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Simple Summary: Proteasome inhibitors, such as bortezomib and carfilzomib, are vital for treating relapsed or refractory multiple myeloma, but their potential link to cancer therapy-related cardiovascular dysfunction (CTRCD) raises concerns. Bortezomib, a reversible first-generation inhibitor, and carfilzomib, a second-generation irreversible inhibitor, have been associated with hypertension, heart failure, and arrhythmias. This study explored their impact on cardiac function, focusing on left ventricular ejection fraction (LVEF), and vascular function through arterial stiffness and vascular reactivity assessments. Twelve-week-old male mice were treated with either carfilzomib or bortezomib, with some receiving L-NAME to induce hypertension. Echocardiography was used to evaluate cardiac and vascular parameters at different time points, followed by ex vivo arterial stiffness and reactivity measurements. Results showed no significant changes in arterial stiffness at baseline pressures, but a steeper pressure-stiffness curve was noted in carfilzomib-treated normotensive and hypertensive mice. Carfilzomib also showed a trend toward reduced LVEF in hypertensive mice, with bortezomib showing similar trends. Vascular reactivity remained largely unchanged, but proteasome inhibition appeared to enhance endothelial-independent relaxation. Overall, short-term treatment with both drugs was deemed relatively safe under the tested conditions. Proteasome inhibitors such as bortezomib and carfilzomib induce apoptosis and are a cornerstone in the treatment of relapsed or refractory multiple myeloma. However, concerns have emerged concerning their link to cancer therapy-related cardiovascular dysfunction (CTRCD). Bortezomib, a reversible first-generation inhibitor, and carfilzomib, a second-generation irreversible inhibitor, are associated with hypertension, heart failure, and cardiac arrhythmias. The current study investigated the effects of bortezomib and carfilzomib on cardiac (left ventricular ejection fraction, LVEF) and vascular (arterial stiffness, vascular reactivity) function. Cardiac function assessment aimed to build upon existing evidence of proteasome inhibitors CTRCD, while arterial stiffness served as an early indicator of potential vascular remodeling. Groups of 12-week-old C57BL/6J male mice (n = 8 per group) were randomly assigned to receive vehicle, carfilzomib (8 mg/kg I.P.), or bortezomib (0.5 mg/kg I.P.). Additionally, proteasome inhibition was assessed in mice treated with L-NAME (0.5 mg/kg) to induce hypertension. Cardiac and vascular parameters were evaluated via echocardiography on days 0 and 3. On day 6, mice were sacrificed for ex vivo analysis of arterial stiffness and vascular reactivity. Overall, no changes in arterial stiffness were detected either in vivo or ex vivo at basal pressures. However, a steeper pressure–stiffness curve was observed for carfilzomib in normotensive (p < 0.01) and hypertensive (p < 0.0001) mice ex vivo. Additionally, in hypertensive mice, carfilzomib decreased LVEF (p = 0.06), with bortezomib exhibiting similar trends. Vascular reactivity remained largely unchanged, but proteasome inhibition tended to enhance endothelial-independent relaxations in both control and hypertensive mice. In conclusion, short-term treatment with carfilzomib and bortezomib is considered relatively safe for the protocols assessed in the study. [ABSTRACT FROM AUTHOR]

Methamphetamine (METH) is a drug of abuse, which induces behavioral sensitization following repeated doses. Since METH alters blood pressure, in the present study we assessed whether systolic and diastolic blood pressure (SBP and DBP, respectively) are sensitized as well. In this context, we investigated whether alterations develop within A1/C1 neurons in the vasomotor center. C57Bl/6J male mice were administered METH (5 mg/kg, daily for 5 consecutive days). Blood pressure was measured by tail-cuff plethysmography. We found a sensitized response both to SBP and DBP, along with a significant decrease of catecholamine neurons within A1/C1 (both in the rostral and caudal ventrolateral medulla), while no changes were detected in glutamic acid decarboxylase. The decrease of catecholamine neurons was neither associated with the appearance of degeneration-related marker Fluoro-Jade B nor with altered expression of α-synuclein. Rather, it was associated with reduced free radicals and phospho-cJun and increased heat shock protein-70 and p62/sequestosome within A1/C1 cells. Blood pressure sensitization was not associated with altered arterial reactivity. These data indicate that reiterated METH administration may increase blood pressure persistently and may predispose to an increased cardiovascular response to METH. These data may be relevant to explain cardiovascular events following METH administration and stressful conditions. [ABSTRACT FROM AUTHOR]

Shock is characterized with vascular hyporesponsiveness to vasoconstrictors, thereby to cause refractory hypotension, insufficient tissue perfusion, and multiple organ dysfunction. The vascular hyporeactivity persisted even though norepinephrine and fluid resuscitation were administrated, it is of critical importance to find new potential target. Ion channels are crucial in the regulation of cell membrane potential and affect vasoconstriction and vasodilation. It has been demonstrated that many types of ion channels including K+ channels, Ca2+ permeable channels, and Na+ channels exist in vascular smooth muscle cells and endothelial cells, contributing to the regulation of vascular homeostasis and vasomotor function. An increasing number of studies suggested that the structural and functional alterations of ion channels located in arteries contribute to vascular hyporesponsiveness during shock, but the underlying mechanisms remained to be fully clarified. Therefore, the expression and functional changes in ion channels in arteries associated with shock are reviewed, to pave the way for further exploring the potential of ion channel‐targeted compounds in treating refractory hypotension in shock. [ABSTRACT FROM AUTHOR]

α-Lipoic acid (LA) is an antioxidant of endogenous production, also obtained exogenously. Oxidative stress is closely associated with hypertension, which causes kidney injury and endothelial dysfunction. Here, we evaluated the cardiovascular and renal effects of LA in the two-kidney-one-clip (2K1C) hypertension model. The rats were divided into four groups: Sham surgery (Sham), the two-kidneys-one-clip (2K1C) group, and groups treated with LA for 14 days (Sham-LA and 2K1C-LA). No changes were observed in the pattern of food, water intake, and urinary volume. The left/right kidney weight LKw/RKw ratio was significantly higher in 2K1C animals. LA treatment did not reverse the increase in cardiac mass. In relation to vascular reactivity, there was an increase in the potency of phenylephrine (PHE) curve in the hypertensive animals treated with LA compared to the 2K1C group and also compared to the Sham group. Vasorelaxation induced by acetylcholine (Ach) and sodium nitroprusside (SNP) were not improved by treatment with LA. Urea and creatinine levels were not altered by the LA treatment. In conclusion, the morphological changes in the aorta and heart were not reversed; however, the treatment with LA mitigated the contraction increase induced by the 2K1C hypertension. [ABSTRACT FROM AUTHOR]

Although coffee is one of the most popular beverages, the relationship between chronic consumption and cardiovascular health remains controversial. Therefore, this study investigated the effects of chronic consumption of caffeinated or decaffeinated coffee on biochemical profile and cardiovascular response. Three groups of rats were treated with HPLC characterized caffeinated or decaffeinated coffee and control for six weeks; blood pressure and biochemical profile were analyzed, followed by in vitro aortic ring experiments. The results showed that both coffees reduced blood glucose, AST and ALT. However, only caffeinated coffee elevated blood pressure in vivo, whereas aortic rings with endothelium increased the vasocontractile response; this effect was reversed by the addition of indomethacin and L-NAME also reduced the endothelium-mediated vasodilator response. In conclusion, chronic intake of any type of coffee positively improves biochemical profile. However, caffeinated coffee reduces nitric oxide biosynthesis and increases vasoconstrictor prostanoid production, whereas decaffeinated coffee preserves vascular function.

Introduction: Vasodilatation in response to NO is a fundamental response of the vasculature, and during aging, the vasculature is characterized by an increase in stiffness and decrease in sensitivity to NO mediated vasodilatation. Vascular tone is regulated by the activation of smooth muscle and nonmuscle (NM) myosin, which are regulated by the activities of myosin light chain kinase (MLCK) and MLC phosphatase. MLC phosphatase is a trimeric enzyme with a catalytic subunit, myosin targeting subunit (MYPT1) and 20 kDa subunit of unknown function. Alternative mRNA splicing produces LZ+/LZ- MYPT1 isoforms and the relative expression of LZ+/LZ- MYPT1 determines the sensitivity to NO mediated vasodilatation. This study tested the hypothesis that aging is associated with changes in LZ+ MYPT1 and NM myosin expression, which alter vascular reactivity. Methods: We determined MYPT1 and NM myosin expression, force and the sensitivity of both endothelial dependent and endothelial independent relaxation in tertiary mesenteric arteries of young (6mo) and elderly (24mo) Fischer344 rats. Results: The data demonstrate that aging is associated with a decrease in both the expression of NM myosin and force, but LZ+ MYPT expression and the sensitivity to both endothelial dependent and independent vasodilatation did not change. Further, smooth muscle cell hypertrophy increases the thickness of the medial layer of smooth muscle with aging. Discussion: The reduction of NM myosin may represent an aging associated compensatory mechanism to normalize the stiffness of resistance vessels in response to the increase in media thickness observed during aging. [ABSTRACT FROM AUTHOR]

