%, respectively; n = 5) than with orthograde perfusion (16±4.2%, 25±2.9%, and 35±3.5%; n = 9). ENDO synthesis inhibition with 10-4 M nitro-L-arginine methyl ester (L-NAME) decreased the diameter to a greater extent in Af-Arts (22±3.0%; n = 11 ) compared to Ef-Arts with either orthograde (9.5±2.3%; n = 8) or retrograde perfusion (1.2±2.1%; n = 6). With L-NAME pretreatment, Af-Art constriction induced by 10-10 M (14±4.0%, n = 9) and 10-9 M Ang 11 (38±3.9%) was significantly greater compared to nontreated Af-Arts. In contrast, L-NAME pretreatment had no effect on Ang II-induced constriction in Ef-Arts with either perfusion. In conclusion, this study demonstrates higher sensitivity of Ef-Arts to Ang II, particularly with retrograde perfusion. Our results suggest that EDNO significantly modulates the vasoconstrictor action of Ang II in Af-Arts II but not Ef-Arts, contributing to the differential sensitivity

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The renal afferent arterioles (Af-Arts) account for most of the renal vascular resistance, which is controlled similar to other arterioles and by tubuloglomerular feedback (TGF). The latter signal is generated by sensing sodium chloride concentrations in the macula densa; this in turn results in a signal which acts through the extraglomerular mesangium leading to constriction of the Af-Art. In the outer renal cortex, the connecting tubule (CNT) returns to the glomerular hilus and contacts the Af-Art suggesting that crosstalk may exist here as well. To investigate this, we simultaneously perfused a microdissected Af-Art and adherent CNT. Increasing the sodium chloride concentration perfusing the CNT significantly dilated preconstricted Af-Arts. We called this crosstalk 'connecting tubule glomerular feedback' (CTGF) to differentiate it from TGF. We tested whether entry of Na(+) and/or CI(-) into the CNT is required to induce CTGF by replacing Na(+) with choline(+). Increasing choline chloride concentration did not dilate the Af-Art. To test whether epithelial Na channels (ENaCs) mediate CTGF, we blocked ENaC with amiloride and found that the dilatation induced by CTGF was completely blocked. Inhibiting sodium chloride cotransporters with hydrochlorothiazide failed to prevent Af-Art dilatation. Finally, we tested whether nitric oxide released by the CNT mediates CTGF by the addition of a non-selective nitric oxide synthase inhibitor to the CNT. This potentiated CTGF rather than blocking it. We suggest that crosstalk exists between CNTs and attached Af-Arts, which is initiated by sodium reabsorption through amiloride-sensitive channels and this can contribute to the regulation of renal blood flow and glomerular filtration.

Purpose Activation of the endothelin (ET) system has been implicated in the pathogenesis of retinal ischemic disease. Although ET-1, the predominant endogenous isoform of ET, has been shown to cause constriction of retinal vessels, the expression and functional significance of its synthesis and the involved specific ET receptors in retinal arterioles remain unknown. The authors examined the roles of ETA and ETB receptors and of endothelin-converting enzyme (ECE)-1 in ET-1–induced vasomotor responses of single retinal arterioles. Methods To exclude systemic confounding effects, porcine retinal arterioles were isolated for vasoreactivity and molecular studies. Results Isolated and pressurized retinal arterioles developed basal tone and constricted in a manner dependent on concentration to ET-1. ET-1 precursor big ET-1 elicited time-dependent vasoconstriction over 20 minutes, which was blocked by the ECE-1 inhibitor phosphoramidon. ETA receptor antagonist BQ123 inhibited most (approximately 90%) of vasoconstrictions to ET-1 and big ET-1. ETB receptor agonist sarafotoxin also elicited concentration-dependent constriction of retinal arterioles but with significantly less potency than ET-1. ETB receptor antagonist BQ788 abolished vasoconstriction to sarafotoxin but only slightly reduced responses to ET-1 and big ET-1. Protein and mRNA expressions of ETA, ETB, and ECE-1 were detected in retinal arterioles. Immunohistochemistry revealed ETA and ETB receptors predominantly in smooth muscle and ECE-1 predominantly in endothelium and smooth muscle. Conclusions ET-1 elicits constriction of retinal arterioles predominantly through the activation of smooth muscle ETA receptors. Endogenous production of ET-1 from vascular ECE-1 is sufficient to evoke ETA receptor–dependent constriction in retinal arterioles.

CRP inhibits endothelium-dependent NO-mediated dilation in retinal arterioles by producing superoxide from NAD(P)H oxidase, which appears to be linked with p38 kinase and RhoA/Rho-kinase activation. By impairing endothelium-dependent NO-mediated vasoreactivity, CRP can potentially facilitate the development of retinal vascular diseases. In addition, statins are beneficial by preserving endothelial function, possibly through inactivation of the RhoA/Rho-kinase pathway.