Vasodilator Function Research Articles

Effect of 5β-dihydrotestosterone on vasodilator function and on cell proliferation.

Aging is one of the main factors associated with cardiovascular diseases. Androgens exert beneficial effects on the cardiovascular system and testosterone (TES) replacement therapy improves cardiometabolic risk factors. However, TES is contraindicated in patients with prostate cancer due to its proliferative effects on prostatic tumor cells. Additionally, TES and its reduced metabolites 5α- and 5β-dihydrotestosterone (5α-DHT and 5β-DHT) exert vasodilatory effects. Since androgen levels decrease during aging and 5β-DHT lacks genomic effects, this study is focused on analyzing its effect on vasodilator function and the proliferation rate of prostatic tumor and vascular smooth muscle cells. To study the vascular function, mesenteric arteries from aged-orchidectomized Sprague-Dawley rats were used. Mesenteric segments were divided into one control (without treatment) and three groups with the androgens (10 nM, 30 min) to analyze: acetylcholine- and sodium nitroprusside-induced responses and nitric oxide and superoxide anion production. To analyze cell proliferation, the effect of androgens on cell viability was determined. The results showed that 5β-DHT improves vasodilator function in arteries from aged-orchidectomized rats and induces antioxidant action, while the proliferation rate of the androgen-dependent prostatic tumor cells remains unaltered. These results make 5β-DHT a promising therapeutic agent for the treatment of cardiovascular pathologies.

Pleiotropic Effects of Resveratrol on Aging-Related Cardiovascular Diseases-What Can We Learn from Research in Dogs?

Resveratrol (RES) is a polyphenol with natural anti-inflammatory and antioxidant properties. It is found in abundance in plants, i.e., grapes and mulberry fruit. In addition, synthetic forms of RES exist. Since the discovery of its specific biological properties, RES has emerged as a candidate substance not only with modeling effects on the immune response but also as an important factor in preventing the onset and progression of cardiovascular disease (CVD). Previous research provided strong evidence of the effects of RES on platelets, mitochondria, cardiomyocytes, and vascular endothelial function. In addition, RES positively affects the coagulation system and vasodilatory function and improves blood flow. Not only in humans but also in veterinary medicine, cardiovascular diseases have one of the highest incidence rates. Canine and human species co-evolved and share recent evolutionary selection processes, and interestingly, numerous pathologies of companion dogs have a human counterpart. Knowledge of the impact of RES on the cardiovascular system of dogs is becoming clearer in the literature. Dogs have long been recognized as valuable animal models for the study of various human diseases as they share many physiological and genetic similarities with humans. In this review, we aim to shed light on the pleiotropic effects of resveratrol on cardiovascular health in dogs as a translational model for human cardiovascular diseases.

Vasoactive intestinal peptide promotes secretory differentiation and mitigates radiation-induced intestinal injury

BackgroundVasoactive intestinal peptide (VIP) is a neuronal peptide with prominent distribution along the enteric nervous system. While effects of VIP on intestinal motility, mucosal vasodilation, secretion, and mucosal immune cell function are well-studied, the direct impact of VIP on intestinal epithelial cell turnover and differentiation remains less understood. Intestinal stem and progenitor cells are essential for the maintenance of intestinal homeostasis and regeneration, and their functions can be modulated by factors of the stem cell niche, including neuronal mediators. Here, we investigated the role of VIP in regulating intestinal epithelial homeostasis and regeneration following irradiation-induced injury.MethodsJejunal organoids were derived from male and female C57Bl6/J, Lgr5-EGFP-IRES-CreERT2 or Lgr5-EGFP-IRES-CreERT2/R26R-LSL-TdTomato mice and treated with VIP prior to analysis. Injury conditions were induced by exposing organoids to 6 Gy of irradiation (IR). To investigate protective effects of VIP in vivo, mice received 12 Gy of abdominal IR followed by intraperitoneal injections of VIP.ResultsWe observed that VIP promotes epithelial differentiation towards a secretory phenotype predominantly via the p38 MAPK pathway. Moreover, VIP prominently modulated epithelial proliferation as well as the number and proliferative activity of Lgr5-EGFP+ progenitor cells under homeostatic conditions. In the context of acute irradiation injury in vitro, we observed that IR injury renders Lgr5-EGFP+ progenitor cells more susceptible to VIP-induced modulations, which coincided with the strong promotion of epithelial regeneration by VIP. Finally, the observed effects translate into an in vivo model of abdominal irradiation, where VIP showed to prominently mitigate radiation-induced injury.ConclusionsVIP prominently governs intestinal homeostasis by regulating epithelial progenitor cell proliferation and differentiation and promotes intestinal regeneration following acute irradiation injury.

