Endothelium-dependent Vasodilation Research Articles

Gestational hypoxia elicits long-term cardiovascular dysfunction in female guinea pigs

BackgroundGestational hypoxia (GH) has been implicated in the developmental programming of cardiovascular diseases (CVDs) in the offspring, with most studies focusing on males, conversely, the effects on female cardiovascular health remain understudied. We aimed to investigate the impact of GH on the cardiovascular system of female guinea pig offspring from the early postnatal period to adulthood. MethodsPregnant guinea pigs were subjected to normoxic or hypoxic conditions from gestational day 30 until delivery (∼70 days). Female offspring were monitored with biometric parameters and peripheral vascular function (ultrasound) from birth to one year old. In addition, we assessed cardiovascular structure, oxidative stress, inflammatory state (IHC, qPCR, and immunoblot assays), and thoracic aorta reactivity (wire-myography) at one year of age. Key findingsGH increased heart rate and peripheral pulsatility index. At one year old, GH-exposed females exhibited cardiac remodeling, characterized by increased left ventricular luminal area and coronary artery muscle occupation. Furthermore, GH increased aortic vascular wall, intima-media thickness and contractile capacity. This was accompanied by reduced endothelium-dependent vasodilation and enhanced oxidative stress. Additionally, GH increased collagen deposition and oxidative stress in the right ventricle, accompanied by reduced antioxidant enzymes expression and reduced inflammatory mediator levels. SignificanceGH exerts long-lasting effects on the cardiovascular health of female guinea pig offspring, contributing to cardiac remodeling, vascular dysfunction, oxidative stress, and inflammatory changes. These findings highlight the importance of GH as a risk factor for developing CVDs in female offspring and emphasize the need for sex-specific interventions to mitigate adverse long-term gestational effects.

Pulse wave analysis as a tool to assess endothelial function following lipid lowering intervention in hypercholesterolemia

BackgroundPulse wave analysis (PWA) assesses endothelial dependent vasodilation (EDV) via the change in augmentation index (AIx) and has been used as a tool to assess endothelial function. However, its effectiveness in assessing the response to lipid lowering treatment has not been evaluated. The study aimed to describe and correlate the change in EDV following lipid lowering intervention in patients with hypercholesterolemia. Methods48 newly diagnosed patients with hypercholesterolemia underwent 6 months intervention with statin and/or therapeutic lifestyle changes (TLC) in clinical setting. Lipid profile measurement and endothelial function assessment using PWA were performed pre- and post-intervention. ResultsSignificant reductions in low density lipoprotein cholesterol (LDL-C), non-high density lipoprotein cholesterol (non-HDL-C) and total cholesterol (TC) with corresponding significant improvement in EDV (2.94 ± 3.69 % to 7.50 ± 3.79 %, p < 0.001) were observed following intervention. Sub-analyses revealed greater LDL-C reductions and EDV improvements in the statin group compared to TLC. There was a significant inverse correlation between the change in EDV and the change in LDL-C after intervention (r = −0.298, p = 0.040). ConclusionEndothelial function assessed by PWA showed a parallel change with lipid profile pattern following lipid lowering intervention. The simple and non-invasive method may provide a potential tool for evaluating endothelial function and treatment outcomes in patients with hypercholesterolemia.

Dose-related effect of acetylcholine on human gingival blood flow

BackgroundThis study investigates the dose-response relationship of acetylcholine (ACh) on healthy human gingival blood flow (GBF). Understanding this dose-response relationship contributes to studying vasodilatory mechanisms in various pathological conditions.MethodsThe study involved 22 young healthy men (21 - 32 years) to investigate the dose-response relationship of ACh on GBF. Semi-circular wells were created on the labial surface of the upper right second incisor (FDI #12) and upper left first incisor (FDI #21), including the gingival sulcus, for the application of drugs. ACh-chloride solutions at 0.1, 1, and 10 mg/mL were administered to the gingival sulcus of tooth FDI #12 with a Hamilton syringe. Physiological saline was applied on the contralateral side to FDI #21 as a control. The GBF was measured non-invasively by the laser speckle contrast imaging method in four 1mm high adjacent regions: coronal, midway1, midway2, and apical, and was expressed in a laser speckle perfusion unit (LSPU). After the baseline blood flow recording, ACh doses were applied sequentially, with washout periods in between. Data were statistically analyzed using a linear mixed model.ResultsThe GBF did not change on the saline site throughout the experiment. The GBF was significantly higher at the coronal region after all ACh doses (baseline: 218±31 LSPU, and 227±38 LSPU p < 0.05, 239±40 LSPU p < 0.001, 291±54 LSPU p < 0.001, respectively) compared to the saline. It was also elevated following 1 and 10 mg/mL at the midway1 (245±48 LSPU,p < 0.05, 293±65 LSPU p < 0.001). At midway2 and apical, only the 10 mg/mL dose was effective (285±71 LSPU, p < 0.001; 302±82 LSPU, p < 0.001).ConclusionsOur findings suggest a dose-dependent vasodilation to ACh, emphasizing its role in human gingival microcirculation. Only the 10 mg/mL ACh could evoke remote vasodilation 3 mm from the application. The described method could facilitate the investigation of endothelium-dependent vasodilation in disorders affecting microcirculation, such as periodontitis or diabetes.