Objective: Placental vascular reactivity (PlVR) indicates the ability of the placental vasculature to match blood supply to fetal demand. Many pregnancy disorders alter the characteristics of PlVR, resulting in suboptimal oxygen delivery, although current understanding is limited by the lack of non‐invasive, repeatable methods to measure PlVR in utero. Our objective was to quantify PlVR by measuring the placental response to transient changes in maternal carbon dioxide (CO2) using blood‐oxygen‐level‐dependent (BOLD) magnetic resonance imaging (MRI). We hypothesized that PlVR will increase with gestational age to meet the changing demands of a growing fetus, and that PlVR will be driven by a maternal response to changes in CO2 concentration. Methods: This was a cross‐sectional study of 35 women with a healthy singleton pregnancy, of whom 31 were included in the analysis. The median gestational age was 32.6 (range, 22.6–38.4) weeks. Pregnant women were instructed to follow audiovisual breathing cues during a MRI scan. Maternal end‐tidal CO2 (EtCO2) was measured concurrently with resting placental BOLD MRI for a total of 7–8 min. Preprocessing of magnetic resonance images consisted of manual delineation of placental anatomy and motion correction. In each placental voxel, vascular reactivity was computed using a coherence‐weighted general linear model between MRI signal and EtCO2 stimulus. Global PlVR was computed as the mean of voxel‐wise PlVR values across the placenta. Results: PlVR, quantified by the placental response to induced, transient changes in maternal CO2, was consistently measured in utero using BOLD MRI. PlVR increased non‐linearly with advancing gestational age (P < 0.001) and was higher on the fetal side of the placenta. PlVR was associated positively with fetal brain volume after accounting for gestational age. PlVR did not show any significant associations with maternal characteristics. Conclusions: We present, for the first time, a non‐invasive paradigm to quantify PlVR in ongoing human pregnancies without the use of exogenous gases or contrast agents. Our findings suggest that PlVR is driven by a fetal response to changes in maternal CO2. Ease of translation to the clinical setting makes PlVR a promising biomarker for the identification and management of high‐risk pregnancies. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Exercise training (ET) has several health benefits; however, our understanding of regional adaptations to ET is limited. We examined the functional and molecular adaptations to short- and long-term ET in elastic and muscular conduit arteries of db/db mice in relation to changes in cardiovascular risk factors. Diabetic mice and their controls were exercised at moderate intensity for 4 or 8 weeks. The vasodilatory and contractile responses of thoracic aortae and femoral arteries isolated from the same animals were examined. Blood and aortic samples were used to measure hyperglycemia, oxidative stress, inflammation, dyslipidemia, protein expression of SOD isoforms, COX, eNOS, and Akt. Short-term ET improved nitric oxide (NO) mediated vasorelaxation in the aortae and femoral arteries of db/db mice in parallel with increased SOD2 and SOD3 expression, reduced oxidative stress and triglycerides, and independent of weight loss, glycemia, or inflammation. Long-term ET reduced body weight in parallel with reduced systemic inflammation and improved insulin sensitivity along with increased SOD1, Akt, and eNOS expression and improved NO vasorelaxation. Exercise did not restore NOS- and COX-independent vasodilatation in femoral arteries, nor did it mitigate the hypercontractility in the aortae of db/db mice; rather ET transiently increased contractility in association with upregulated COX-2. Long-term ET differentially affected the aortae and femoral arteries contractile responses. ET improved NO-mediated vasodilation in both arteries likely due to collective systemic effects. ET did not mitigate all diabetes-induced vasculopathies. Optimization of the ET regimen can help develop comprehensive management of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Summary: Background: Sepsis is a leading cause of mortality in intensive care units and vasoactive drugs are widely used in septic patients. The cardiovascular response of septic shock patients during resuscitation therapies and the relationship of the cardiovascular response and clinical outcome has not been clearly described. Methods: We included adult patients admitted to the ICU with sepsis from Peking Union Medical College Hospital (internal), Medical Information Mart for Intensive Care IV (MIMIC-IV) and eICU Collaborative Research Database (eICU-CRD). The Blood Pressure Response Index (BPRI) was defined as the ratio between the mean arterial pressure and the vasoactive-inotropic score. BRRI was compared with existing risk scores on predicting in-hospital death. The relationship between BPRI and in-hospital mortality was calculated. A XGBoost's machine learning model identified the features that influence short-term changes in BPRI. Findings: There were 2139, 9455, and 4202 patients in the internal, MIMIC-IV and eICU-CRD cohorts, respectively. BPRI had a better AUROC for predicting in-hospital mortality than SOFA (0.78 vs. 0.73, p = 0.01) and APS (0.78 vs. 0.74, p = 0.03) in the internal cohort. The estimated odds ratio for death per unit decrease in BPRI was 1.32 (95% CI 1.20–1.45) when BPRI was below 7.1 vs. 0.99 (95% CI 0.97–1.01) when BPRI was above 7.1 in the internal cohort; similar relationships were found in MIMIC-IV and eICU-CRD. Respiratory support and latest cumulative 12-h fluid balance were intervention-related features influencing BPRI. Interpretation: BPRI is an easy, rapid, precise indicator of the response of patients with septic shock to vasoactive drugs. It is a comparable and even better predictor of prognosis than SOFA and APS in sepsis and it is simpler and more convenient in use. The application of BPRI could help clinicians identify potentially at-risk patients and provide clues for treatment. Funding: Fundings for the Beijing Municipal Natural Science Foundation; the National High Level Hospital Clinical Research Funding; the CAMS Innovation Fund for Medical Sciences (CIFMS) from Chinese Academy of Medical Sciences and the National Key R&D Program of China, Ministry of Science and Technology of the People's Republic of China.

Abstract Excessive fructose intake presents the major risk factor for metabolic cardiovascular disease. Perivascular adipose tissue (PVAT) is a metabolic tissue and possesses a paracrine function in regulating aortic reactivity. However, whether and how PVAT alters vascular function under fructose overconsumption remains largely unknown. In this study, male Sprague-Dawley rats (8 weeks old) were fed a 60% high fructose diet (HFD) for 12 weeks. Fasting blood sugar, insulin, and triglycerides were significantly increased by HFD intake. Plasma adiponectin was significantly enhanced in the HFD group. The expression of uncoupling protein 1 (UCP1) and mitochondrial mass were reduced in the aortic PVAT of the HFD group. Concurrently, the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM) were suppressed. Furthermore, decreased fusion proteins (OPA1, MFN1, and MFN2) were accompanied by increased fission proteins (FIS1 and phospho-DRP1). Notably, the upregulated α-smooth muscle actin (α-SMA) and osteocalcin in the PVAT were concurrent with the impaired reactivity of aortic contraction and relaxation. Coenzyme Q10 (Q, 10 mg/100 mL, 4 weeks) effectively reversed the aforementioned events induced by HFD. Together, these results suggested that the dysregulation of mitochondrial dynamics mediated HFD-triggered PVAT whitening to impair aortic reactivity. Fortunately, coenzyme Q10 treatment reversed HFD-induced PVAT whitening and aortic reactivity.

Proteasome inhibitors such as bortezomib and carfilzomib induce apoptosis and are a cornerstone in the treatment of relapsed or refractory multiple myeloma. However, concerns have emerged concerning their link to cancer therapy-related cardiovascular dysfunction (CTRCD). Bortezomib, a reversible first-generation inhibitor, and carfilzomib, a second-generation irreversible inhibitor, are associated with hypertension, heart failure, and cardiac arrhythmias. The current study investigated the effects of bortezomib and carfilzomib on cardiac (left ventricular ejection fraction, LVEF) and vascular (arterial stiffness, vascular reactivity) function. Cardiac function assessment aimed to build upon existing evidence of proteasome inhibitors CTRCD, while arterial stiffness served as an early indicator of potential vascular remodeling. Groups of 12-week-old C57BL/6J male mice (n = 8 per group) were randomly assigned to receive vehicle, carfilzomib (8 mg/kg I.P.), or bortezomib (0.5 mg/kg I.P.). Additionally, proteasome inhibition was assessed in mice treated with L-NAME (0.5 mg/kg) to induce hypertension. Cardiac and vascular parameters were evaluated via echocardiography on days 0 and 3. On day 6, mice were sacrificed for ex vivo analysis of arterial stiffness and vascular reactivity. Overall, no changes in arterial stiffness were detected either in vivo or ex vivo at basal pressures. However, a steeper pressure–stiffness curve was observed for carfilzomib in normotensive (p < 0.01) and hypertensive (p < 0.0001) mice ex vivo. Additionally, in hypertensive mice, carfilzomib decreased LVEF (p = 0.06), with bortezomib exhibiting similar trends. Vascular reactivity remained largely unchanged, but proteasome inhibition tended to enhance endothelial-independent relaxations in both control and hypertensive mice. In conclusion, short-term treatment with carfilzomib and bortezomib is considered relatively safe for the protocols assessed in the study.