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.

Asymmetric Dimethylarginine (ADMA) in Cardiovascular Disease, Cardiac Ischemia/reperfusion Injury, and Ischemic Non-obstructive Coronary Artery Disease: Biochemical and Pharmacological Implications

: Several studies have shown that high plasma concentrations of asymmetric dimethylarginine (ADMA), a known endogenous competitive inhibitor of endothelial nitric oxide synthase (eNOS), correlate with the severity of coronary artery disease (CAD), with worsening of cardiac ischemia/reperfusion (I/R) injury and coronary atherosclerosis. It is believed that it may be an important risk factor for myocardial infarction. ADMA, when in high concentrations, can determine a significant decrease in the synthesis and bioavailability of NO (Nitric oxide) and therefore alter the mechanisms of regulation of coronary vasodilation and vasomotor function of epicardial coronary arteries. Higher serum ADMA concentration is associated with worsening of post-ischemic remodeling since coronary angiogenesis, vasculogenesis, and collateral coronary growth are seriously impaired. In addition, there are reasons to believe that elevated plasma ADMA levels are related to the development of diseases affecting coronary microcirculation, such as ischemic non-obstructive coronary artery disease (INOCA). With the aim of providing the pharmacologist engaged in the design and discovery of new ADMA-lowering drugs with a complete examination of the subject, in this review, we discuss the most important studies related to the correlations between serum ADMA levels and cardiovascular diseases mentioned above. In addition, we critically discuss the main aspects of enzymology, synthesis, and metabolism of ADMA as a prerequisite for understanding the molecular mechanisms through which high concentrations of ADMA could contribute to promoting cardiovascular diseases. ADMA represents a new target for pharmacological modulation of cardiovascular endothelial function and therefore, there is a possibility of using selective pharmacological ADMA lowering drugs in cardiovascular disease with endothelial dysfunction and high plasma ADMA levels.

Resistance exercise breaks during prolonged sitting augment the blood flow response to a subsequent oral glucose load in sedentary adults.

Sitting-induced impairments in postprandial blood flow are an important link between sedentary behaviour and cardiometabolic disease risk. The objective of this work was to examine the effects of resistance exercise breaks (REB) performed every 30min during an otherwise sedentary 3-h period on the vasodilatory response to a subsequent oral glucose load in sedentary adults. Twenty-four sedentary adults (27±7 years, 16 females) completed two conditions.Fasting blood glucose, insulin, popliteal artery blood flow (PABF) and gastrocnemius perfusion were measured immediately before standardized breakfast consumption. After breakfast, the 3-h REB or uninterrupted (SIT) intervention period commenced. Participants sat at a workstation, and popliteal artery shear rate (PASR) was measured 60 and 120min into this period. In the REB condition, participants performed a 3-min REB (3 × [20s squats, 20s high knees, 20s calf raises]) every 30min. Following the intervention period, baseline measurements were repeated. Participants then consumed a 75g glucose beverage, and PABF and perfusion were measured every 30-60min for the following 120min. Relative to SIT, REB increased PASR at 60min (+31.4±9.2/s, P=0.037) and 120min (+37.4±10.2/s, P=0.019) into the intervention period. Insulin and glucose increased (P<0.001) in response to glucose consumption, with no differences between conditions (P≥0.299). In response to the glucose load, perfusion (1.57vs. 1.11mL/100mL/min, P=0.023) and PABF (+45.3±11.8mL/min, P=0.001) were greater after REB versus SIT. Performing 3-min REB every 30min during an otherwise sedentary 3-h period augmented leg blood flow responses to an oral glucose load. HIGHLIGHTS: What is the central question of this study? Can 3-min resistance exercise breaks (REB) performed during an otherwise sedentary 3-h period augment the vasodilatory response to a subsequent oral glucose load in sedentary adults? What is the main finding and its importance? Performing 3-min REB, which included squats, high knees, and calf raises, every 30min augmented lower limb blood flow responses to a subsequent oral glucose load compared to 3h of uninterrupted sitting in sedentary adults. Sitting-induced impairment in postprandial vasodilatory function has been identified as a link between sedentary behaviour and cardiometabolic disease. Thus, the current study presents a potentially effective strategy to offset this risk.