Abstract 4147602: The Paradox Role of Sirtuin 6 In Coronary Microvascular Function under Metabolic Stress

Coronary microvascular dysfunction (CMD), which is associated with diabetic cardiomyopathy, Takotsubo cardiomyopathy, andheart failure with preserved ejection fraction (HFpEF), is understudied. CMD is characterized by impaired endothelial-dependent vasodilation, but detailed mechanisms have yet to be elucidated. Nuclear Sirtuin 6 (SIRT6) plays essential roles in gene transcriptional, stress tolerance, DNA repair, inflammation, and aging. SIRT6 is strongly associated with cardiovascular pathologies, but how SIRT6 regulates endothelial metabolisms and homeostasis under metabolic stress and the underlying mechanism remains poorly understood. It might be because global Sirt6 knockout mice are perinatally lethal caused by hypoglycemia, suggesting the essential role of SIRT6 in glucose metabolism. In our preliminary studies, we generated inducible global Sirt6 knockout mice by crossing with Sirt6 f/f mice with CAG-cre (Sirt6 f/f, CAG ), and mice were viable with normal glucose levels. However, they showed impaired endothelial-dependent dilation (EDD) and impaired coronary flow reserve (CFR), an index clinically used to diagnose CMD. It suggests that deletion of Sirt6 might cause EC dysfunction because Sirt6 is reported to protect EC from premature senescence and oxidative stress by sustaining high eNOS levels. Surprisingly, when we studied non-inducible Sirt6 endothelial-specific knockout (Sirt6 f/f, tie-2 cre ) and inducible Sirt6 endothelial-specific knockout (Sirt6 f/f, Cdh5-cre/ERT2 ) and wild-type (WT) mice, Sirt6 f/f, Tie-2 and Sirt6 f/f, Cadh5 mice do not phenocopy the inducible global SIRT6 knockout mice, they had normal EDD and CFR. When the mice were fed a high fat and high sugar (HFHS) diet, the Sirt6 f/f, Tie-2 and Sirt6 f/f, Cadh5 had impaired EDD, suggesting Sirt 6 functioned differently in the mice fed with chow diet or HFHS diet. We hypothesize Sirt 6 deficiency causes coronary endothelial dysfunction and contributes to CMD; activating Sirt6 will ameliorate CMD. EDD was assessed using myography (DMT). Myocardial blood flow (MBF) was measured by Doppler. Our preliminary data show that the mediator of coronary vasodilation switched from NO to H 2 O 2 in the Sirt6 knockout mice with impaired EDD. Interestingly, when the mice fed on HFHS were treated with Sirt 6 activator MDL-800, the coronary microvascular function was improved, and the blood glucose level was decreased. The underlying mechanism and the pathways involved will be elucidated.

Increasing the effectiveness of total-skin electron beam therapy by reducing the manifestations of radiation dermatitis in patients with primary lymphomas. A comparative randomized prospective study

Background. One of the main adverse events that significantly reduce the quality of life of patients and limit the total focal dose is radiation-induced skin reactions (RISR). Their timely diagnosis, prevention, and treatment remain urgent tasks of modern radiotherapy. Aim. To improve the effectiveness of total skin irradiation (TSI) in patients with primary skin lymphomas by reducing the clinical manifestations of RISR by using additional therapy with a hydrogel containing active components with vasoprotective and anti-inflammatory action. Materials and methods. A comparative randomized prospective study was conducted, including data from 52 patients who received electron TSI by conventional fractionation at a total focal dose of 14 to 30 Gy for primary cutaneous lymphomas at the Granov Russian Research Center of Radiology and Surgical Technologies from September 2021 to January 2024. Before the first TSI session, during treatment and 2 weeks after the end of radiation therapy, all patients underwent assessment for RISR, quantitative assessment of various degrees of severity of radiodermatitis using instrumental methods and assessment scales; for the observation group, a therapeutic regimen for the prevention and treatment of RISR was used, including a hydrogel with troxerutin (2%) and trolamine (0.07%), and in the control group, basic skin care using moisturizers. Results. Analysis of the physiological parameters of the skin showed statistically significant differences between the study groups: patients of the study group (group I; 30 subjects receiving the above-mentioned therapeutic regimen) compared with the control group (group II; 28 subjects who did not receive specific treatment for radiodermatitis) reported significantly lower rates of erythema (386±12.3 and 572±14.4; p=0.005), transepidermal water loss (25±0.3 and 38±0.4 g/m2/h; p0.001) and a decrease in peak endothelial-dependent vasodilation of microvasculature and blood flow in the skin. A lower proportion of severe radiodermatitis (86.3 and 73.3%; p0.05) and a statistically significant difference in the subjective quality of life scores by the 29-point Skindex-29 scale by an average of 22.2% were also found. Conclusion. A comparative analysis of the quantitative indicators of radiodermatitis in the study group and the control group showed that the topical application of the hydrocolloid gel containing troxerutin and trolamine reduces the clinical manifestations of RISR concerning objectively measured physiological parameters of the skin and blood flow parameters of the microvasculature measured by high-frequency ultrasound, thus improving the quality of life of patients during and after the course of radiation therapy.