Methamphetamine (METH) is a drug of abuse, which induces behavioral sensitization following repeated doses. Since METH alters blood pressure, in the present study we assessed whether systolic and diastolic blood pressure (SBP and DBP, respectively) are sensitized as well. In this context, we investigated whether alterations develop within A1/C1 neurons in the vasomotor center. C57Bl/6J male mice were administered METH (5 mg/kg, daily for 5 consecutive days). Blood pressure was measured by tail-cuff plethysmography. We found a sensitized response both to SBP and DBP, along with a significant decrease of catecholamine neurons within A1/C1 (both in the rostral and caudal ventrolateral medulla), while no changes were detected in glutamic acid decarboxylase. The decrease of catecholamine neurons was neither associated with the appearance of degeneration-related marker Fluoro-Jade B nor with altered expression of α-synuclein. Rather, it was associated with reduced free radicals and phospho-cJun and increased heat shock protein-70 and p62/sequestosome within A1/C1 cells. Blood pressure sensitization was not associated with altered arterial reactivity. These data indicate that reiterated METH administration may increase blood pressure persistently and may predispose to an increased cardiovascular response to METH. These data may be relevant to explain cardiovascular events following METH administration and stressful conditions.

Shoemaker, ME, Smith, CM, Gillen, ZM, and Cramer, JT. Sex differences in test-retest reliability of near-infrared spectroscopy during postocclusive reactive hyperemia of the vastus lateralis. J Strength Cond Res 38(2): e40-e48, 2024--The purpose of this study was to determine test-retest reliability for vascular reactivity measures and ranges for normalization of near-infrared spectroscopy (NIRS) variables from the vastus lateralis using postocclusive reactive hyperemia (PORH) procedure in male subjects, female subjects, and combined. Concentrations of oxygenated hemoglobin (Hb) + myoglobin (Mb) (O2Hb) and deoxygenated Hb + Mb (HHb) to derive total Hb + Mb (THb), difference in Hb + Mb signal (Hbdiff), and muscle tissue oxygen saturation (StO2) from the vastus lateralis were measured during the PORH in 12 male subjects (age: 23.17 6 1.77 years; stature: 180.88 6 4.59 cm; and mass: 81.4769.68 kg) and 10 female subjects (age: 23.8062.07 years; stature: 165.9564.92 cm; and mass: 70.93610.55 kg) on 2 separate days. Adipose tissue thickness at the NIRS site was measured with ultrasonography. There were no significant differences between the mean values from visit 1 to visit 2 (p. 0.076-0.985). In the composite sample, intraclass correlation coefficient (ICC) and coefficient of variation (CV) ranged from 0.35 to 0.91 and 4.74 to 39.18%, respectively. In male subjects, ICC and CV values ranged from 0.57 to 0.89 and 2.44 to 28.55%, respectively. In female subjects, ICC and CV values ranged from 2 0.05 to 0.75 and 7.83 to 61.19%, respectively. Although NIRS variables were overall reliable during PORH, when separated by sex, reliability in male subjects generally increased, whereas female subjects were not reliable, suggesting adipose tissue thickness may be a contributing factor. Understanding sex differences in reliability is important when using this technique for normalization or examining vascular reactivity during athletic performance. With greater utilization of NIRS monitoring in athletes to examine training adaptations, it is important for practitioners to understand the capabilities and potential limitations of the tool. [ABSTRACT FROM AUTHOR]

Excessive fructose intake presents the major risk factor for metabolic cardiovascular disease. Perivascular adipose tissue (PVAT) is a metabolic tissue and possesses a paracrine function in regulating aortic reactivity. However, whether and how PVAT alters vascular function under fructose overconsumption remains largely unknown. In this study, male Sprague-Dawley rats (8 weeks old) were fed a 60% high fructose diet (HFD) for 12 weeks. Fasting blood sugar, insulin, and triglycerides were significantly increased by HFD intake. Plasma adiponectin was significantly enhanced in the HFD group. The expression of uncoupling protein 1 (UCP1) and mitochondrial mass were reduced in the aortic PVAT of the HFD group. Concurrently, the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM) were suppressed. Furthermore, decreased fusion proteins (OPA1, MFN1, and MFN2) were accompanied by increased fission proteins (FIS1 and phospho-DRP1). Notably, the upregulated α-smooth muscle actin (α-SMA) and osteocalcin in the PVAT were concurrent with the impaired reactivity of aortic contraction and relaxation. Coenzyme Q10 (Q, 10 mg/100 mL, 4 weeks) effectively reversed the aforementioned events induced by HFD. Together, these results suggested that the dysregulation of mitochondrial dynamics mediated HFD-triggered PVAT whitening to impair aortic reactivity. Fortunately, coenzyme Q10 treatment reversed HFD-induced PVAT whitening and aortic reactivity. [ABSTRACT FROM AUTHOR]

Infants with congenital diaphragmatic hernia (CDH) often develop pulmonary hypertension but frequently fail to respond to vasodilator therapy, for instance because of an altered pulmonary vasoreactivity. Investigating such alterations in vivo is impossible. We hypothesised that these alterations are also present in fetoplacental vessels, since both vasculatures are exposed to the same circulating factors (e.g. endothelin-1) and respond similarly to certain stimuli (e.g. hypoxia). As proof-of-concept, we compared fetoplacental vasoreactivity between healthy and CDH-affected placentas. Fetoplacental vascular function of healthy and antenatally diagnosed left-sided CDH fetuses was assessed by wire myography. Placental expression of enzymes and receptors involved in the altered vasoreactive pathways was measured using quantitative PCR. CDH arteries (n = 6) constricted more strongly to thromboxane A2 agonist U46619 (p < 0.001) and dilated less to bradykinin (p = 0.01) and nitric oxide (NO)-donor sodium nitroprusside (p = 0.04) than healthy arteries (n = 8). Vasodilation to prostacyclin analogue iloprost and adenylate cyclase stimulator forskolin, and vasoconstriction to endothelin-1 were not different between both groups. Angiotensin II did not induce vasoconstriction. Phosphodiesterase inhibitors sildenafil and milrinone did not affect responses to sodium nitroprusside, forskolin, or U46619. The mRNA expression of guanylate cyclase 1 soluble subunit alpha 1 (p = 0.003) and protein kinase cyclic guanine monophosphate (cGMP)-dependent 1 (p = 0.02) were reduced in CDH versus healthy placentas. The identified changes in the thromboxane and NO-cGMP pathways in the fetoplacental vasculature correspond with currently described alterations in the pulmonary vasculature in CDH. Therefore, fetoplacental arteries may provide an opportunity to predict pulmonary therapeutic responses in infants with CDH. • Fetoplacental vasoreactivity is altered in congenital diaphragmatic hernia (CDH). • Vasoconstriction through the thromboxane A2 receptor is enhanced in CDH placentas. • CDH fetoplacental arteries show less vasodilation through the NO–cGMP pathway. • Fetoplacental alterations correspond with known pulmonary alterations in CDH. • CDH placentas exhibit reduced gene expression of GUCY1A1 and PRKG1. [ABSTRACT FROM AUTHOR]

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-β accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters – amplitude, time-to-peak (TTP), and time-to-baseline (TTB) – and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized β = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R2 = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (β = 8.34 × 10−6, 95%CI [1.84 × 10−6, 1.48 × 10−5], p = 0.02, Adj. R2 = 0.25) and TTB (β = 6.57 × 10−6, 95%CI [1.92 × 10−6, 1.12 × 10−5], p = 0.008, Adj. R2 = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal. [ABSTRACT FROM AUTHOR]

Cadmium is a heavy metal that is widespread in the environment and has been described as a metalloestrogen and a cardiovascular risk factor. Experimental studies conducted in male animals have shown that cadmium exposure induces vascular dysfunction, which could lead to vasculopathies caused by this metal. However, it is necessary to investigate the vascular effects of cadmium in female rats to understand its potential sex-dependent impact on the cardiovascular system. While its effects on male rats have been studied, cadmium may act differently in females due to its potential as a metalloestrogen. In vitro studies conducted in a controlled environment allow for a direct assessment of cadmium's impact on vascular function, and the use of female rats ensures that sex-dependent effects are evaluated. Therefore, the aim of this study was to investigate the in vitro effects of Cadmium Chloride (CdCl2, 5 µM) exposure on vascular reactivity in the isolated aorta of female Wistar rats. Exposure to CdCl2 damaged the architecture of the vascular endothelium. CdCl2 incubation increased the production and release of O2•−, reduced the participation of potassium (K+) channels, and increased the participation of the angiotensin II pathway in response to phenylephrine. Moreover, estrogen receptors alpha (Erα) modulated vascular reactivity to phenylephrine in the presence of cadmium, supporting the hypothesis that cadmium could act as a metalloestrogen. Our results demonstrated that in vitro cadmium exposure induces damage to endothelial architecture and an increase in oxidative stress in the isolated aorta of female rats, which could precipitate vasculopathies. [ABSTRACT FROM AUTHOR]

Objective: Protein kinase C (PKC) influences myocardial contractility and susceptibility to long-term cardiac dysfunction after ischemia–reperfusion injury. In diabetes, PKC inhibition has a protective effect in terms of microvascular dysfunction. SK-channel dysfunction also influences endothelial dysfunction in cardioplegic hypoxia–reoxygenation (CP-H/R). Here, we examine whether acute inhibition of PKC beta protects against CP-H/R–induced coronary endothelial and SK channel dysfunction. Methods: Isolated mouse coronary arterioles, half pretreated with selective PKC inhibitor ruboxistaurin (RBX), were subjected to hyperkalemic, cardioplegic hypoxia (1 hour), and reoxygenation (1 hour) with Krebs buffer. Sham control vessels were continuously perfused with oxygenated Krebs buffer without CP-H/R. After 1 hour of reoxygenation, responses to the endothelium-dependent vasodilator adenosine-diphosphate (ADP) and the SK-channel activator NS309 were examined. Endothelial SK-specific potassium currents from mouse heart endothelial cells were examined using whole-cell path clamp configurations in response to NS309 and SK channel blockers apamin and TRAM34. Results: CP-H/R significantly decreased coronary relaxation responses to ADP (P = .006) and NS309 (P = .0001) compared with the sham control group. Treatment with selective PKC beta inhibitor RBX significantly increased recovery of coronary relaxation responses to ADP (P = .031) and NS309 (P = .004) after CP-H/R. Treatment with RBX significantly increased NS309-mediated potassium currents following CP-H/R (P = .0415). Apamin and TRAM34 sensitive currents were significantly greater in CP-H/R + RBX versus CP-H/R mouse heart endothelial cells (P = .0027). Conclusions: Acute inhibition of PKC beta significantly protected mouse coronary endothelial function after CP-H/R injury. This suggests that acute PKC beta inhibition may be a novel approach for preventing microvascular dysfunction during CP-H/R.