Methylglyoxal induces endothelial cell apoptosis and coronary microvascular dysfunction through regulating AR-cPLA2 signaling

ObjectiveSince diabetic patients with coronary microvascular dysfunction (CMD) exhibit high cardiac mortality and women have higher prevalence of non-obstructive coronary artery disease than men, we tried to expand the limited understanding about the etiology and the sex difference of diabetic CMD. Approach and resultsAccumulated methylglyoxal (MGO) due to diabetes promotes vascular damage and it was used for mimicking diabetic status. Flow cytometry analysis and isometric tension measurement were performed to evaluate coronary artery endothelial injury. MGO induced apoptosis of coronary endothelial cells, accompanied by downregulation of androgen receptor (AR). Lentivirus-mediated stable expression of AR in coronary endothelial cells increased anti-apoptotic Bcl-2 expression and attenuated MGO-induced cell apoptosis. cPLA2 activation was the downstream of AR downregulation by MGO treatment. Moreover, MGO also activated cPLA2 rapidly to impair endothelium-dependent vasodilation of coronary arteries from mice. Reactive oxygen species (ROS) overproduction was demonstrated to account for MGO-mediated cPLA2 activation and endothelial dysfunction. Importantly, AR blockade increased endothelial ROS production whereas AR activation protected coronary artery endothelial vasodilatory function from the MGO-induced injury. Although galectin-3 upregulation was confirmed by siRNA knockdown in endothelial cells not to participate in MGO-induced endothelial apoptosis, pharmacological inhibitor of galectin-3 further enhanced MGO-triggered ROS generation and coronary artery endothelial impairment. ConclusionsOur data proposed the AR downregulation-ROS overproduction-cPLA2 activation pathway as one of the mechanisms underlying diabetic CMD and postulated a possible reason for the sex difference of CMD-related angina. Meanwhile, MGO-induced galectin-3 activation played a compensatory role against coronary endothelial dysfunction.

Lasting Effects of Surgically Used Topical Vasodilators on DIEP Artery Vascular Function.

Surgeons routinely apply papaverine, lidocaine, or verapamil to produce acute vasodilation and prevent vasospasms during microvascular surgeries. There is evidence that topical vasodilators may induce postoperative endothelial and smooth muscle dysfunction, which would present after the acute vasodilatory effects of the topical drugs wear off. Therefore, the purpose of the current study was to evaluate the lasting effects of papaverine, lidocaine, and verapamil on human deep inferior epigastric perforator artery vasodilatory function after the acute effects of the topical drugs had worn off. Deep inferior epigastric arterial samples were obtained from 12 patients during surgery. Each artery was dissected into four rings which where incubated for 1 minute in either physiological saline solution (control), papaverine (30 mg/mL), lidocaine (20 mg/mL), or verapamil (2.5 mg/mL), followed by a 2-hour washout. Endothelial-dependent and -independent vasorelaxation were then assessed by the isometric tension responses to acetylcholine or sodium nitroprusside, respectively. Peak acetylcholine-evoked vasorelaxation (mean ± standard deviation) was not different between control (62 ± 23%) and lidocaine (57 ± 18%, p = 0.881), but was reduced (all p < 0.002) in papaverine (22 ± 27%) and verapamil (22 ± 20%). Peak sodium nitroprusside-evoked vasorelaxation was not different (all p > 0.692) among control (132 ± 35%), lidocaine (121 ± 22%), and verapamil (127 ± 22%), but was less in papaverine (104 ± 41%; p = 0.045) than control. Surgically used doses of papaverine and verapamil, but not lidocaine, have lasting negative effects on arterial vasodilatory function despite the acute effects of the drugs having worn off. These findings, in conjunction with the spasmolytic properties of each drug, may help guide the selection of an optimal topical vasodilator for use during microvascular surgeries.

Przewaquinone A inhibits Angiotensin II-induced endothelial diastolic dysfunction activation of AMPK