Targeting GPR39 in structure-based drug discovery reduces Ang II-induced hypertension.

The endothelium-dependent vascular injury, a primary pathological feature of angiotensin II (Ang II)-induced hypertension. This study aimed to explore the role and underlying mechanisms of G protein-coupled receptor 39 (GPR39) in the pathogenesis of Ang II-induced hypertension. For in vivo studies, GPR39 knockout (KO) mice (C57BL/6 J, male) were generated and administered Ang II for 4 weeks. GPR39 expression was upregulated in the aorta of hypertensive patients and mice. The ablation of GPR39 mitigated vascular fibrosis, augmented endothelium-dependent vasodilation, and inhibited endothelial inflammation, oxidative stress, and apoptosis in mice. Additionally, GPR39 KO decreased NOD-like receptor protein 3 (Nlrp3) gene expression in Ang II-stimulated endothelial cells. Notably, Nlrp3 activation counteracted the therapeutic benefits of GPR39 KO. We identified the potential ligand of GPR39 using structure-based high throughput virtual screening (HTVS) and validated its antihypertensive function in vitro and in vivo. The small molecule ligand Z1780628919 of GPR39 can also reduce Ang II-induced hypertension and improve vascular function. GPR39 KO and the small molecule ligand Z1780628919 potentially downregulates Nlrp3, thereby mitigating vascular fibrosis, endothelial inflammation, oxidative stress, and apoptosis. This effect contributes to the alleviation of Ang II-induced hypertension and the rectification of vascular dysfunctions. These findings suggest new avenues for therapeutic intervention.

Menstrual cycle and the protective effects of remote ischemic preconditioning against endothelial ischemia/reperfusion injury: comparison with postmenopausal women.

The aim of this study was to determine whether the capacity of remote ischemic preconditioning (IPC) against endothelial ischemia/reperfusion (I/R) injury changes across the menstrual cycle in premenopausal women and to compare IPC responses to postmenopausal women. Thirty-five women were studied (22 premenopausal/13 postmenopausal). Changes in endothelial function were determined during the early follicular vs. the late follicular phase (after positive urine ovulation test; Study 1), vs. the mid-luteal phase (after positive urine progesterone test; Study 2), and vs. estrogen-deficient postmenopausal women; Study 3). Endothelium-dependent vasodilation was assessed by the forearm blood flow (FBF) to reactive hyperemia with/without I/R injury with remote IPC (3 × 5 min cycles of upper arm ischemia). In the premenopausal women, peak FBF responses during the early follicular phase were blunted 20% (P < 0.0001) with I/R injury (from baseline: 23.4 ± 6.2 to 19.5 ± 4.9 mL/100 mL tissue/min) compared with the late follicular/mid-luteal phases despite IPC. In postmenopausal women, peak FBF was diminished (from: 21.1 ± 5.1 to 17.2 ± 4.4 mL/100 mL tissue/min), and total FBF (area under the curve) was decreased a third (-32%; P < 0.001) with I/R injury. Protection from I/R injury was preserved during the late follicular (from baseline: 21.7 ± 5.3 to 24.8 ± 5.9 mL/100 mL tissue/min; P = 0.109) and mid-luteal phases (from: 25.1 ± 3.9 to 27.2 ± 5.7 mL/100 mL tissue/min; P = 0.267). Reduced estrogen during the early follicular phase and the rise in estrogen associated with ovulation and the mid-luteal phase may contribute to changes in IPC-mediated protection in premenopausal women and shed light on how cardioprotection may change with ovarian hormone deficiency with the menopause transition.NEW & NOTEWORTHY The capacity of remote ischemic preconditioning to protect against vascular endothelial ischemia/reperfusion injury varies widely across the phases of the menstrual cycle in healthy premenopausal women. Robust protection was afforded during the late follicular and mid-luteal phases. In contrast, weakened protection was demonstrated during the early follicular phase, with a level of impairment similar to estrogen-deficient postmenopausal women.