Introduction Lower extremity peripheral artery disease (PAD), due to narrowing of the arteries supplying the legs, represents a major cause of physical disability. Exercise training is an important part of PAD treatment, improving functional capacity. Recent research suggests that exercise training-induced endothelial function improvement is involved in the benefits of exercise in PAD (Lee et al., 2023); however, the underlying molecular mechanisms remain unknown. In addition, the potential vascular benefits of high intensity training in PAD remain unexplored. Therefore, the aim of the study was to compare the effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on endurance capacity, vascular endothelial function and expression of genes related to nitric oxide (NO) bioavailability in a mouse model of PAD. Methods PAD disease model was generated in male C57BL/6 mice by ligation of the right iliac artery. Mice with PAD were divided into 3 groups: sedentary control group (SED), MICT (40 min running at 70% of maximal aerobic speed) and HIIT (8 intervals of 2.5 minutes running at 90% of maximal aerobic speed combined with 2.5 minutes of running at 50% of maximal aerobic speed). Mice were exercised three times per week for 8 weeks. Maximal running time was determined by an incremental test until exhaustion. Vascular reactivity was assessed by measuring vasoconstrictor responses to phenylephrine as well as endothelium-dependent and -independent vasodilator responses to acetylcholine and DEA-NONOate, respectively, in isolated aortic rings. Gene expression of antioxidant enzymes (catalase and superoxide dismutase isoforms), prooxidant NADPH oxidase subunits (p22phox and p47phox), enzyme involved in NO production (endothelial NO synthase), vascular smooth muscle cell relaxation (soluble guanylate cyclase) and receptors involved in vascular tone regulation (a1 and b2 adrenergic receptors) was determined in aortic tissue by qPCR. Results Maximal running time was improved in both MICT and HIIT as compared to SED at the end of the study, but with no significant difference between the two exercise groups. Phenylephrine-induced vasoconstriction as well as vasodilator responses to acetylcholine and DEA-NONOate were significantly improved in MICT compared to SED while no significant differences were reported between HIIT and SED. There was no significant difference in gene expression among the three groups. Discussion/Conclusion MICT and HIIT were equally effective at improving endurance capacity in mice with PAD. However, only MICT improved vascular reactivity. References Lee, J., Zarezadehmehrizi, A., LaVoy, E., Markofski, M., & Park, Y. (2023). Exercise training improves brachial artery endothelial function, but does not alter inflammatory biomarkers in patients with peripheral artery disease: A systematic review and meta-analysis. Journal of Cardiovascular Translational Research. Advance online publication. https://doi.org/10.1007/s12265-023-10451-0

Carbon dioxide (CO2) is traditionally considered as metabolic waste, yet its regulation is critical for brain function. It is well accepted that hypercapnia initiates vasodilation, but its effect on neuronal activity is less clear. Distinguishing how stimulus- and CO2-induced vasodilatory responses are (dis)associated with neuronal activity has profound clinical and experimental relevance. We used an optical method in mice to simultaneously image fluorescent calcium (Ca2+) transients from neurons and reflectometric hemodynamic signals during brief sensory stimuli (i.e., hindpaw, odor) and CO2 exposure (i.e., 5%). Stimuli-induced neuronal and hemodynamic responses swiftly increased within locally activated regions exhibiting robust neurovascular coupling. However, hypercapnia produced slower global vasodilation which was temporally uncoupled to neuronal deactivation. With trends consistent across cerebral cortex and olfactory bulb as well as data from GCaMP6f/jRGECO1a mice (i.e., green/red Ca2+ fluorescence), these results unequivocally reveal that stimuli and CO2 generate comparable vasodilatory responses but contrasting neuronal responses. In summary, observations of stimuli-induced regional neurovascular coupling and CO2-induced global neurovascular uncoupling call for careful appraisal when using CO2 in gas mixtures to affect vascular tone and/or neuronal excitability, because CO2 is both a potent vasomodulator and a neuromodulator. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is a condition of pregnancy defined by new-onset hyperglycemia. GDM is associated with impaired maternal endothelial and vascular reactivity. Endothelin-1 (ET-1) is a potent vasoconstrictor that contributes to endothelial dysfunction, however, its abundance and actions in GDM are unclear. Maternal plasma was obtained from pregnancies complicated by GDM (n = 24) and gestation-matched controls (n = 42); circulating ET-1 levels were assessed by ELISA. Human omental arteries from healthy pregnancies and those complicated by GDM were dissected from omental fat biopsies and collected at cesarean section. mRNA expression of ET-1 and its receptors, ETA and ETB, in addition to vascular cell adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1) were assessed by qPCR (n = 28). Using wire myography, we investigated vascular constriction to ET-1 (10−11–10−4 M) in omental arteries from pregnancies complicated by GDM, compared to gestation-matched controls (n = 7). GDM cases were stratified by clinical management, diet intervention (n = 5), or insulin treatment (n = 6). Additionally, arteries from healthy pregnancies were treated with insulin (1 mU/mL (n = 7) and 10 mU/mL (n = 5)) or vehicle control. Vasoactive response to ET-1 was measured via wire myography. Circulating ET-1 levels and mRNA expression of the ET-1 system in omental arteries were not found to be significantly different between pregnancies complicated by GDM compared to healthy controls. However, we found insulin treatment during pregnancy and in ex vivo models reduced ET-1 vasoconstriction of maternal vasculature in GDM. These data suggest insulin may improve vascular function in GDM, however, further investigation is needed to define the role of ET-1 in pregnancy. [ABSTRACT FROM AUTHOR]

Abstract Background Vascular hyporeactivity and leakage are key pathophysiologic features that produce multi-organ damage upon sepsis. We hypothesized that pericytes, a group of pluripotent cells that maintain vascular integrity and tension, are protective against sepsis via regulating vascular reactivity and permeability. Methods We conducted a series of in vivo experiments using wild-type (WT), platelet-derived growth factor receptor beta (PDGFR-β)-Cre + mT/mG transgenic mice and Tie2-Cre + Cx43flox/flox mice to examine the relative contribution of pericytes in sepsis, either induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge. In a separate set of experiments with Sprague–Dawley (SD) rats, pericytes were depleted using CP-673451, a selective PDGFR-β inhibitor, at a dosage of 40 mg/(kg·d) for 7 consecutive days. Cultured pericytes, vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) were used for mechanistic investigations. The effects of pericytes and pericyte-derived microvesicles (PCMVs) and candidate miRNAs on vascular reactivity and barrier function were also examined. Results CLP and LPS induced severe injury/loss of pericytes, vascular hyporeactivity and leakage (P

The purpose of this study was to investigate effects of the modified Otago exercise program on blood pressure and vascular function in older adults with hypertension. Twenty-four female older adults with hypertension (aged 60 to 75 years) were studied. The participants were randomly assigned to either the non-exercising Control Group (CON; n = 12) or the Modified Otago Exercise Group (MOE; n = 15). The MOE was designed to be used as aerobic exercise training that consists of 10 strength and balance exercises and a walking program (walking with balance training, stair walking, and walking and turn), performed at 50% to 70% of maximum heart rate for 60 min·session-1, 3 times·wk-1 for 12 weeks. Results showed that MOE significantly decreased systolic and diastolic blood pressure (P < 0.05), while there we no changes in the CON Group. Physical fitness including chair stand, time up and go, and 6-minute walk test scores as well as balance ability were all improved in the MOE Group (P < 0.05). Vascular reactivity as assessed by brachial flow-mediated dilation increased only in the MOE Group (P < 0.05). No significant change in arterial stiffness, as assessed by brachial-ankle pulse wave velocity was observed in either Group. In conclusion, the modified Otago exercise was an effective program to decrease blood pressure and improve vascular function in older adults with hypertension. [ABSTRACT FROM AUTHOR]

