Does False Lumen Thrombosis Lead to Better Outcomes in Patients with Aortic Dissection: A Meta-Analysis and Systematic Review.

OBJECTIVES: For a long time, the association of the false lumen status and the outcomes of patients suffering from aortic dissection has been unclear, so this review article aims to study whether the unobstructed of the false lumen is related to the outcome of patients suffering from aortic dissection. METHODS: We performed this systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta Analyzes Protocols (PRISMA) statement 2009 and registered with PROSPERO (CRD42022381869). We searched PubMed, the Cochrane library, Web of Science and Embase to collect potential studies. The Newcastle-Ottawa Scale was used to assess the quality of the included studies. The main outcome is long-term survival. Data included in the study were summarized using the risk ratio or mean difference and 95% confidence interval. RESULTS: There were 16 trials, 2829 patients in total, with a mean age of 62.1 years. Compared with completely thrombosed false lumen, patent group has better long-term survival (risk ratio (RR), 0.88; 95% CI, 0.79 to 0.97; p = 0.01; I2 = 58%) and smaller yearly aortic growth rate (mean difference (MD), 1.03; 95% CI, 0.23 to 1.82; p = 0.01; I2 = 98%). In addition, patients with a patent false lumen had a lower risk of aortic event (RR, 0.81; 95% CI, 0.68 to 0.97; p = 0.02; I2 = 37%), but higher risk of aortic rupture (RR, 7.02; 95% CI, 2.55 to 19.3; p = 0.0002; I2 = 0) and hospital death (RR, 2.72; 95% CI, 1.45 to 5.08; p = 0.002; I2 = 0). CONCLUSION: Completely thrombosed of the false lumen is more beneficial to the long-term survival of patients with aortic dissection. And the risk of aortic rupture and hospital death in patients with patent false lumen is 7 times and 3 times that of patients with complete thrombosed false lumen. It is expected to provide individualized medical care for different types of patients according to different false lumen status to minimize death and related complications.

Effect of SGLT2 inhibition on salt-induced hypertension in female Dahl SS rats.

Sodium-glucose co-transporters (SGLTs) in the kidneys play a pivotal role in glucose reabsorption. Several clinical and population-based studies revealed the beneficial effects of SGLT2 inhibition on hypertension. Recent work from our lab provided significant new insight into the role of SGLT2 inhibition in a non-diabetic model of salt-sensitive hypertension, Dahl salt-sensitive (SS) rats. Dapagliflozin (Dapa) blunted the development of salt-induced hypertension by causing glucosuria and natriuresis without changes in the Renin-Angiotensin-Aldosterone System. However, our initial study used male SS rats only, and the effect of SGLT2 inhibitors on hypertension in females has not been studied. Therefore, the goal of this study was to determine whether SGLT2 inhibition alters blood pressure and kidney function in female Dahl SS rats. The result showed that administration of Dapa for 3 weeks prevented the progression of salt-induced hypertension in female rats, similar to its effects in male SS rats. Diuresis and glucose excretion were significantly increased in Dapa-treated rats. SGLT2 inhibition also significantly attenuated kidney but not heart fibrosis. Despite significant effects on blood pressure, Dapa treatment caused minor changes to electrolyte balance and no effects on kidney and heart weights were observed. Our data suggest that SGLT2 inhibition in a non-diabetic model of salt-sensitive hypertension blunts the development of salt-induced hypertension independent of sex.

Kidney Renin Release under Hypoxia and Its Potential Link with Nitric Oxide: A Narrative Review.

The renin-angiotensin system (RAS) and hypoxia have a complex interaction: RAS is activated under hypoxia and activated RAS aggravates hypoxia in reverse. Renin is an aspartyl protease that catalyzes the first step of RAS and tightly regulates RAS activation. Here, we outline kidney renin expression and release under hypoxia and discuss the putative mechanisms involved. It is important that renin generally increases in response to acute hypoxemic hypoxia and intermittent hypoxemic hypoxia, but not under chronic hypoxemic hypoxia. The increase in renin activity can also be observed in anemic hypoxia and carbon monoxide-induced histotoxic hypoxia. The increased renin is contributed to by juxtaglomerular cells and the recruitment of renin lineage cells. Potential mechanisms regulating hypoxic renin expression involve hypoxia-inducible factor signaling, natriuretic peptides, nitric oxide, and Notch signaling-induced renin transcription.

Graphdiyne-polymer composites for a hybrid bound-state pulsed fiber laser.