Conditional over-expression of heme-oxygenase 1 in myelomonocytic cells reduces AngII-induced hypertension and vascular inflammation in mice

Abstract Background Systemic arterial Hypertension is one of the most important risk factor responsible for morbidity and mortality world-wide. Angiotensin II (Ang II), a potent vasoconstrictor and key player in the renin-angiotensin-aldosterone system (RAAS) is responsible for vascular dysfunction, inflammation, and tissue damage. Heme oxygenase-1 (HO-1) overexpression may confer antioxidant and anti-inflammatory properties in Ang II-induced hypertension through its action on heme catabolism, generating carbon monoxide (CO), ferritin and biliverdin/bilirubin by the action of biliverdin reductase A (BLVRA). Methods and results Male 9–12-weeks-old HO-1indxLySMCre/wt and LySMCre/wt mice were infused with AngII (1mgAngII/Day/Kg) for 7 days to induce hypertension and compared to sham treatment. Blood pressure monitoring by tail-cuff method, and endothelium-dependent vasodilator studies via organ chamber system using acetylcholine (ACh) in isolated aortic segments (~4 mm), revealed that overexpression of HO-1 in myeloid cells resulted in decreased systolic blood pressure and improved endothelial function in AngII-infused HO-1indxLySMCre/wt mice compared to controls. Concurrently, increased BLVRA expression in liver tissue and elevated plasma bilirubin levels were detected by transcriptome analysis and high-performance liquid chromatography, respectively. These results were supported by a reduction in the expression of inducible cytokines and cell adhesion molecules (CAMs) in the aorta, assessed using qPCR. Bone marrow transplant experiments demonstrated that bone marrow from LysMcre mice in HO-1indxLySMCre/wt mice abrogated the protective effect of HO-1, resulting in endothelial damage and increased blood pressure, potentially due to decreased liver BLVRA expression and the accumulation of bone marrow-derived cells in the vessel wall in response to AngII. Additionally, adeno-associated viral vector (AAV) transfection targeting specifically BLVRA activity in liver lead to an increase in blood pressure values and worse endothelium relaxation, in parallel with higher oxidative stress and the blood neutrophils concentration, as assessed in whole blood by using oxidative burst method and blood count system respectively. Conclusion The overexpression of HO-1 in myeloid cells confers anti-inflammatory protection in AngII-induced arterial hypertension in mice. Myeloid cells bone marrow-derived overexpressing HO-1 regulate the differentiation and infiltration of pro-inflammatory immune cells in the vasculature. BLVRA expression and bilirubin levels downstream of HO-1 play a critical role in protecting against vascular damage by reducing leukocyte infiltration.

Coronary microvascular dysfunction in postmenopausal minipigs with multiple risk factors

Abstract Background Coronary microvascular angina occurs in both men and women, however, the majority of patients are postmenopausal women with multiple cardiovascular risk factors, such as diabetes mellitus (DM), chronic kidney disease (CKD) and dyslipidemia. No treatment is available for coronary microvascular dysfunction, requiring more in depth knowledge on the mechanisms underlying this syndrome in this expanding group of patients. Purpose Here we studied microvascular function in vivo and and in vitro in isolated small coronary arteries, in post-menopausal miniswine with multiple cardiovascular risk factors. Methods DM (streptozotocin), hypercholesterolemia (HC, high fat, high sugar diet), CKD (renal artery embolization) and menopause (ovariectomy, OVX) were induced in 5 adult female minipigs (1.5-2 years old, ~40kg, DM+HC+CKD+OVX) for 6 months, while 11 healthy age- and weight-matched female minipigs on normal pig chow served as controls (Normal). At sacrifice, coronary flow reserve (CFR) in response to intracoronary infusion of adenosine was measured under anesthesia. Isolated small coronary arteries were used to study the endothelium-dependent response to bradykinin in the presence and absence of eNOS blockade with LNAME, and cyclooxygenase inhibition by indomethacin, and endothelium-independent response to the nitric oxide (NO) donor, SNAP. Results 6 months of sustained hyperglycemia (17.5±1.0 in DM+HC+CKD+OVX vs 8.2±0.9 mmol/l in Normal, P&amp;lt;0.05 by t-test), hypercholesterolemia (15.4±2.0 vs 1.7±0.1 mmol/l, P&amp;lt;0.05), renal dysfunction (NGAL: 205±72 vs 67±5 ng/ml, P&amp;lt;0.05) and low progesterone levels (13.1±5.7 in DM+HC+CKD+OVX vs 92.0±30.0 nmol/l in Normal, P=0.1) were accompanied by systemic inflammation (TNFα: 62±7 vs 47±1 pg/ml, P&amp;lt;0.05). CFR was significantly reduced in DM+HC+CKD+OVX as compared to the healthy animals (panel A). Coronary small arteries from DM+HC+CKD+OVX animals showed impaired endothelium-dependent vasodilation to bradykinin (panel B), which was mediated by a loss of NO (panels C &amp; D). The loss of NO was partly compensated for by activation of the cyclooxygenase pathway, as indomethacin blunted the dilation to bradykinin in the DM+HC+CKD+OVX animals, but had no effect on the dilation to bradykinin in Normals (panels C &amp; D). Endothelium-independent dilation to SNAP was also impaired in DM+HC+CKD+OVX animals, indicating blunted vascular smooth muscle responsiveness to nitric oxide (panel E). Conclusion Postmenopausal minipigs with multiple risk factors, displayed severe coronary microvascular dysfunction as evidenced by a significantly reduced coronary flow reserve and both reduced NO sensitivity/ production, indicating endothelial and smooth muscle cell dysfunction. Loss of NO-mediated vasodilation was partially compensated by activation of cyclooxygenase pathway. Such perturbations may contribute to reduced myocardial perfusion that is often observed in post-menopausal women with multiple cardiovascular risk factors.