BackgroundEndothelial dysfunction (ED), characterized by markedly reduced nitric oxide (NO) bioavailability, vasoconstriction, and a shift toward a proinflammatory and prothrombotic state, is an important contributor to hypertension, atherosclerosis, and other cardiovascular diseases. Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) is widely involved in cardiovascular development. Przewaquinone A (PA), a lipophilic diterpene quinone extracted from Salvia przewalskii Maxim, inhibits vascular contraction. PurposeHerein, the goal was to explore the protective effect of PA on ED in vivo and in vitro, as well as the underlying mechanisms. MethodsA human umbilical vein endothelial cell (HUVEC) model of ED induced by angiotensin II (AngII) was used for in vitro observations. Levels of AMPK, endothelial nitric oxide synthase (eNOS), vascular cell adhesion molecule-1 (VCAM-1), nitric oxide (NO), and endothelin-1 (ET-1) were detected by western blotting and ELISA. A mouse model of hypertension was established by continuous infusion of AngII (1000 ng/kg/min) for 4 weeks using osmotic pumps. Following PA and/or valsartan administration, NO and ET-1 levels were measured. The levels of AMPK signaling-related proteins in the thoracic aorta were evaluated by immunohistochemistry. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were measured using the tail cuff method. Isolated aortic vascular tone measurements were used to evaluate the vasodilatory function in mice. Molecular docking, molecular dynamics, and surface plasmon resonance imaging (SPRi) were used to confirm AMPK and PA interactions. ResultsPA inhibited AngII-induced vasoconstriction and vascular adhesion as well as activated AMPK signaling in a dose-dependent manner. Moreover, PA markedly suppressed blood pressure, activated vasodilation in mice following AngII stimulation, and promoted the activation of AMPK signaling. Furthermore, molecular simulations and SPRi revealed that PA directly targeted AMPK. AMPK inhibition partly abolished the protective effects of PA against endothelial dysfunction. ConclusionPA activates AMPK and ameliorates endothelial dysfunction during hypertension.

TMAO Impairs Mouse Aortic Vasodilation by Inhibiting TRPV4 Channels in Endothelial Cells.

Trimethylamine oxide (TMAO) is an intestinal flora metabolite associated with risk of cardiovascular diseases. Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable ion channel that is essential for vasodilation and endothelial function. Currently, there are few studies on the effect of TMAO on TRPV4 channels. In the present study, Ca2+ imaging of vascular tissue showed that TMAO inhibited TRPV4-mediated Ca2+ influx into aortic endothelial cells in a dose-dependent manner. Furthermore, a whole-cell patch clamp assay showed that TMAO blocked TRPV4-mediated cation currents. Notably, results of aortic vascular tension measurement showed that TMAO impaired endothelium-dependent vasodilation in mouse aortic vessels through the TRPV4-NO pathway. Our results indicated that TMAO inhibited Ca2+ entry in endothelial cells and impaired vasodilation through the TRPV4-NO pathway in mice. These results provide scientific evidence for novel pathogenic mechanisms underlying the role of TMAO in cardiovascular disease.

Central and peripheral cardiovascular responses after acute dietary nitrate supplementation in post-menopausal women

The transition to menopause is accompanied by augmented cardiovascular disease risk, partially attributed to reduced nitric oxide (NO) bioavailability. Despite a lower arterial stiffness than men, postmenopausal women are susceptible to increased aortic pulsatile hemodynamic load because of greater pressure wave reflection and vascular dysfunction. Increasing bioavailable NO with dietary nitrate has shown promise to reduce aortic (aSBP) and brachial (bSBP) systolic pressure healthy postmenopausal women. However, there are limited reports comparing hypertensive (HTN) and normotensive (NTN) postmenopausal women regarding wave separation analysis and vascular function following dietary nitrate supplementation. This study investigated if acute dietary nitrate supplementation would improve aortic hemodynamics, wave reflection characteristics, vascular stiffness, and vasodilatory function. We hypothesized that dietary nitrate would lower pulse wave velocity in hypertensives, lower aortic and brachial blood pressures and forward and backward wave magnitude and increase microvascular, but not macrovascular function in both groups. Fourteen postmenopausal women (n=7 HTN; n=7 NTN) participated in a two-day randomized crossover study design with dietary nitrate (nitrate rich, NR) or a placebo control (NP). Central and peripheral hemodynamics and carotid-femoral pulse wave velocity (cfPWV) were performed with a SphygmoCOR Excel, simultaneous resting macro- and- microvascular function was assessed using flow-mediated vasodilation (FMD) and post occlusive reactive hyperemia (PORH) using near-infrared spectroscopy. aSBP was reduced significantly following NR supplement within groups (HTN: NP 126±2 NR 120±1mmHg) and NTN group (NP 110± 1 NR 104±3mmHg p&lt;0.05). Forward pulse height HTN (NP 29±1.4 NR 26.3±1.4mmHg) NTN (NP 25.6±0.9 NR 24±2.7mmHg) and reflected pulse height HTN (NP 18.2±0.08 NR 17.2±0.4mmHg) NTN (NP 17.7±0.2 NR 15.7±1.07mmHg) were not different. cfPWV was faster in the HTN group and slowed with a NR supplement (HTN: NP 8.2±0.29 NR 7.4±0.31m/s; NTN NP 7.1±0.23 NR 6.6±0.62m/s p&lt;0.05). A significant interaction for %FMD was found (HTN: NP 7.3±0.8 NR 6.2±0.8%; NTN NP 6.6±0.7 NR 9.4±0.7%). Further, we found no difference in the NIRS derived microvascular function measurements (HTN: NP 1.9±0.2 NR 1.7±0.3%/s; NTN NP 1.6±0.1 NR 1.4±0.2%/s p&gt;0.05). These data indicate that dietary nitrate consumption led to a substantial reduction in aortic hemodynamics and reduced pulse wave velocity regardless of hypertension status. Interestingly, macrovascular, but not microvascular vasodilatory function was improved in the NTN women only. Dietary nitrate supplementation appears to have differential effects when considering HTN and NTN postmenopausal women. Supported with funds from The University of Wisconsin-La Crosse RSEL graduate grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Postmenopausal Women with Obesity have Reduced Leg Endothelial Function and Exercise Vasodilatory Capacity