Background: Sirtuin 1 (SIRT1) has been associated with longevity and protection against cardiometabolic diseases, but little is known about how it influences human vascular function. Therefore, this study evaluated the effects of SIRT1 activation by resveratrol and energy restriction on vascular reactivity in adults. Methods: A randomized trial allocated 48 healthy adults (24 women and 24 men), aged 55 to 65 years, to resveratrol supplementation or energy restriction for 30 days. Blood lipids, glucose, insulin, C-reactive protein, noradrenaline, SIRT1 (circulating and gene expression), and flow-mediated vasodilation (FMD) and nitrate-mediated vasodilation (NMD) were measured. Results: Both interventions increased circulating SIRT1 (p < 0.001). Pre- and post-tests changes of plasma noradrenaline were significant for both groups (resveratrol: p = 0.037; energy restriction: p = 0.008). Baseline circulating SIRT1 was inversely correlated with noradrenaline (r = −0.508; p < 0.01), and post-treatment circulating SIRT1 was correlated with NMD (r = 0.433; p < 0.01). Circulating SIRT1 was a predictor of FMD in men (p = 0.045), but not in women. SIRT1 was an independent predictor of NMD (p = 0.026) only in the energy restriction group. Conclusions: Energy restriction and resveratrol increased circulating SIRT1 and reduced sympathetic activity similarly in healthy adults. SIRT1 was independently associated with NMD only in the energy restriction group. [ABSTRACT FROM AUTHOR]

Multi-Component School-Based Weight-Management Program Improves Physical Fitness and Vascular Reactivity in Obese Adolescents. JEPonline 2023;26(3):45-57. This study determined the effects of a multi-component school-based weight-management program on body composition, physical fitness, and vascular function and structure in obese adolescents. Twenty-eight obese adolescents (14.1 [0.8] yr old, 7 girls, =2 SD on BMI for age-and-sex-specific growth charts) were randomly assigned to the Control Group (CON; n = 12) and the Intervention Group (INT, n = 16) groups. The multicomponent school-based intervention consisted of supervised after-school physical activities (i.e., running, playing games, and resistance training) at moderate to vigorous activities for 50 min·d-1, 3 d·wk-1 on alternate days for 10 weeks. Also, dietary, daily physical activity related advice, school health promotion environment, and health education lectures for school staffs, students, and parents were included in the program. Body composition, physical fitness, vascular function (brachial-FMD), and structure (IMT and baPWV) were measured before and after the program. After the 10 weeks of multicomponent school-based weight-management program, body mass (89.7 ± 8.6 vs. 88.0 ± 10.5, P < 0.05) and body fat percentage (44.13 ± 5.27 vs. 41.22 ± 6.74, P < 0.05) significantly decreased only in the INT Group. Peak oxygen consumption (29.25 ± 2.41 vs. 31.56 ± 3.05, P < 0.05) and health related physical fitness increased only in the INT Group (P < 0.05). Moreover, vascular reactivity of the INT Group was improved after the 10-week program compared to the CON Group (6.81 ± 2.25 vs. 3.62 ± 1.48, P < 0.05). There was no change in artery wall thickness and stiffness in any group. Multi-component school-based weightmanagement program could be an effective primary prevention for reducing cardiovascular disease risk factors in obese adolescents. [ABSTRACT FROM AUTHOR]

Objectives: Homozygous familial hypercholesteremia (HoFH) is a rare, life-threatening metabolic disease, mainly caused by a mutation in the LDL receptor. If untreated, HoFH causes premature death from acute coronary syndrome. Lomitapide is approved by the FDA as a therapy to lower lipid levels in adult patients with HoFH. Nevertheless, the beneficial effect of lomitapide in HoFH models remains to be defined. In this study, we investigated the effect of lomitapide on cardiovascular function using LDL receptor-knockout mice (LDLr−/−). Methods: Six-week-old LDLr−/− mice were fed a standard diet (SD) or a high-fat diet (HFD) for 12 weeks. Lomitapide (1 mg/Kg/Day) was given by oral gavage for the last 2 weeks in the HFD group. Body weight and composition, lipid profile, blood glucose, and atherosclerotic plaques were measured. Vascular reactivity and markers for endothelial function were determined in conductance arteries (thoracic aorta) and resistance arteries (mesenteric resistance arteries (MRA)). Cytokine levels were measured by using the Mesoscale discovery V-Plex assays. Results: Body weight (47.5 ± 1.5 vs. 40.3 ± 1.8 g), % of fat mass (41.6 ± 1.9% vs. 31.8 ± 1.7%), blood glucose (215.5 ± 21.9 vs. 142.3 ± 7.7 mg/dL), and lipid levels (cholesterol: 600.9 ± 23.6 vs. 451.7 ± 33.4 mg/dL; LDL/VLDL: 250.6 ± 28.9 vs. 161.1 ± 12.24 mg/dL; TG: 299.5 ± 24.1 vs. 194.1 ± 28.1 mg/dL) were significantly decreased, and the % of lean mass (56.5 ± 1.8% vs. 65.2 ± 2.1%) was significantly increased in the HFD group after lomitapide treatment. The atherosclerotic plaque area also decreased in the thoracic aorta (7.9 ± 0.5% vs. 5.7 ± 0.1%). After treatment with lomitapide, the endothelium function of the thoracic aorta (47.7 ± 6.3% vs. 80.7 ± 3.1%) and mesenteric resistance artery (66.4 ± 4.3% vs. 79.5 ± 4.6%) was improved in the group of LDLr−/− mice on HFD. This was correlated with diminished vascular endoplasmic (ER) reticulum stress, oxidative stress, and inflammation. Conclusions: Treatment with lomitapide improves cardiovascular function and lipid profile and reduces body weight and inflammatory markers in LDLr−/− mice on HFD. [ABSTRACT FROM AUTHOR]

The activation of purinergic receptors by nucleotides and/or nucleosides plays an important role in the control of vascular function, including modulation of vascular smooth muscle excitability, and vascular reactivity. Accordingly, purinergic receptor actions, acting as either ion channels (P2X) or G protein-coupled receptors (GCPRs) (P1, P2Y), target diverse downstream effectors, and substrates to regulate vascular smooth muscle function and vascular reactivity. Both vasorelaxant and vasoconstrictive effects have been shown to be mediated by different purinergic receptors in a vascular bed- and species-specific manner. Purinergic signaling has been shown to play a key role in altering vascular smooth muscle excitability and vascular reactivity following acute and short-term elevations in extracellular glucose (e.g., hyperglycemia). Moreover, there is evidence that vascular smooth muscle excitability and vascular reactivity is severely impaired during diabetes and that this is mediated, at least in part, by activation of purinergic receptors. Thus, purinergic receptors present themselves as important candidates mediating vascular reactivity in hyperglycemia, with potentially important clinical and therapeutic potential. In this review, we provide a narrative summarizing our current understanding of the expression, function, and signaling of purinergic receptors specifically in vascular smooth muscle cells and discuss their role in vascular complications following hyperglycemia and diabetes.

The possibility of using a new contactless method of imaging photoplethysmography to assess thermoregulatory vasodilatation of blood vessels was studied. Perfusion reaction in a region of the outer forearm in response to local heating up to 41 ± 1 °C was monitored in six volunteers aged 39–52 years using a video recording of the study area, synchronized with an electrocardiogram, and subsequent correlation processing of the data obtained. It was shown that the change in perfusion during local heating has a biphasic type and is due to the response of the nervous system mediated by the axon reflex in the first phase of vasodilation and the synthesis of nitric oxide in endothelial cells in the second phase of vasodilation. It was revealed that the multiple increase in perfusion in the first phase of heating depends both on the initial temperature of the skin and on the difference in its heating temperature. It was found that for a significant development of a vascular response to hyperthermia associated with the activation of endothelial function, heating of tissues for more than 15 minutes is necessary. It was shown that the method of imaging photoplethysmography reliably reflects the work of the mechanisms of regulation of peripheral vascular resistance which is of great prognostic value for the detection of primary signs of cardiovascular diseases.