Impaired systemic microvascular function in patients with resistant arterial hypertension and microalbuminuria: an observational study

Abstract Background Systemic arterial hypertension (SAH) is one of the most prevalent diseases worldwide and is known to be associated with alterations of microvascular function. It is well known that microalbuminuria (MAU) is considered an early marker of renal and cardiac injury in SAH and is an independent risk factor for cardiovascular events in this population. Additionally, it is associated with altered endothelial function, which occurs from the early stages and can be considered an early marker. In some cases, SAH presents as resistant arterial hypertension (RAH), resulting in a worse prognosis compared to individuals with non-resistant hypertension. Moreover, MAU is associated with higher mortality, independent of glomerular filtration rate. Endothelial dysfunction is also a risk marker found in different conditions and can add to MAU in patients with RAH. Purpose To investigate systemic microvascular function in patients with RAH, with or without MAU. Methods 64 patients with RAH, of both genders (50% men), were evaluated, with 32 having MAU and 32 without MAU (defined as a urinary albumin/creatinine ratio between 30 and 300 mg/g in a routine urine sample). Microvascular function assessment was performed using a laser speckle system, allowing analysis of cutaneous microvascular flow. Flow measurements were expressed in arbitrary perfusion units (APU) divided by the mean arterial pressure to obtain cutaneous vascular conductance (CVC). A post-occlusive reactive hyperemia (PORH) test was performed, with brachial artery occlusion using a sphygmomanometer 50 mmHg above systolic pressure for 3 minutes; cutaneous flow was measured after release of the occlusion. Results Patients with or without MAU did not differ in terms of age, frequency of diabetes, and chronic kidney disease. The peak CVC values during PORH were 0.64 ± 0.15 and 0.55 ± 0.15 APU/mmHg in RH and RH + MAU patients, respectively (P=0.03). The delta values (peak – baseline) during PORH were 0.31 ± 0.11 and 0.25 ± 0.09 APU/mmHg in RH and RH + MAU patients, respectively (P=0.04)(Figure 1). Conclusions PORH-induced vasodilation was found to be reduced in patients with RAH and MAU compared to patients without MAU. This finding shows alteration of endothelium-dependent vasodilation mechanisms in these patients, indicating reduced systemic microvascular endothelial function. Endothelial dysfunction may be associated with glomerular permeability changes, contributing to MAU and further increasing the risk for these patients. This suggests the need for more intensive therapeutic interventions and better risk stratification for these patients, as endothelial dysfunction can be found in the early stages of the disease.Figure 1

Increased TRPV4 Channel Expression Enhances and Impairs Blood Vessel Function in Hypertension.

Endothelial cell TRPV4 (transient receptor potential vanilloid 4) channels provide a control point that is pivotal in regulating blood vessel diameter by mediating the Ca2+-dependent release of endothelial-derived vasoactive factors. In hypertension, TRPV4-mediated control of vascular function is disrupted, but the underlying mechanisms and precise physiological consequences remain controversial. Here, using a comprehensive array of methodologies, endothelial TRPV4 channel function was examined in intact mesenteric resistance arteries from normotensive Wistar-Kyoto and spontaneously hypertensive rats. Our results show there is a notable shift in vascular reactivity in hypertension characterized by enhanced endothelium-dependent vasodilation at low levels of TRPV4 channel activation. However, at higher levels of TRPV4 activity, this vasodilatory response is reversed, contributing to the aberrant vascular tone observed in hypertension. The change in response, from dilation to constriction, was accompanied by a shift in intracellular Ca2+ signaling modalities arising from TRPV4 activity. Oscillatory TRPV4-evoked IP3 (inositol triphosphate)-mediated Ca2+ release, which underlies dilation, decreased, while the contraction inducing sustained Ca2+ rise, arising from TRPV4-mediated Ca2+ influx, increased. Our findings also reveal that while the sensitivity of endothelial cell TRPV4 to activation was unchanged, expression of the channel is upregulated and IP3 receptors are downregulated in hypertension. These data highlight the intricate interplay between endothelial TRPV4 channel expression, intracellular Ca2+ signaling dynamics, and vascular reactivity. Moreover, the data support a new unifying hypothesis for the vascular impairment that accompanies hypertension. Specifically, endothelial cell TRPV4 channels play a dual role in modulating blood vessel function in hypertension.

Impaired Endothelium-Dependent Vasodilation and Increased Levels of Soluble Fms-like Tyrosine Kinase-1 Induced by Reduced Uterine Perfusion Pressure in Pregnant Rats: Evidence of Protective Effects with Sodium Nitrite Treatment in Preeclampsia.