Background: Obesity (OB) is highly prevalent in postmenopausal women; particularly increased abdominal visceral adipose tissue contributes to endothelial dysfunction and cardiovascular risk. The endothelium plays an important role on blood flow (BF) and pressure control at rest and during exercise. However, it is unknown how different body mass index (BMI) categories influence upper and lower limb endothelial function and BF responses to exercise in postmenopausal women. Purpose: The purpose was to examine upper and lower limb endothelial function at rest and BF regulation during low-intensity exercises in OB, overweight (OW), and lean (LN) postmenopausal women. We hypothesized that endothelial function and BF responses to submaximal exercise in both limbs will be attenuated in OB compared to the OW and LN groups. Methods: Women were classified as OB (30.0-39.9 kg/m2; n = 13), OW (25.0-29.9 kg/m2; n = 15), and LN (18.5-24.9 kg/m2; n = 11) by BMI. Flow-mediated dilation (FMD) of the brachial (BA-FMD) and superficial femoral arteries (FA-FMD) were measured using ultrasound. BF and vascular conductance (VC) in the brachial (BA-BF and BA-VC) and femoral (FA-BF and FA-VC) arteries were measured during separate 3-stage incremental rhythmic handgrip and plantarflexion exercises (PFE) at 5, 15, and 30 % of maximal strength and calculated 1-repetition max (1RM), respectively. Results: No differences in BA-FMD were observed among the groups. FA-FMD was significantly lower in OB (2.6 ± 1.4%) compared to OW (4.3 ± 1.9%) and LN (4.2 ± 0.7%) groups (P &lt; 0.05). Increases in FA-BF (OB: 462 ± 229 vs. OW: 616 ± 173 vs. LN: 640 ± 141 mL/min; P &lt; 0.001) and FA-VC (OB: 410 ± 176 vs. OW: 585 ± 155 vs LN: 623 ± 153 mL/min*100mmHg; P &lt; 0.001) were attenuated during PFE at 30% of 1RM in OB compared to OW and LN. Upper-body exercise vasodilation was not attenuated by OB. FA-BF and FA-VC during PFE at 30% of 1RM were correlated with FA-FMD (FA-BF: r = 0.423, P = 0.007, FA-VC: r = 0.367, P = 0.021) and BMI (FA-BF: r = -.386, P = 0.015, FA-VC: r = -.456, P = 0.004). Conclusion: Postmenopausal women with OB have blunted leg endothelial function and exercise vasodilator function during submaximal dynamic plantarflexion exercise compared to LN and OW. These findings suggest that OB may contribute to reduce leg endothelial function, and vasodilator function during exercise in postmenopausal women. No support of funding information to disclose. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mitochondrial and Microvascular Impairments in a Novel Swine Model of Peripheral Artery Disease