Available studies have shown the involvement of nitric oxide (NO) in the processes that lead to neurodegeneration in Parkinson's disease (PD). Also, the use of inhibitors of the inducible isoform of NO-synthase (iNOS) promotes neuroprotection and attenuates dopamine (DA) loss in experimental models of Parkinsonism. In addition, NO also appears to be involved in cardiovascular changes in 6-hydroxydopamine (6-OHDA)-induced Parkinsonism. The current study aimed to evaluate the effects of iNOS inhibition on cardiovascular and autonomic function in animals that were subjected to Parkinsonism by the administration of 6-OHDA. The animals underwent stereotaxic surgery for bilateral microinfusion of the neurotoxin 6-OHDA (6 mg/mL in 0.2% ascorbic acid in sterile saline solution) or vehicle solution for the Sham group. From the day of stereotaxis until the day of femoral artery catheterization, the animals were treated with the iNOS inhibitor, S-methylisothiourea (SMT; 10 mg/kg; i. p.) or saline solution (0.9%; i. p.) for 7 days. The animals were divided into four groups: Sham-Saline, Sham-SMT, 6-OHDA-Saline, and 6-OHDA-SMT. Subsequent analyses were performed on these four groups. After 6 days, they underwent catheterization of the femoral artery, and 24 h later, mean arterial pressure (MAP) and heart rate (HR) were recorded. Another group of animals (the 6-OHDA and Sham groups) was assessed for aortic vascular reactivity after 7 days of bilateral infusion of 6-OHDA or vehicle, in which cumulative concentration-effect curves (CCEC) were made for phenylephrine (Phenyl), acetylcholine and sodium nitroprusside (NPS). Also, CCEC in the presence of Nw-nitro-arginine-methyl-ester (l -NAME) (10-5 M), SMT (10-6 M), and indomethacin (10-5 M) blockers were made. The effectiveness of the 6-OHDA lesion was confirmed with the reduction of DA in 6-OHDA animals. However, treatment with SMT could not reverse the loss of DA. Concerning the baseline parameters, SBP and MAP values were lower in 6-OHDA animals compared to their Sham control, with no effect of treatment with SMT. In the analysis of SBP variability, a decrease in variance, the VLFabs component, and the LFabs component were observed in the 6-OHDA groups when compared to their controls, regardless of treatment with SMT. It was also observed that intravenous injections of SMT resulted in an increase in BP and a decrease in HR. However, the response was not different between the Sham and 6-OHDA groups. In vascular function, there was a hyporeactivity to Phenyl in the 6-OHDA group, and when investigating the mechanisms of this hyporeactivity, it was seen that the Rmax to Phenyl increased with incubation with SMT, indicating that iNOS could be involved in the vascular hyporeactivity of animals with Parkinsonism. Thus, the set of results presented in this study suggests that part of the cardiovascular dysfunction in animals subjected to 6-OHDA Parkinsonism may be peripheral and involve the participation of endothelial iNOS. • vascular reactivity is impaired in 6-OHDA induced parkinsonism. • iNOS isoform participates in the cardiovascular dysfunction of 6-OHDA rats. • Endothelial iNOS activity may be increased in 6-OHDA rats. [ABSTRACT FROM AUTHOR]

Pericytes are the mural cells of the microvascular network that are in close contact with underlying endothelial cells. Endothelial-secreted PDGFB leads to recruitment of pericytes to the vessel wall, but this is disrupted in Pdgfbret/ret mice when the PDGFB retention motif is deleted. This results in severely reduced pericyte coverage on blood vessels. In this study, we investigated vascular abnormalities and hemodynamics in Pdgfb ret/ret mice throughout the cerebrovascular network and in different cortical layers by in vivo two-photon microscopy. We confirmed that Pdgfb ret/ret mice are severely deficient in pericytes throughout the vascular network, with enlarged brain blood vessels and a reduced number of vessel branches. Red blood cell velocity, linear density, and tube hematocrit were reduced in Pdgfb ret/ret mice, which may impair oxygen delivery to the tissue. We also measured intravascular PO2 and found that concentrations were higher in cortical Layer 2/3 in Pdgfb ret/ret mice, indicative of reduced blood oxygen extraction. Finally, we found that Pdgfb ret/ret mice had a reduced capacity for vasodilation in response to an acetazolamide challenge during functional MRI imaging. Taken together, these results suggest that severe pericyte deficiency can lead to vascular abnormalities and altered cerebral blood flow, reminiscent of pathologies such as arteriovenous malformations. [ABSTRACT FROM AUTHOR]

Food restriction (FR) enhances sensitivity to cardiopulmonary reflexes and a1-adrenoreceptors in females in the presence of hypotension. However, the effect of FR on cardiopulmonary and vascular function in males is not well-understood. This study examines the effects of FR on cardiopulmonary, isolated arterial function, and potential underlying mechanisms. Male Sprague-Dawley (SD) rats were randomly divided into 3 groups and monitored for 5 weeks: (1) control (n = 30), (2) 20% food reduction (FR20, n = 30), and (3) 40% food reduction (FR40, n = 30). Non-invasive blood pressure was measured twice a week. Pulmonary arterial pressure (PAP) was measured using isolated/perfused lungs. The isolated vascular reactivity was assessed using doublewire myographs. FR rats exhibited a lower mean arterial pressure and heart rate; however, only the FR40 group exhibited statistically significant differences. We observed that FR enhanced sensitivity (EC50) to vasoconstriction induced by the a1-adrenoreceptor phenylephrine (PhE) but not to serotonin, U46619, or high K+ in the mesenteric arteries. PhE-mediated vasoconstriction in the mesenteric arteries was eliminated in the presence of the eNOS inhibitor (L-NAME). In addition, incubation with NOX2/4 inhibitors (apocynin, GKT137831, and VAS2870) and the reactive oxygen species (ROS) scavenger inhibitor (Tiron) eliminated the differences in PhE-mediated vasoconstriction, but the cyclooxygenase inhibitor (indomethacin) in the mesenteric arteries did not. Augmentation of a1-adrenergic-mediated contraction via the inhibition of the eNOS-NO pathway increased the activation of ROS through NOX2/4 in response to FR. Reduced eNOS-NO signaling may be a pathophysiological counterbalance to prevent hypovolemic shock in response to FR. [ABSTRACT FROM AUTHOR]

Background: Vascular hyporeactivity and leakage are key pathophysiologic features that produce multi-organ damage upon sepsis. We hypothesized that pericytes, a group of pluripotent cells that maintain vascular integrity and tension, are protective against sepsis via regulating vascular reactivity and permeability. Methods: We conducted a series of in vivo experiments using wild-type (WT), platelet-derived growth factor receptor beta (PDGFR-β)-Cre + mT/mG transgenic mice and Tie2-Cre + Cx43flox/flox mice to examine the relative contribution of pericytes in sepsis, either induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge. In a separate set of experiments with Sprague–Dawley (SD) rats, pericytes were depleted using CP-673451, a selective PDGFR-β inhibitor, at a dosage of 40 mg/(kg·d) for 7 consecutive days. Cultured pericytes, vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) were used for mechanistic investigations. The effects of pericytes and pericyte-derived microvesicles (PCMVs) and candidate miRNAs on vascular reactivity and barrier function were also examined. Results: CLP and LPS induced severe injury/loss of pericytes, vascular hyporeactivity and leakage (P < 0.05). Transplantation with exogenous pericytes protected vascular reactivity and barrier function via microvessel colonization (P < 0.05). Cx43 knockout in either pericytes or VECs reduced pericyte colonization in microvessels (P < 0.05). Additionally, PCMVs transferred miR-145 and miR-132 to VSMCs and VECs, respectively, exerting a protective effect on vascular reactivity and barrier function after sepsis (P < 0.05). miR-145 primarily improved the contractile response of VSMCs by activating the sphingosine kinase 2 (Sphk2)/sphingosine-1-phosphate receptor (S1PR)1/phosphorylation of myosin light chain 20 pathway, whereas miR-132 effectively improved the barrier function of VECs by activating the Sphk2/S1PR2/zonula occludens-1 and vascular endothelial-cadherin pathways. Conclusions: Pericytes are protective against sepsis through regulating vascular reactivity and barrier function. Possible mechanisms include both direct colonization of microvasculature and secretion of PCMVs. [ABSTRACT FROM AUTHOR]

Cumulating evidence demonstrated that chronic intermittent hypobaric hypoxia (CIHH) had beneficial effects on the body. This study investigated the role of perivascular adipose tissue (PVAT) in ameliorating effect of CIHH on vascular reactivity by adiponectin in mesenteric artery of metabolic syndrome (MS) rats. Main methods: 6-week-old male Sprague-Dawley rats were randomly divided into four groups: control (CON), MS model, CIHH treatment, and MS + CIHH treatment group. The size of adipocytes in PVAT was measured by scanning electron microscopy. Serum adiponectin was measured. The microvessel recording technique was used to observe the effect of CIHH on contraction and relaxation in mesenteric artery rings. Also, the expressions of interleukin-1β, tumor necrosis factor-α, adiponectin, AdipoR1, AdipoR2, APPL1, and endothelial nitric oxide synthase (eNOS) were assayed by Western blotting. Key findings: in MS rats, adipocyte size increased, serum adiponectin decreased, contraction reaction increased while relaxation reaction decreased, the expression of pro-inflammatory cytokines was upregulated, while adiponectin was downregulated in PVAT, and the expressions of AdipoR1, AdipoR2, APPL, and phosphorylated-eNOS were downregulated in mesenteric artery. All aforementioned abnormalities of MS were ameliorated in MS + CIHH rats. We concluded that CIHH treatment improves vascular reactivity through upregulating adiponectin expression and downregulating pro-inflammatory cytokine expression of PVAT in MS rats. [ABSTRACT FROM AUTHOR]

The increase of vascular arginase activity during aging causes endothelial dysfunction. This enzyme competes with the endothelial nitric oxide synthase (eNOS) for L-arginine substrate. Our hypothesis is that glucose 6-P dehydrogenase (G6PD) overexpression could improve the endothelial function modulating the arginase pathway in aorta from mice. For this study, three groups of male mice were used: young wild type (WT) (6–9 months), old WT (21–22 months) and old G6PD-Tg (21–22 months) mice. Vascular reactivity results showed a reduced acetylcholine-dependent relaxation in the old WT but not old G6PD-Tg group. Endothelial dysfunction was reverted by nor-NOHA, an arginase inhibitor. Mice overexpressing G6PD underexpressed arginase II and also displayed a lower activity of this enzyme. Moreover, histological analyses demonstrated that age causes a thickness of aortic walls, but this did not occur in G6PD-Tg mice. We conclude that the overexpressing G6PD mouse is a model to improve vascular health via the arginase pathway. [ABSTRACT FROM AUTHOR]