In this paper, the graphdiyne (GDY)-polymethyl methacrylate (PMMA) films are prepared by a spin-coating method. The PMMA films have the function of isolating GDY from air and protecting the GDY from mechanical damage. The nonlinear optical properties of GDY-PMMA films are probed experimentally. The nonlinear optical responses of GDY-PMMA films with a modulation depth of ∼4.94% and saturated magnetization of ∼0.3M W/c m 2 are proved. When the GDY-PMMA films are applied to an erbium-doped hybrid passively mode-locked fiber laser (saturable absorber), the bound-state solitons, which are also called soliton molecules, can be obtained. The soliton molecule has a time separation of 13.31 ps, and the spectral modulation period of 0.58 nm. Along with the pump power increase, the separation of bound-state pulses becomes larger. When the pump power is fixed, stable bound solitons can be observed without any degeneration for more than 4.5 h. It is demonstrated that GDY-PMMA films have excellent nonlinear optical performance in a near-infrared regime, which we believe can be a novel type of photonics instrument and has a number of properties that are potentially promising in the ultrafast properties of laser.

Sestrin2 Mediates Metformin Rescued the Age-Related Cardiac Dysfunctions of Cardiorenal Syndrome Type 3.

Acute kidney injury (AKI) leads to acute cardiac injury and dysfunction in cardiorenal syndrome Type 3 (CRS3) through oxidative stress (OS). The stress-inducible Sestrin2 (Sesn2) protein reduces reactive oxygen species (ROS) accumulation and activates AMP-dependent protein kinase (AMPK) to regulate cellular metabolism and energetics during OS. Sesn2 levels and its protective effects decline in the aged heart. Antidiabetic drug metformin upregulates Sesn2 levels in response to ischemia-reperfusion (IR) stress. However, the role of metformin in CRS3 remains unknown. This study seeks to explore how the age-related decrease in cardiac Sesn2 levels contributes to cardiac intolerance to AKI-induced insults, and how metformin ameliorates CRS3 through Sesn2. Young (3-5 months) and aged (21-23 months) C57BL/6J wild-type mice along with cardiomyocyte-specific knockout (cSesn2-/-) and their wild type of littermate (Sesn2f/f) C57BL/6J mice were subjected to AKI for 15 min followed by 24 h of reperfusion. Cardiac and mitochondrial functions were evaluated through echocardiograms and seahorse mitochondria respirational analysis. Renal and cardiac tissue was collected for histological analysis and immunoblotting. The results indicate that metformin could significantly rescue AKI-induced cardiac dysfunction and injury via Sesn2 through an improvement in systolic and diastolic function, fibrotic and cellular damage, and mitochondrial function in young, Sesn2f/f, and especially aged mice. Metformin significantly increased Sesn2 expression under AKI stress in the aged left-ventricular tissue. Thus, this study suggests that Sesn2 mediates the cardioprotective effects of metformin during post-AKI.

The Role of Macula Densa Nitric Oxide Synthase 1 Beta Splice Variant in Modulating Tubuloglomerular Feedback.

Abnormalities in renal electrolyte and water excretion may result in inappropriate salt and water retention, which facilitates the development and maintenance of hypertension, as well as acid-base and electrolyte disorders. A key mechanism by which the kidney regulates renal hemodynamics and electrolyte excretion is via tubuloglomerular feedback (TGF), an intrarenal negative feedback between tubules and arterioles. TGF is initiated by an increase of NaCl delivery at the macula densa cells. The increased NaCl activates luminal Na-K-2Cl cotransporter (NKCC2) of the macula densa cells, which leads to activation of several intracellular processes followed by the production of paracrine signals that ultimately result in a constriction of the afferent arteriole and a tonic inhibition of single nephron glomerular filtration rate. Neuronal nitric oxide (NOS1) is highly expressed in the macula densa. NOS1ß is the major splice variant and accounts for most of NO generation by the macula densa, which inhibits TGF response. Macula densa NOS1ß-mediated modulation of TGF responses plays an essential role in control of sodium excretion, volume and electrolyte hemostasis, and blood pressure. In this article, we describe the mechanisms that regulate macula densa-derived NO and their effect on TGF response in physiologic and pathologic conditions. © 2023 American Physiological Society. Compr Physiol 13:4215-4229, 2023.

Tacrolimus Causes Hypertension by Increasing Vascular Contractility via RhoA (Ras Homolog Family Member A)/ROCK (Rho-Associated Protein Kinase) Pathway in Mice.