Introduction: Impaired skeletal muscle mitochondria and microvascular function have been reported in human peripheral artery disease (PAD). However, no large animal models of PAD have mimicked these impairments. Purpose: The purpose of this study was to examine the skeletal muscle microvasculature and mitochondria in a novel swine model of PAD. Hypothesis: We hypothesized that hindlimb ischemia leads to dysfunction of skeletal muscle microvessels and mitochondria. Methods: Ossabaw swine (n=5) with metabolic syndrome underwent endovascular coil occlusion of the right external iliac artery to generate hindlimb ischemia (ISC). The left leg served as a non-ischemic control (CON). After 4-weeks, biopsies were collected from both legs (lateral gastrocnemius). Skeletal muscle arterioles were assessed using video microscopy. Microvascular vasodilatory function was assessed in response to flow (Shear stress), acetylcholine (ACh), and sodium nitroprusside (SNP). Skeletal muscle mitochondrial function was assessed using high-resolution respirometry. Substrates were administered as follows: malate (M) &amp; glutamate (G), adenosine diphosphate (ADP), succinate (S), oligomycin, and ascorbate (Asc) &amp; N,N,N,N-tetramethyl-phenylenediamine (TMPD). Complex I state 2 (CI-S2) was assessed as M+G, complex I state 3 (CI-S3) was assessed as (M+G+ADP)-(M+G), complex II state 3 (CII-S3) was assessed as (M+G+ADP+S)-(M+G+ADP), complex I&amp;II state 3 (CI&amp;II S3) was assessed as (M+G+ADP+S)-(M+G), state 4 (S4) was assessed after oligomycin, and complex IV (CIV) respiration was assessed after Asc+TMPD. The respiratory control ratio (RCR) was calculated as CI&amp;II-S3/S4. Results: Vasodilation in response to flow was reduced in ISC vs. CON (Δ-13.1±13.7%, p=0.01). but not in response to ACh (Δ-6.2±17.7%, p=0.23) or SNP (Δ1.7±11.0%, p=0.53). Additionally, CI-S2 (Δ-0.3±3.7 pmolO2·s−1·mg−1, p=0.65), S4 (Δ-1.7±4.4 pmolO2·s−1·mg−1, p=0.14), and CIV (Δ-2.8±20.9 pmolO2·s−1·mg−1, p=0.65) were not different between ISC and CON. However, CI-S3 (Δ-4.7±5.0 pmolO2·s−1·mg−1, p&lt;0.01), CII-S3 (Δ-3.5±5.0 pmolO2·s−1·mg−1, p=0.02), CI&amp;II-S3 (Δ-8.5±8.7 pmolO2·s−1·mg−1, p&lt;0.01), and RCR (Δ-0.8±1.3 pmolO2·s−1·mg−1, p=0.04) were all reduced in ISC vs. CON. Conclusions: We found that skeletal muscle microvessels and mitochondria were impaired in our swine model. Based on the present findings, we conclude that our novel porcine model closely replicates the pathophysiology PAD, making it a promising large animal model for studying human PAD. This research was supported by the National Institutes of Health (R01HD106911, R01AG062198, R01AG0778031) and the Great Plains IdeA-CTR (U54 GM115458). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The effect of acute estrogen suppression on cutaneous endothelium-dependent vasodilation in women with endometriosis

Cardiovascular disease risk is elevated in women with endometriosis and may be exacerbated by treatments that suppress estrogen. The purpose of this study was to determine the effects of acute estrogen suppression on endothelial function in women with endometriosis. We hypothesized that estrogen suppression would attenuate cutaneous endothelium-dependent vasodilation in endometriosis patients (ENDO; n = 2, 30 (1) y, 21.4 (0.2) kg·m2) but not in healthy controls (CON; n = 6, 28 (5) y, 24.9 (5.2) kg·m2). Trials were conducted with (POST) and without (PRE) 4 days of estrogen suppression (400 mg/day gonadotropin-releasing hormone antagonist, Elagolix®) during the first week of separate menstrual cycles. The cutaneous circulation was utilized as a model of microvascular vasodilatory function. Laser Doppler flowmetry was continuously measured during graded perfusions of acetylcholine through intradermal microdialysis (ACh, 1x10−10 – 1x10−1 M). Maximal vasodilation was elicited via 28 mM sodium nitroprusside perfusion and local heating (42°C). Cutaneous vascular conductance was calculated as LDF/mean arterial pressure (MAP). Dose response curves were generated with nonlinear modeling of normalized data with constraints and compared via median effective ACh dose (ED50) and HillSlope. Data are presented as mean (SD) and significance was set at α = 0.05. Baseline MAP was similar between trials for CON (PRE, 80.70 (6.32) mmHg; POST, 82.30 (5.37) mmHg; t[5] = -0.74, P = 0.49) and ENDO (PRE, 72.22 (0.31) mmHg; POST, 79.17 (7.31) mmHg; t[1] = -1.29, P = 0.42). ED50 was not impacted by estrogen suppression in CON (PRE, -3.61 (2.19) logM; POST, -2.80 (1.13) logM; t[5] = -1.04, P = 0.35) or ENDO (PRE, -3.08 (1.74); POST, -2.85 (0.68); t[1] = -0.13, P = 0.91). Similarly, HillSlope was not altered in CON (PRE, 1.00 (0.96); POST, 0.99 (1.14); t[5] = 0.01, P = 0.99) or ENDO (PRE, 0.81 (0.72); POST, 1.16 (1.15); t[1] = -0.26, P = 0.84). Acute estrogen suppression did not impact cutaneous endothelium-dependent vasodilation in healthy controls or women with endometriosis. A greater sample size will further evaluate this relationship. National Institutes of Health Grant 1R01HL161000. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hot head-out water immersion increases internal carotid artery shear rate but does not alter intracranial vascular reactivity to carbon dioxide