Oxidative stress is the main player in the development of diabetic vascular complications. Co-Q10 is a natural antioxidant present in the body and in many foods. This study was designed to evaluate the effect of Co-Q10 administration to improve vascular complications and increase insulin sensitivity in diabetic rats. Fifty male rats were divided into five groups: control, diabetic untreated, diabetic insulin-treated, diabetic Co-Q10-treated, and diabetic combined-treated groups. After 8 weeks, blood pressure and vascular reactivity to NE and ACh, fasting glucose, insulin, C-peptide, MDA, TAC, HbA1c, and the HOMA-IR were measured. Diabetes increased fasting glucose, HbA1c, HOMA-IR, MDA, blood pressure, and decreased TAC and vascular reactivity. Ttreatment with insulin or Co-Q10 improved glycemic parameters and increasing antioxidant levels compared to diabetic group. Combined Co-Q10 with insulin was found to increase insulin sensitivity and decrease its resistance, which helps to decrease insulin doses in diabetic patients and reduce its side effects. [ABSTRACT FROM AUTHOR]

The role of androgens in vascular reactivity is controversial, particularly regarding their age-related actions. The objective of this study was to c onduct a temporal evaluation of the vascular reactivity of resistance arteries of young male rats, as well as to understand how male sex hormones can influence the vascula r function of these animals. Endothelium-mediated relaxation was characterized in third-order mesenteric arteries of 10-, 12-, 16-, and 18w (week-old) male rats. Concen tration--response curves to acetylcholine (ACh, 0.1 nmol/L--10 μmol/L) were constructed in arteries previously contracted with phenylephrine (PE, 3 μmol/L), before and after the use of nitric oxide synthase or cyclooxygenase inhibitors. PE concentration--response curves (1 nmol/L--100 μmol/L) were also built. The levels of vascular nitric oxide, su peroxide anion, and hydrogen peroxide were assessed and histomorphometry analysis was performed. The 18w group had impaired endothelium-dependent relaxation. All groups showed prostanoid-independent and nitric oxide-dependent vasodilatory response, although this dependence seems to be smaller in the 18w group. The 18w group had the lowest nitric oxide and hydrogen peroxide production, in addition to the highest superoxide anion levels. Besides functional impairment, 18w animals showed morphological differences in third-order mesenteric arteries compared with the other groups. Our data show that time-dependent exposure to male sex hormones appears to play an important role in the development of vascular changes that can lead to impaired v ascular reactivity in mesenteric arteries, which could be related to the onset of age -related cardiovascular changes in males. [ABSTRACT FROM AUTHOR]

This study analyzed how glyphosate exposure in the gestational period affects vascular function in their offspring, focusing on the influence of age and whether oxidative stress is involved in this effect. To this, pregnant Wistar rats were exposed through drinking water to 0.2% of a glyphosate commercial formulation, and we analyzed the response to acetylcholine and phenylephrine in the aorta from offspring of glyphosate herbicide-based (O-GHB) and controls (O-CON) rats at 3, 6, and 12 months of age. O-GHB groups showed no changes in arterial blood pressure or aorta histological analysis. Relaxation to acetylcholine was reduced in O-GHB than O-CON. Acute TEMPOL increased relaxation to acetylcholine in O-GHB at 6 and 12 months of age. The aorta from O-GHB was hyperactive to phenylephrine only at 6 months of age. Preincubation with N-nitro- L -arginine methyl ester (L -NAME) increased contraction to phenylephrine more in O-CON than O-GHB. TEMPOL similarly reduced phenylephrine response. This effect was prevented by L -NAME. Results reinforce the concept that oxidative stress during the perinatal period contributes to the development of vascular changes in adulthood. Results also reveal that although no changes in cardiac or histological parameters have been demonstrated, the current levels considered safe for exposure to glyphosate deserve further investigation, especially during pregnancy. [ABSTRACT FROM AUTHOR]

Vaping, or electronic cigarette (ecig) use, is prevalent among pregnant women, although little is known about the effects of perinatal ecig use on cardiovascular health of the progeny (even when using nicotine-free e-liquid). Maternal toxicant inhalation may adversely affect vital conduit vessel development. We tested the hypothesis that perinatal exposure to maternal vaping would lead to a dose-dependent dysfunction that would persist into later life of offspring. Pregnant Sprague-Dawley rats were exposed to either nicotine-free (ecig0) or nicotine-containing ecig aerosol (18 mg/mL, ecig18) starting on gestational day 2 and continued until pups were weaned (postnatal day 21). Pups were never directly exposed. Conduit artery function (stiffness and reactivity) and structure were assessed in 3- and 7-mo-old offspring. At 3 mo, pulse wave velocity (PWV) in the ecig0 and ecig18 offspring was significantly higher than controls in both the 20 puffs/day (6.6 ± 2.1 and 4.8 ± 1.3 vs. 3.2 ± 0.7 m/s, respectively, P < 0.05, means ± SD) and in 60 puffs/day exposure cohort (7.5 ± 2.8 and 7.5 ± 2.5 vs. 3.2 ± 0.5 m/s, respectively, P < 0.01). Wire myography revealed (range of 23%-31%) impaired aortic relaxation in all ecig exposure groups (with or without nicotine). Incubation of vessels with TEMPOL or Febuxostat reversed the aortic dysfunction, implicating the involvement of reactive oxygen species. Nearly identical changes and pattern was seen in vascular outcomes of 7-mo-old offspring. The take-home message from this preclinical study is that maternal vaping during pregnancy, with or without nicotine, leads to maladaptations in vascular (aortic) development that persist into adult life of offspring. [ABSTRACT FROM AUTHOR]

Objective: To assess if the low-dose acetylsalicylic acid (ASA) would be capable of modifying endothelial function throughout pregnancy in nulliparous patients. Methods: A double-blind, randomized clinical trial with 277 were included. A total of 139 were orally administered 100 mg/day of ASA, and 138 received placebo. Endothelial function was assessed by flow-mediated dilation (FMD) in the brachial artery before the start of medication (11–14 weeks) and 20–24 and 30–34 weeks of gestation. The intervention was maintained until 34 weeks. The Mann-Whitney U test was used to compare the placebo and ASA groups. The comparison of FMD during pregnancy was performed using the Friedman test. Results: The groups (ASA and placebo) were similar regarding to age, weight, height, and body mass index (BMI) (p > .005). The comparison of values of FMD (%) between placebo vs. ASA at 11 and 14 weeks (8.9 vs. 9.7%, p: .253), 20 and 24 weeks (8.8 vs. 10.7%, p: .152), and 30 and 34 weeks (10.7 vs. 9.8%, p: .314) did not show significant changes throughout pregnancy. We observed a significant prevalence of PE in the placebo regarding to ASA group [14 (10.2%) vs. 8 (5.8%), p: .171]. Conclusion: Acetylsalicylic acid did not modify the endothelial function assessed by FMD of the brachial artery during pregnancy in nulliparous women. [ABSTRACT FROM AUTHOR]

Purpose : This study aims to investigate retinal and choroidal vascular reactivity to carbogen in central serous chorioretinopathy (CSC) patients. Methods: An experimental pilot study including 68 eyes from 20 CSC patients and 14 age and sex-matched controls was performed. The participants inhaled carbogen (5% CO2 + 95% O2) for 2 min through a high-concentration disposable mask. A 30° disc-centered fundus imaging using infra-red (IR) and macular spectral domain optical coherence tomography (SD-OCT) using the enhanced depth imaging (EDI) technique was performed, both at baseline and after a 2-min gas exposure. A parametric model fitting-based approach for automatic retinal blood vessel caliber estimation was used to assess the mean variation in both arterial and venous vasculature. Choroidal thickness was measured in two different ways: the subfoveal choroidal thickness (SFCT) was calculated using a manual caliper and the mean central choroidal thickness (MCCT) was assessed using an automatic software. Results: No significant differences were detected in baseline hemodynamic parameters between both groups. A significant positive correlation was found between the participants' age and arterial diameter variation (p < 0.001, r = 0.447), meaning that younger participants presented a more vasoconstrictive response (negative variation) than older ones. No significant differences were detected in the vasoreactive response between CSC and controls for both arterial and venous vessels (p = 0.63 and p = 0.85, respectively). Although the vascular reactivity was not related to the activity of CSC, it was related to the time of disease, for both the arterial (p = 0.02, r = 0.381) and venous (p = 0.001, r = 0.530) beds. SFCT and MCCT were highly correlated (r = 0.830, p < 0.001). Both SFCT and MCCT significantly increased in CSC patients (p < 0.001 and p < 0.001) but not in controls (p = 0.059 and 0.247). A significant negative correlation between CSC patients' age and MCCT variation (r = − 0.340, p = 0.049) was detected. In CSC patients, the choroidal thickness variation was not related to the activity state, time of disease, or previous photodynamic treatment. Conclusion: Vasoreactivity to carbogen was similar in the retinal vessels but significantly higher in the choroidal vessels of CSC patients when compared to controls, strengthening the hypothesis of a choroidal regulation dysfunction in this pathology. [ABSTRACT FROM AUTHOR]