BACKGROUND: To provide tacrolimus is first-line treatment after liver and kidney transplantation. However, hypertension and nephrotoxicity are common tacrolimus side effects that limit its use. Although tacrolimus-related hypertension is well known, the underlying mechanisms are not. Here, we test whether tacrolimus-induced hypertension involves the RhoA (Ras homolog family member A)/ROCK (Rho-associated protein kinase) pathway in male C57Bl/6 mice. METHODS: Intra-arterial blood pressure was measured under anesthesia. The reactivity of renal afferent arterioles and mesenteric arteries were assessed in vitro using microperfusion and wire myography, respectively. RESULTS: Tacrolimus induced a transient rise in systolic arterial pressure that was blocked by the RhoA/ROCK inhibitor Fasudil (12.0±0.9 versus 3.2±0.7; P<0.001). Moreover, tacrolimus reduced the glomerular filtration rate, which was also prevented by Fasudil (187±20 versus 281±8.5; P<0.001). Interestingly, tacrolimus enhanced the sensitivity of afferent arterioles and mesenteric arteries to Ang II (angiotensin II), likely due to increased intracellular Ca2+ mobilization and sensitization. Fasudil prevented increased Ang II-sensitivity and blocked Ca2+ mobilization and sensitization. Preincubation of mouse aortic vascular smooth muscle cells with tacrolimus activated the RhoA/ROCK/MYPT-1 (myosin phosphatase targeting subunit 1) pathway. Further, tacrolimus increased cytoplasmic reactive oxygen species generation in afferent arterioles (107±5.9 versus 163±6.4; P<0.001) and in cultured mouse aortic vascular smooth muscle cells (100±7.5 versus 160±23.2; P<0.01). Finally, the reactive oxygen species scavenger Tempol inhibited tacrolimus-induced Ang II hypersensitivity in afferent arterioles and mesenteric arteries. CONCLUSIONS: The RhoA/ROCK pathway may play an important role in tacrolimus-induced hypertension by enhancing Ang II-specific vasoconstriction, and reactive oxygen species may participate in this process by activating the RhoA/ROCK pathway.

Reducing ischemic kidney injury through application of a synchronization modulation electric field to maintain Na+/K+-ATPase functions.

Renal ischemia-reperfusion injury is an important contributor to the development of delayed graft function after transplantation, which is associated with higher rejection rates and poorer long-term outcomes. One of the earliest impairments during ischemia is Na+/K+-ATPase (Na/K pump) dysfunction due to insufficient ATP supply, resulting in subsequent cellular damage. Therefore, strategies that preserve ATP or maintain Na/K pump function may limit the extent of renal injury during ischemia-reperfusion. Here, we applied a synchronization modulation electric field to activate Na/K pumps, thereby maintaining cellular functions under ATP-insufficient conditions. We tested the effectiveness of this technique in two models of ischemic renal injury: an in situ renal ischemia-reperfusion injury model (predominantly warm ischemia) and a kidney transplantation model (predominantly cold ischemia). Application of the synchronization modulation electric field to a renal ischemia-reperfusion injury mouse model preserved Na/K pump activity, thereby reducing kidney injury, as reflected by 40% lower plasma creatinine (1.17 ± 0.03 mg/dl) in the electric field-treated group as compared to the untreated control group (1.89 ± 0.06 mg/dl). In a mouse kidney transplantation model, renal graft function was improved by more than 50% with the application of the synchronization modulation electric field according to glomerular filtration rate measurements (85.40 ± 12.18 µl/min in the untreated group versus 142.80 ± 11.65 µl/min in the electric field-treated group). This technique for preserving Na/K pump function may have therapeutic potential not only for ischemic kidney injury but also for other diseases associated with Na/K pump dysfunction due to inadequate ATP supply.

ßENaC and ASIC2 associate in VSMCs to mediate pressure-induced constriction in the renal afferent arteriole.