Preeclampsia (PE) is a hypertensive disorder of pregnancy and is associated with increases in soluble fms-like tyrosine kinase-1 (sFlt-1) and reductions in nitric oxide (NO) levels. Placental ischemia and hypoxia are hypothesized as initial pathophysiological events of PE. Nitrite (NO metabolite) may be recycled back to NO in ischemic and hypoxic tissues. Therefore, this study examined the sodium nitrite effects in an experimental model of PE. Pregnant rats received saline (Preg group) or sodium nitrite (Preg + Na-Nitrite group). Pregnant rats submitted to the placental ischemia received saline (RUPP group) or sodium nitrite (RUPP + Na-Nitrite group). Blood pressure, placental and fetal weights, and the number of pups were recorded. Plasma levels of NO metabolites and sFlt-1 were also determined. Vascular and endothelial functions were also measured. Blood pressure, placental and fetal weights, the number of pups, NO metabolites, sFlt-1 levels, vascular contraction, and endothelium-dependent vasodilation in the RUPP + Na-Nitrite rats were brought to levels comparable to those in Preg rats. In conclusion, sodium nitrite may counteract the reductions in NO and increases in sFlt-1 levels induced by the placental ischemia model of PE, thus suggesting that increased blood pressure and vascular and endothelial dysfunctions may be attenuated by sodium nitrite-derived NO.

Resistance artery vasodilator pathways involved in the antihypertensive effects of cocoa shell extract in rats exposed to fetal undernutrition.

Fetal undernutrition establishes the foundations for hypertension development, with oxidative stress being a key hallmark. A growing interest in nutraceuticals for treating hypertension and environmental waste concerns prompted the present study aiming to evaluate whether supplementation with a polyphenol enriched extract from cocoa shell (CSE), a by-product from the chocolate industry with antioxidant properties, reduces hypertension of developmental origin, thus improving mesenteric resistance artery (MRA) vasodilatation. Adult male and female offspring from rats exposed to 50% food restriction from mid-gestation (maternal undernutrition, MUN) and controls were used. Supplementation was given through a gelatine (vehicle, VEH) or containing CSE (250mgkg-1day-1) 5daysweek-1 for 3weeks. Systolic blood pressure (SBP) was assessed by tail-cuff plethysmography. MRA function was studied by wire myography, and superoxide anion and nitric oxide were investigated by fluorescent indicators and confocal microscopy. Compared to control-VEH, MUN-VEH males showed significantly higher SBP, reduced MRA as well as relaxation to ACh, sodium nitroprusside and the AMPK agonist 5-aminoimidazole-4-carboxamide riboside, but not to isoproterenol. In MUN males, endothelial endothelium-derived hyperpolarizing factor and nitric oxide were unaltered, but MRA released a vasoconstrictor prostanoid and produced higher levels of superoxide anion. CSE normalized blood pressure and improved all above-mentioned MRA alterations in MUN males without an effect on control counterparts, except the reduction of superoxide anion. MUN-VEH females were normotensive and only showed a tendency towards larger superoxide anion production, which was abolished by CSE. CSE supplementation reduces SBP improving endothelium-dependent and independent MRA vasodilatation, related to local superoxide anion reduction, being a potential nutraceutical ingredient to counteract hypertension, in addition to contributing to the circular economy. KEY POINTS: Fetal undernutrition induces hypertension in males associated with deficient resistance artery vasodilatation, being normalized by cocoa shell extract (CSE). Release of a cyclooxygenase-derived contractile factor is the main endothelial alteration, which is abolished by CSE. AMPK and soluble guanylyl cyclase-mediated relaxation are also reduced in smooth muscle cells from maternal undernutrition resistance arteries, being improved by CSE. Vascular oxidative damage caused by excess superoxide anion generation can account for impaired vasodilatation, which is improved by CSE. The capacity of CSE to improve relaxation is probably related to its antioxidant bioactive factors, and thus cocoa shell is a potential food by-product to treat hypertension.

Aerobic exercise training-induced bone and vascular adaptations in mice lacking adiponectin

Adiponectin regulates lipid and glucose metabolism, and insulin sensitivity in various target organs; however, the effects of adiponectin on bone health remain controversial. Exercise training can enhance bone density, bone microarchitecture, and blood flow. This study aimed to elucidate the role of adiponectin in adaptations of bone microarchitecture and bone vasculature in response to aerobic exercise training.Adult male C57BL/6 wild-type (WT) and homozygous adiponectin knockout (AdipoKO) mice were either treadmill exercise trained or remained sedentary for 8–10 weeks. The trabecular structures of the distal femoral metaphysis, a weight-bearing bone, and the mandible, a non-weight-bearing bone, were examined using microcomputed tomography. The femoral principal nutrient arteries were isolated to assess vasoreactivity (vasodilation and vasoconstriction) and structural remodeling.At the femoral metaphysis, impaired trabecular bone structures, including reduced connectivity density and increased trabecular spacing, were observed in AdipoKO mice compared to WT mice. In addition, nitric oxide-mediated, endothelium-dependent vasodilation was substantially reduced, and wall-to-lumen ratio was significantly increased in the femoral principal nutrient artery of AdipoKO mice. Interestingly, although exercise training-induced enhancements in trabecular connectivity density were observed at the femoral metaphysis of both WT and AdipoKO, increased vasoconstrictor responses were only observed in the femoral principal nutrient artery of WT mice, not in the AdipoKO mice. In mandibular trabecular bone, exercise training increased trabecular bone volume fraction (BV/TV, %) and intersection surface in the mandible of both WT and AdipoKO mice.These findings indicate that adiponectin is crucial for maintaining normal bone microarchitecture and vasculature. Although the absence of adiponectin compromises bone vascular adaptation to exercise training in mice, some exercise training-induced alterations in bone microarchitecture occurred in the absence of adiponectin, suggesting contribution of compensatory mechanisms during exercise training.