Acute head-out water immersion (HOWI) in hot water increases cerebral blood flow (CBF) until core temperature rises by ~1.0°C. The increase in CBF may promote increases in arterial shear rate that could enhance cerebrovascular reactivity to CO2 (CVRCO2) as a result of elevated nitric oxide (NO) bioavailability. An increase in NO bioavailability improves peripheral vasodilator function, and therefore, a similar response may occur in the cerebral vasculature. This likely only aids in cerebral vasodilation during hypercapnia, and not cerebral vasoconstriction during hypocapnia. However, it is unclear if a single session of hot HOWI alters cerebral artery shear rate and CVRCO2 to hyper- and hypocapnia. Purpose: We tested the hypotheses that during a single session of hot HOWI (39°C), cerebral artery shear rate and hypercapnic CVRCO2 would be greater and hypocapnic CVRCO2 would be lower compared to temperate HOWI (35°C). Methods: Eighteen healthy participants (age: 25±5 y, 6 women) completed two experimental visits. Middle and posterior cerebral artery blood velocities (transcranial Doppler; MCAv and PCAv) were continuously recorded. Blood velocities and diameters of the right internal carotid artery (ICA) and vertebral artery (VA) were obtained via dual-mode Doppler ultrasound to calculate shear rate. Hypocapnic and hypercapnic CVRCO2 were assessed in the MCA and PCA during self-paced hyperventilation (until PETCO2 decreased by 10 mmHg from baseline) and during 30 s of 7% CO2 inhalation, respectively. Measures were completed before immersion (PRE) and after a +1.0°C increase in core temperature during hot HOWI and time-matched during temperate HOWI. Data are reported as mean ± SD. Results: There were no differences between conditions at PRE. MCAv (55±9 vs. 64±12 cm/s; P=0.01) and PCAv (29±5 vs. 39±7 cm/s; p&lt;0.01) were lower in hot vs. temperate HOWI at +1.0°C. ICA shear rate was greater in hot vs. temperate HOWI at +1.0°C (247±51 vs. 180±43 s−1; p&lt;0.01) but VA shear rate did not differ between conditions (P=0.78). There were no differences between conditions for hypercapnic CVRCO2 (MCA: P =0.48, PCA: P=0.43) or hypocapnic CVRCO2 (MCA: P=0.18). A condition effect was observed for PCA hypocapnic CVRCO2 (p&lt;0.01), but multiple comparisons did not reveal where differences occurred (all P≥0.10). Conclusion: Hot head out water immersion elicits similar changes in hemodynamics and CVRCO2 in intracranial arteries (i.e., MCA and PCA) as temperate head out water immersion. Hot head out water immersion produces a greater shear rate in the ICA compared to temperate water, which may be beneficial for cerebrovascular health if done recurrently. This study was partially supported by the Mark Diamond Research Fund at the University at Buffalo and the Offce of Naval Research Director of Research Early Career Grant (N00014-17-1-2878). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of BNT162b2 mRNA Covid-19 vaccine on vascular function.

The effects of Covid-19 vaccines on vascular function are still controversial. We evaluated the effects of BNT162b2 vaccine (BioNTech and Pfizer) on endothelial function assessed by flow-mediated vasodilation (FMD) and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation (NID). This study was a prospective observational study. A total of 23 medical staff at Hiroshima University Hospital were enrolled in this study. FMD and NID were measured before vaccination and two weeks and six months after the 2nd dose of vaccination. FMD was significantly smaller two weeks after the 2nd dose of vaccination than before vaccination (6.5±2.4% and 8.2±2.6%, p = 0.03). FMD was significantly larger at six months than at two weeks after the 2nd dose of vaccination (8.2±3.0% and 6.5±2.4%, p = 0.03). There was no significant difference between FMD before vaccination and that at six months after the 2nd dose of vaccination (8.2±2.6% to 8.2±3.0%, p = 0.96). NID values were similar before vaccination and at two weeks, and six months after vaccination (p = 0.89). The BNT162b2 Covid-19 vaccine temporally impaired endothelial function but not vascular smooth muscle function, and the impaired endothelial function returned to the baseline level within six months after vaccination.

Long-acting cilostazol versus isosorbide mononitrate for patients with vasospastic angina: a randomized controlled trial.