In independent studies, our laboratory has shown the importance of the degenerin proteins ß-epithelial Na+ channel (ßENaC) and acid-sensing ion channel 2 (ASIC2) in pressure-induced constriction (PIC) in renal interlobar arteries. Most, but not all, of the PIC response is abolished in mice lacking normal levels of ßENaC or in ASIC2-null mice, indicating that the functions of ßENaC and ASIC2 cannot fully compensate for the loss of the other. Degenerin proteins are known to associate and form heteromeric channels in expression systems, but whether they interact biochemically and functionally in vascular smooth muscle cells is unknown. We hypothesized that ßENaC and ASIC2 interact to mediate PIC responses in renal vessels. To address this possibility, we 1) used biochemical approaches to show that ßENaC associates into high-molecular-weight complexes and immunoprecipitants with ASIC2 in vascular smooth muscle cells and then 2) examined PIC in renal afferent arterioles in mice lacking normal levels of ßENaC (ßENaCm/m) or/and ASIC2 (ASIC2-/-) using the isolated afferent arteriole-attached glomerulus preparation. We found that the sensitivity of the PIC response (slope of the relationship between intraluminal pressure and percent myogenic tone) decreased to 26%, 27%, and -8% of wild-type controls in ASIC2-/-, ßENaCm/m, and ASIC2-/-/ßENaCm/m groups, respectively, suggesting that the PIC response was totally abolished in mice deficient in both ASIC2 and ßENaC. Surprisingly, we found that resting internal diameters were 20-30% lower (60 mmHg, Ca2+ free) in ASIC2-/-/ßENaCm/m (11.3 ± 0.5 µm) mice compared with control (14.4 ± 0.6 µm, P = 0.0007, independent two-tailed t test) or singly modified (15.7 ± 1.0 to 16.3 ± 1.1 µm) mice, suggesting compensatory vasoconstriction or remodeling. We then examined mean arterial blood pressure (MAP) using radiotelemetry and glomerular injury using histological examination of renal sections. We found that 24-h MAP was mildly elevated (+8 mmHg) in ASIC2-/-/ßENaCm/m mice versus wild-type controls and the glomerular injury score was modestly increased by 38%. These findings demonstrate that myogenic constriction in afferent arterioles is dependent on normal expression of ßENaC and ASIC2 and that mice lacking normal levels of ASIC2 and ßENaC have mild renal injury and increased MAP.NEW & NOTEWORTHY Transmission of systemic blood pressure to delicate renal microvessels is a primary determinant of vascular injury in chronic kidney disease progression to end-stage renal disease. Here, we identified two degenerin family members, with an evolutionary link to mechanosensing, that interact biochemically and functionally to regulate systemic blood pressure and renal injury. Thus, degenerin proteins may serve as a target for the development of therapies to prevent or delay renal disease progression.

Role of the macula densa sodium glucose cotransporter type 1-neuronal nitric oxide synthase-tubuloglomerular feedback pathway in diabetic hyperfiltration.

An increase of glomerular filtration rate (GFR) is a common observation in early diabetes and is considered a key risk factor for subsequent kidney injury. However, the mechanisms underlying diabetic hyperfiltration have not been fully clarified. Here, we tested the hypothesis that macula densa neuronal nitric oxide synthase (NOS1) is upregulated via sodium glucose cotransporter type 1 (SGLT1) in diabetes, which then inhibits tubuloglomerular feedback (TGF) promoting glomerular hyperfiltration. Therefore, we examined changes in cortical NOS1 expression and phosphorylation, nitric oxide production in the macula densa, TGF response, and GFR during the early stage of insulin-deficient (Akita) diabetes in wild-type and macula densa-specific NOS1 knockout mice. A set of sophisticated techniques including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of kidney tubules in vivo, and clearance kinetics of plasma fluorescent-sinistrin were employed. Complementary studies tested the role of SGLT1 in SGLT1 knockout mice and explored NOS1 expression and phosphorylation in kidney biopsies of cadaveric donors. Diabetic mice had upregulated macula densa NOS1, inhibited TGF and elevated GFR. Macula densa-selective NOS1 knockout attenuated the diabetes-induced TGF inhibition and GFR elevation. Additionally, deletion of SGLT1 prevented the upregulation of macula densa NOS1 and attenuated inhibition of TGF in diabetic mice. Furthermore, the expression and phosphorylation levels of NOS1 were increased in cadaveric kidneys of diabetics and positively correlated with blood glucose as well as estimated GFR in the donors. Thus, our findings demonstrate that the macula densa SGLT1-NOS1-TGF pathway plays a crucial role in the control of GFR in diabetes.

Orthotopic Heart Auto-Transplantation in a Swine Model.