Position of Beta-blockers in the Treatment of Hypertension Today: An Indian Consensus.

Management of essential hypertension (HTN) remains challenging, with contemporary control being achieved in <1/10 of the cases, especially when aligned with the recently updated guidelines of American College of Cardiology (ACC) or International Society of Hypertension (ISH). The place and positioning of beta-blockers have been evolving, with recent focused updates, such as the European Society of Hypertension (ESH) 2023 guidelines, that may hold relevance for the Indian phenotypic traits of premature cardiovascular disease (CVD), fragile coronary architecture, and/or high resting heart rate. To further develop consensus on the clinical role and relevance of beta-blockers, including nebivolol, an Indian consensus was evolved with graded recommendations on their clinical role in HTN, HTN with additional cardiovascular (CV) risk, or type 2 diabetes mellitus (T2DM). An expert review panel was constituted, comprising interventional and clinical cardiologists as experts, to synthesize the literature for the development of a validated knowledge, attitude, and practice (KAP) survey questionnaire. Research databases, including Cochrane Systematic Reviews, PubMed, and Google Scholar, were accessed for contemporary information and guidelines on beta-blockers updated until Dec 2023. Delphi rounds were conducted to develop graded recommendations based on the strength, quality of evidence, and the agreement among the panelists (n = 9). Consensus was achieved on the graded recommendations, with ≥70% of national panelists in agreement. Ninety-six percent of respondents opined that the new ESH HTN guidelines (2023) help gain confidence in using beta-blockers, which are considered first-line drugs for the treatment of HTN. Beta-blockers, including nebivolol, can be recommended in patients with HTN with high resting heart rates, including young hypertensive patients under 40 years of age. For people under 60 years old with HTN, regardless of whether they have comorbid diseases, beta-blockers are the recommended drug choice. Ninety-five percent of respondents opined that nebivolol is the preferred beta-blocker in hypertensive patients with T2DM, followed by bisoprolol and metoprolol. More than 90% of respondents opined that the three most commonly preferred beta-blockers by experts in patients with angina were nebivolol, metoprolol, and bisoprolol. Beta-blockers, including nebivolol, can be considered initial-line therapy for HTN management in real-life settings in India and nebivolol is preferred because of its two important properties: highest beta-1 selectivity and endothelial-dependent vasodilation.

Impaired microvascular insulin-dependent dilation in women with a history of gestational diabetes.

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10-10-10-1 M) and insulin (10-8-10-4 M) in control sites and sites treated with 15 mM l-NAME [NG-nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine (P = 0.006) and insulin (P = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC (P = 0.009) but had no effect in GDM (P = 0.306). Ascorbate treatment increased acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC (P = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance.NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.

Ginsenoside Rg1 improves hypoxia-induced pulmonary vascular endothelial dysfunction through TXNIP/NLRP3 pathway-modulated mitophagy

BackgroundVascular endothelial dysfunction (VED) is one of the main pathogenic events in pulmonary arterial hypertension (PAH). Previous studies have demonstrated that the ginsenoside Rg1 (Rg1) can ameliorate PAH, but the mechanism by which Rg1 affects pulmonary VED in hypoxia-induced PAH remains unclear. MethodsNetwork pharmacology, molecular docking and other experiments were used to explore the mechanisms by which Rg1 affects PAH. A PAH mouse model was established via hypoxia combined with the vascular endothelial growth factor (VEGFR) inhibitor su5416 (SuHx), and a cell model was established via hypoxia. The functions of Rg1 in VED, oxidative stress, inflammation, mitophagy, and TXNIP and NLRP3 expression were examined. ResultsIn hypoxia-induced VED, progressive exacerbation of oxidative stress, inflammation, and mitophagy were observed, and were associated with elevated TXNIP and NLRP3 expression in vivo and in vitro. Rg1 improved hypoxia-induced impaired endothelium-dependent vasodilation and increased nitric oxide (NO) and endothelial NO synthase (eNOS) expression. Rg1, SRI37330 (a TXNIP inhibitor), MCC950 (an NLRP3 inhibitor), and Liensinine (a mitophagy inhibitor) attenuated oxidative stress, inflammation, and mitophagy by reducing the expression of TXNIP and NLRP3 in mice and cells. Furthermore, the combination of SB203580 (a mitophagy agonist) with Rg1 disrupted the protective effect of Rg1 on hypoxia-induced pulmonary artery and human pulmonary artery endothelial cells (HPAECs). ConclusionRg1 improves hypoxia-induced pulmonary vascular endothelial dysfunction through TXNIP/NLRP3 pathway-modulated oxidative stress, inflammation and mitophagy.