Vaping, or electronic cigarette (ecig) use, is prevalent among pregnant women, although little is known about the effects of perinatal ecig use on cardiovascular health of the progeny (even when using nicotine-free e-liquid). Maternal toxicant inhalation may adversely affect vital conduit vessel development. We tested the hypothesis that perinatal exposure to maternal vaping would lead to a dose-dependent dysfunction that would persist into later life of offspring. Pregnant Sprague-Dawley rats were exposed to either nicotine-free (ecig0) or nicotine-containing ecig aerosol (18 mg/mL, ecig18) starting on gestational day 2 and continued until pups were weaned (postnatal day 21). Pups were never directly exposed. Conduit artery function (stiffness and reactivity) and structure were assessed in 3- and 7-mo-old offspring. At 3 mo, pulse wave velocity (PWV) in the ecig0 and ecig18 offspring was significantly higher than controls in both the 20 puffs/day (6.6 ± 2.1 and 4.8 ± 1.3 vs. 3.2 ± 0.7 m/s, respectively, P < 0.05, means ± SD) and in 60 puffs/day exposure cohort (7.5 ± 2.8 and 7.5 ± 2.5 vs. 3.2 ± 0.5 m/s, respectively, P < 0.01). Wire myography revealed (range of 23%-31%) impaired aortic relaxation in all ecig exposure groups (with or without nicotine). Incubation of vessels with TEMPOL or Febuxostat reversed the aortic dysfunction, implicating the involvement of reactive oxygen species. Nearly identical changes and pattern was seen in vascular outcomes of 7-mo-old offspring. The take-home message from this preclinical study is that maternal vaping during pregnancy, with or without nicotine, leads to maladaptations in vascular (aortic) development that persist into adult life of offspring. [ABSTRACT FROM AUTHOR]

Highlights What are the long-term effects of a 2-week period of severe food restriction (sFR) on cardiac structure and function months after refeeding (sFR-Refed) in male and female rats? This study shows sex differences exist in cardiac pathology months after refeeding. A majority of cardiomyocytes were atrophied in F-sFR-Refed rats, while in M-sFR-Refed rats, the cardiomyocytes predominantly exhibited hypertrophic remodeling. While there were no differences in the frequency of ventricular arrhythmias induced by ischemia/reperfusion (I/R) in the isolated heart between M-CT and M-sFR-Refed rats, I/R induced twice as many arrhythmias in the F-sFR-Refed rats compared to the controls. Our findings have implications for the long-term risk of developing cardiovascular disease in individuals who have voluntarily or involuntarily experienced periods of sFR earlier in their lives, and that woman may be at greater cardiovascular risk than men.

[Display omitted] • Chronic consumption of any type of coffee improves the metabolic profile. • Caffeinated coffee increases systemic blood pressure and vasoconstriction. • Caffeinated coffee decreases endothelium-dependent vasorelaxant response. • Decaffeinated coffee intake is recommended to maintain optimal vascular function. Although coffee is one of the most popular beverages, the relationship between chronic consumption and cardiovascular health remains controversial. Therefore, this study investigated the effects of chronic consumption of caffeinated or decaffeinated coffee on biochemical profile and cardiovascular response. Three groups of rats were treated with HPLC characterized caffeinated or decaffeinated coffee and control for six weeks; blood pressure and biochemical profile were analyzed, followed by in vitro aortic ring experiments. The results showed that both coffees reduced blood glucose, AST and ALT. However, only caffeinated coffee elevated blood pressure in vivo, whereas aortic rings with endothelium increased the vasocontractile response; this effect was reversed by the addition of indomethacin and L-NAME also reduced the endothelium-mediated vasodilator response. In conclusion, chronic intake of any type of coffee positively improves biochemical profile. However, caffeinated coffee reduces nitric oxide biosynthesis and increases vasoconstrictor prostanoid production, whereas decaffeinated coffee preserves vascular function. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is a condition of pregnancy defined by new-onset hyperglycemia. GDM is associated with impaired maternal endothelial and vascular reactivity. Endothelin-1 (ET-1) is a potent vasoconstrictor that contributes to endothelial dysfunction, however, its abundance and actions in GDM are unclear. Maternal plasma was obtained from pregnancies complicated by GDM (n = 24) and gestation-matched controls (n = 42); circulating ET-1 levels were assessed by ELISA. Human omental arteries from healthy pregnancies and those complicated by GDM were dissected from omental fat biopsies and collected at cesarean section. mRNA expression of ET-1 and its receptors, ETA and ETB, in addition to vascular cell adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1) were assessed by qPCR (n = 28). Using wire myography, we investigated vascular constriction to ET-1 (10−11–10−4 M) in omental arteries from pregnancies complicated by GDM, compared to gestation-matched controls (n = 7). GDM cases were stratified by clinical management, diet intervention (n = 5), or insulin treatment (n = 6). Additionally, arteries from healthy pregnancies were treated with insulin (1 mU/mL (n = 7) and 10 mU/mL (n = 5)) or vehicle control. Vasoactive response to ET-1 was measured via wire myography. Circulating ET-1 levels and mRNA expression of the ET-1 system in omental arteries were not found to be significantly different between pregnancies complicated by GDM compared to healthy controls. However, we found insulin treatment during pregnancy and in ex vivo models reduced ET-1 vasoconstriction of maternal vasculature in GDM. These data suggest insulin may improve vascular function in GDM, however, further investigation is needed to define the role of ET-1 in pregnancy.

The microvasculature is prominently affected by traumatic brain injury (TBI), including mild TBI (concussion). Assessment of cerebral hemodynamics shows promise as biomarkers of TBI, and may help inform development of therapies aimed at promoting neurologic recovery. The objective of this study was to assess the evolution in cerebral hemodynamics observable with transcranial Doppler (TCD) ultrasound in subjects suffering from a concussion at different intervals during recovery. Pediatric subjects between the ages of 14 and 19 years clinically diagnosed with a concussion were observed at different points post-injury. Blood flow velocity in the middle cerebral artery was measured with TCD. After a baseline period, subjects participated in four breath holding challenges. Pulsatility index (PI), resistivity index (RI), the ratio of the first two pulse peaks (P2R), and the mean velocity (MV) were computed from the baseline section. The breath hold index (BHI) was computed from the challenge sections. TCD detected two phases of hemodynamic changes after concussion. Within the first 48 h, PI, RI, and P2R show a significant difference from the controls (U = -3.10; P

BackgroundWomen with chest pain, ischemia, and no obstructive coronary artery disease often have coronary vascular dysfunction (CVaD). Peripheral vascular reactivity to mental stress may contribute mechanistic understanding of stress-induced ischemia in women with CVaD.Methods62 women (41 CVaD and 21 controls) underwent mental stress testing (MST) with anger recall, mental arithmetic, and forehead cold pressor (COP) challenge. Emotional arousal was measured (Likert scale). Reactive hyperemia index (RHI) was calculated before and after MST by peripheral arterial tonometry (PAT). Stress PAT ratio (SPR) of pulse amplitude during stress to rest was obtained to measure vasoconstriction. Wilcoxson rank sum test was used for analysis.ResultsMean age of CVaD and control groups was 58±9 and 55±10years (p=0.73). Baseline RHI correlated with coronary endothelial function (r=0.36, p=0.03) and inversely with RHI change post-MST (r=-0.51, p

Vascular endothelium is a protective layer of cells lining the lumen of blood vessels that plays important roles by releasing factors responsible for controlling the vascular tone, regulating the expression of pro-inflammatory cytokines, and expressing adhesion molecules involved in vascular hemostasis. Imbalance of vascular properties leads to endothelial dysfunction (ED) and cardiovascular damage. Some diseases, such as sickle cell anemia, are characterized by ED with reduction in the levels of nitric oxide (NO). Previously, we have shown that the fetal hemoglobin inducer agent 3-(1,3-dioxoisoindolin-2-yl) benzyl nitrate (Lapdesf-4c) could act as NO donor, inhibiting platelet aggregation and reducing the inflammation associated with SCA. However, the vascular effect of this compound was not yet studied. Herein, we evaluated the effects of Lapdesf-4c in vascular reactivity experiments using aortic rings from male Wistar rats (300 g/90 days). We have found that Lapdesf-4c induced vasodilation in the presence (E+) or absence of endothelium (E−) with an average of EMax values of 101.8 ± 3.33% and 111.8 ± 3.21%. The mechanism of action was studied using 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ), L-NG-nitroarginine methyl ester (L-NAME), and hydroxocobalamin. The EMax values for those pathways were hydroxocobalamin (30.6 ± 2.21%), ODQ (4.75 ± 0.51%), and L-NAME (109 ± 3.65), suggesting that Lapdesf-4c exhibits NO-dependent mechanisms. Lapdesf-4c was able to prevent angiotensin-induced ED after incubation of aorta rings for 1 h. We found based on the concentration–effect curve using acetylcholine (ACh) that pEC50 values for the control, Ang II, and combination of (Ang II + Lapdesf-4c) were 6.73, 6.46, and 7.15, respectively. In conclusion, Lapdesf-4c has emerged as a new drug candidate that can promote vasodilation and act as a protective agent against ED, being useful to prevent vascular damage. [ABSTRACT FROM AUTHOR]