BACKGROUND AND AIM: The porcine heart bears the best resemblance to the human heart and remains the preferred preclinical model for anatomical, physiological, and medical device studies. In an effort to study phenomena related strictly to ischemia reperfusion and donor preservation protocols, it is essential to avoid the immune responses related to allotransplantation. Orthotopic auto-transplantation is a unique strategy to the field of cardiac transplantation for ex vivo experimentation. Nevertheless, auto-transplantation carries its own technical challenges related to insufficient length of the great vessels that are to be transected and re-anastomosed. METHODS: A novel method for orthotopic cardiac auto-transplantation in the porcine model was developed and was described herein. Porcine models were used for ex vivo experimentation of a novel device to study ischemia reperfusion injury. RESULTS: A total of five porcine models were used for ex vivo experimentation of a novel device to mitigate ischemia reperfusion injury and determine effects of donor preservation. Modifications to routine cardiac transplantation protocols to allow for successful auto-transplantation are described. CONCLUSION: Orthotopic cardiac auto-transplantation in the porcine model is a plausible and technically feasible method for reliable study of ischemia reperfusion injury and donor preservation protocols. Here, we describe methods for both direct orthotopic porcine cardiac auto-transplantations as well as a simplified protocol that can be substituted for full surgical auto-transplantation for the studies of preservation of donor hearts.

Does Warfarin or Rivaroxaban at Low Anticoagulation Intensity Provide a Survival Benefit to Asian Patients With Atrial Fibrillation?

Background: Low-dose rivaroxaban and low-intensity warfarin are widely used in Asia for patients with atrial fibrillation (AF). However, in Asians, it is unclear whether low-dose rivaroxaban and low-intensity warfarin can improve the prognosis of AF. In this study, we investigate the survival benefits of low-dose rivaroxaban and low-intensity warfarin in Asian patients with AF in clinical practice. Methods: This cohort study used medical records in a single tertiary hospital in China, between 2019 and 2020, to identify patients with AF who used rivaroxaban or warfarin, or had no anticoagulant therapy. Follow-ups were performed through telephone contact or medical record review. Cox proportional hazards models were used to compare the risk of mortality of patients in the anticoagulant-untreated group vs. warfarin-treated groups and rivaroxaban-treated groups. Results: A total of 1727 AF patients, discharged between 2019 and 2020, were enrolled in this cohort, of which 873 patients did not use any anticoagulant, 457 patients received warfarin and 397 patients used rivaroxaban. Multivariable analysis showed that, of all the warfarin groups, patients with an international normalized ratio (INR) below 2, good INR control, or poor INR control had a significantly lower risk of mortality compared with that of patients without anticoagulants (HR 0.309, p = 0.0001; HR 0.387, p = 0.0238; HR 0.363, p < 0.0001). Multivariable Cox proportional hazard analyses also demonstrated that, compared with the no anticoagulant group, all rivaroxaban dosage groups (≤10 mg, HR 0.456, p = 0.0129; 15 mg, HR 0.246, p = 0.0003; 20 mg, HR 0.264, p = 0.0237) were significantly associated with a lower risk of mortality. Conclusion: Despite effects being smaller than observed with recommended optimal anticoagulation, the use of warfarin with an INR below 2, poor INR control and the use of low-dose rivaroxaban may still provide survival benefits, suggesting viable alternatives that enable physicians to better resolve decisional conflicts concerning the risks and benefits of anticoagulant therapies, as well as for patients in need of but unable to receive standard anticoagulant therapy due to bleeding risk or other factors, such as financial burden, concerns of adverse outcomes, as well as low treatment compliance and persistence.

Predicting All-Cause Mortality Risk in Atrial Fibrillation Patients: A Novel LASSO-Cox Model Generated From a Prospective Dataset.

Background: Although mortality remains high in patients with atrial fibrillation (AF), there have been limited studies exploring machine learning (ML) models on mortality risk prediction in patients with AF. Objectives: This study sought to develop an ML model that captures important variables in order to predict all-cause mortality in AF patients. Methods: In this single center prospective study, an ML-based mortality prediction model was developed and validated using a dataset of 2,012 patients who experienced AF from November 2018 to February 2020 at the First Affiliated Hospital of Shantou University Medical College. The dataset was randomly divided into a training set (70%, n = 1,223) and a validation set (30%, n = 552). A total of 122 features were collected for variable selection. Least absolute shrinkage and selection operator (LASSO) and random forest (RF) algorithms were used for variable selection. Ten ML models were developed using variables selected by LASSO or RF. The best model was selected and compared with conventional risk scores. A nomogram and user-friendly online tool were developed to facilitate the mortality predictions and management recommendations. Results: Thirteen features were selected by the LASSO regression algorithm. The LASSO-Cox model achieved an area under the curve (AUC) of 0.842 in the training dataset, and 0.854 in the validation dataset. A nomogram based on eight independent features was developed for the prediction of survival at 30, 180, and 365 days following discharge. Both the time dependent receiver operating characteristic (ROC) and decision curve analysis (DCA) showed better performances of the nomogram compared to the CHA2DS2-VASc and HAS-BLED models. Conclusions: The LASSO-Cox mortality predictive model shows potential benefits in death risk evaluation for AF patients over the 365-day period following discharge. This novel ML approach may also provide physicians with personalized management recommendations.