Acute impact of inorganic nitrate supplementation after ischemia and during small muscle mass exercise in postmenopausal females: A pilot study.

Menopause is associated with reduced endothelial-dependent vasodilation and increased cardiovascular disease (CVD) risk. Dietary nitrate, a non-pharmacological approach, may increase vasodilatory capacity consequentially reducing CVD risk. We investigated macro- and microvascular function after acute nitrate supplementation in postmenopausal females (PMF). Vascular function was studied with flow-mediated vasodilation (FMD) and near-infrared post occlusive reactive hyperemia (PORH). Incremental handgrip exercise was performed to investigate blood flow and tissue oxygenation. We hypothesized acute dietary nitrate would not impact resting endothelial measures but would increase post ischemic vasodilation and incremental exercise blood flow. Late-phase PMF (n = 12) participated in a randomized crossover design with 140 mL of nitrate-rich (NR) beetroot juice or nitrate-poor black currant juice. Testing included a 5-min FMD, a 3-min ischemic exercise FMD, and incremental exercise at 10%, 15%, and 20% maximal voluntary contraction to measure blood flow and pressure responses. A p ≤ 0.05 was considered significant. One-way ANOVA indicated lower resting pressures, but no change to FMD, or PORH in either protocol. Two-way repeated measures ANOVA indicated NR supplementation significantly reduced mean arterial pressure at rest and during incremental exercise at all intensities without changes to blood flow. Acute nitrate is effective for resting and exercising blood pressure management in PMF.

NADPH Oxidase 4: Crucial for Endothelial Function under Hypoxia-Complementing Prostacyclin.

Aim: The primary endothelial NADPH oxidase isoform 4 (NOX4) is notably induced during hypoxia, with emerging evidence suggesting its vasoprotective role through H2O2 production. Therefore, we aimed to elucidate NOX4's significance in endothelial function under hypoxia. Methods: Human vessels, in addition to murine vessels from Nox4-/- mice, were explored. On a functional level, Mulvany myograph experiments were performed. To obtain mechanistical insights, human endothelial cells were cultured under hypoxia with inhibitors of hypoxia-inducible factors. Additionally, endothelial cells were cultured under combined hypoxia and laminar shear stress conditions. Results: In human occluded vessels, NOX4 expression strongly correlated with prostaglandin I2 synthase (PTGIS). Hypoxia significantly elevated NOX4 and PTGIS expression and activity in human endothelial cells. Inhibition of prolyl hydroxylase domain (PHD) enzymes, which stabilize hypoxia-inducible factors (HIFs), increased NOX4 and PTGIS expression even under normoxic conditions. NOX4 mRNA expression was reduced by HIF1a inhibition, while PTGIS mRNA expression was only affected by the inhibition of HIF2a under hypoxia. Endothelial function assessments revealed hypoxia-induced endothelial dysfunction in mesenteric arteries from wild-type mice. Mesenteric arteries from Nox4-/- mice exhibited an altered endothelial function under hypoxia, most prominent in the presence of cyclooxygenase inhibitor diclofenac to exclude the impact of prostacyclin. Restored protective laminar shear stress, as it might occur after thrombolysis, angioplasty, or stenting, attenuated the hypoxic response in endothelial cells, reducing HIF1a expression and its target NOX4 while enhancing eNOS expression. Conclusions: Hypoxia strongly induces NOX4 and PTGIS, with a close correlation between both factors in occluded, hypoxic human vessels. This relationship ensured endothelium-dependent vasodilation under hypoxic conditions. Protective laminar blood flow restores eNOS expression and mitigates the hypoxic response on NOX4 and PTGIS.

Hypertension Cure Research progress: The use of Zilebesiran in Hypertension

Chronic hypertension is a lifelong condition, and the patients need lifelong treatment with oral anti-hypertensive medications to say healthy and to prevent the development of serious complications. Demands for changing this situation of lifelong dependence on daily medications have been increasing. The aim of this paper is to highlight the recent breakthrough in hypertension research. Expert opinion: Zilebesiran, a small interfering RNA targeting angiotensinogen has the main advantage of long duration of action which allows meeting many hypertensions patients’ demand of avoiding the inconvenience of talking oral hypertensive medication on daily basis. It is worth mentioning that a more optimal blockade of renin-angiotensin-aldosterone system is not the only advantageous therapeutic approach for the treatment of hypertension. Impairment of endothelium-dependent vasodilation has been increasingly recognized as an important contributor for the development of essential hypertension’s-arginine is an amino acid that is considered the biological precursor of nitric oxide which is an important contributor to microvascular vasodilation and to the reduction atherosclerosis. Oral L-arginine has been emerging as a new effective approach of reducing blood through improving endothelial function in hypertensive patients.