Increased Uric Acid, Gamma-Glutamyl Transpeptidase and Alkaline Phosphatase in Early-Pregnancy Associated With the Development of Gestational Hypertension and Preeclampsia.

Background: Previous studies have reported that biomarkers of liver injury and renal dysfunction were associated with hypertensive disorders of pregnancy (HDP). However, the associations of these biomarkers in early pregnancy with the risk of HDP and longitudinal blood pressure pattern during pregnancy were rarely investigated in prospective cohort studies. Methods: A total of 1,041 pregnant women were enrolled in this prospective cohort study. BP was assessed in four stages throughout pregnancy. The following biomarkers were measured at early pregnancy before 18 weeks gestation: lactate dehydrogenase (LDH), aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), uric acid (UA), and estimated glomerular filtration rate (eGFR). Linear mixed-effects and logistic regression models were used to examine the associations of these biomarkers with longitudinal BP pattern during pregnancy and HDP incidence, respectively. Results: In unadjusted models, higher serum UA, GGT, ALP, and LDH levels, as well as lower eGFR and AST/ALT, were associated with higher BP levels during pregnancy and an increased risk of HDP. After adjustment for maternal age, pre-pregnancy BMI and other potential confounders, UA, GGT, ALP, and LDH remained positively associated with both BP and HDP. However, eGFR and AST/ALT were not associated with HDP after adjusting for potential confounders. When including all 6 biomarkers simultaneously in multivariable analyses, increased UA, GGT, and ALP significantly associated with gestational hypertension and preeclampsia. Conclusion: This study suggests that increased UA, GGT, and ALP in early-pregnancy are independent risk factors of gestational hypertension and preeclampsia.

Knockout of Macula Densa Neuronal Nitric Oxide Synthase Increases Blood Pressure in db/db Mice.

[Figure: see text].

Gut microbiota dependent trimethylamine N-oxide aggravates angiotensin II-induced hypertension.

Gut microbiota produce Trimethylamine N-oxide (TMAO) by metabolizing dietary phosphatidylcholine, choline, l-carnitine and betaine. TMAO is implicated in the pathogenesis of chronic kidney disease (CKD), diabetes, obesity and atherosclerosis. We test, whether TMAO augments angiotensin II (Ang II)-induced vasoconstriction and hence promotes Ang II-induced hypertension. Plasma TMAO levels were indeed elevated in hypertensive patients, thus the potential pathways by which TMAO mediates these effects were explored. Ang II (400 ng/kg-1min-1) was chronically infused for 14 days via osmotic minipumps in C57Bl/6 mice. TMAO (1%) or antibiotics were given via drinking water. Vasoconstriction of renal afferent arterioles and mesenteric arteries were assessed by microperfusion and wire myograph, respectively. In Ang II-induced hypertensive mice, TMAO elevated systolic blood pressure and caused vasoconstriction, which was alleviated by antibiotics. TMAO enhanced the Ang II-induced acute pressor responses (12.2 ± 1.9 versus 20.6 ± 1.4 mmHg; P < 0.05) and vasoconstriction (32.3 ± 2.6 versus 55.9 ± 7.0%, P < 0.001). Ang II-induced intracellular Ca2+ release in afferent arterioles (147 ± 7 versus 234 ± 26%; P < 0.001) and mouse vascular smooth muscle cells (VSMC, 123 ± 3 versus 157 ± 9%; P < 0.001) increased by TMAO treatment. Preincubation of VSMC with TMAO activated the PERK/ROS/CaMKII/PLCß3 pathway. Pharmacological inhibition of PERK, ROS, CaMKII and PLCß3 impaired the effect of TMAO on Ca2+ release. Thus, TMAO facilitates Ang II-induced vasoconstriction, thereby promoting Ang II-induced hypertension, which involves the PERK/ROS/CaMKII/PLCß3 axis.