Cilostazol has a vasodilatory function that may be beneficial for patients with vasospastic angina (VSA). We conducted a randomized, open-label, controlled trial to compare the efficacy and safety of long-acting cilostazol and isosorbide mononitrate (ISMN) for VSA. The study included patients with confirmed VSA between September 2019 and May 2021. Participants were randomly assigned to receive long-acting cilostazol (test group, 200 mg once daily) or conventional ISMN therapy (control group, 20 mg twice daily) for 4 weeks. The clinical efficacy and safety were evaluated using weekly questionnaires. Forty patients were enrolled in the study (long-acting cilostazol, n = 20; ISMN, n = 20). Baseline characteristics were balanced between the two groups. Long acting cilostazol showed better angina symptom control within the first week compared to ISMN [reduction of pain intensity score, 6.0 (4.0-8.0) vs. 4.0 (1.0-5.0), P = 0.005; frequency of angina symptom, 0 (0-2.0) vs. 2.0 (0-3.0), P = 0.027, respectively]. The rate of neurological adverse reactions was lower in the cilostazol group than in the ISMN group (headache or dizziness, 40 vs. 85%, P = 0.009; headache, 30 vs. 70%, P = 0.027). Long-acting cilostazol provided comparable control of angina and fewer adverse neurologic reactions within 4 weeks compared to ISMN. Long-acting cilostazol provides more intensive control of angina within 1 week, suggesting that it may be an initial choice for the treatment of VSA.

Improving Cerebrovascular Reactivity After Carotid Endarterectomy Is Not Accompanied by Improvement in Endothelial Vasodilator Function (P10-5.024)

Improving Cerebrovascular Reactivity After Carotid Endarterectomy Is Not Accompanied by Improvement in Endothelial Vasodilator Function (P10-5.024)

Role of Trimetazidine in Ameliorating Endothelial Dysfunction: A Review.

Endothelial dysfunction is a hallmark of cardiovascular diseases, contributing to impaired vasodilation, altered hemodynamics, and atherosclerosis progression. Trimetazidine, traditionally used for angina pectoris, exhibits diverse therapeutic effects on endothelial dysfunction. This review aims to elucidate the mechanisms underlying trimetazidine's actions and its potential as a therapeutic agent for endothelial dysfunction and associated cardiovascular disorders. Trimetazidine enhances vasodilation and hemodynamic function by modulating endothelial nitric oxide synthase activity, nitric oxide production, and endothelin-1. It also ameliorates metabolic parameters, including reducing blood glucose, mitigating oxidative stress, and dampening inflammation. Additionally, trimetazidine exerts antiatherosclerotic effects by inhibiting plaque formation and promoting its stability. Moreover, it regulates apoptosis and angiogenesis, fostering endothelial cell survival and neovascularization. Understanding trimetazidine's multifaceted mechanisms underscores its potential as a therapeutic agent for endothelial dysfunction and associated cardiovascular disorders, warranting further investigation for clinical translation.

Abstract P197: Dietary Quality Determined by Healthy Eating Index-2015 and Endothelial Function in Healthy Adults

The Healthy Eating Index (HEI) is a measure of diet quality based on Dietary Guidelines for Americans and developed in collaboration with the US Department of Health and Human Services and the US Department of Agriculture. Clinical interest in HEI has increased due to its association with obesity, inflammatory biomarkers and risk of coronary heart disease and stroke. Indeed, higher HEI-2015 score has been linked with reduced cardiovascular risk, morbidity, and mortality. Endothelial dysfunction, particularly impaired endothelium-dependent vasodilation, is a central etiological factor underlying cardiovascular risk and events. We and others have previously demonstrated that diets high in saturated fat and other proatherogenic diets are associated with endothelial vasodilator dysfunction. It is currently unknown whether HEI-2015 dietary score is associated with endothelial function. If so, assessing dietary quality based on HEI-2015 may provide targeted nutritional guidance for enhancing vascular health and mitigating cardiovascular risk. The aim of this study was to determine whether HEI-2015 score is associated with endothelial vasodilator function in healthy adults. Using data from 4-day dietary records, HEI-2015 scores were determined in 103 adults (65 M/38 F; age 44-68 years) free of overt cardiometabolic disease. The HEI-2015 score is based on 13 components summed to yield a total score from 0 to 100; higher score representing higher diet quality. The adults were stratified by HEI-2015 score quartiles: Q1: HEI &lt; 52.5 (n=25; 23 M/2 F); Q2: HEI 52.6-59.1 (n=26; 14 M/12 F); Q3: HEI 59.2-66.0 (n=26; 15 M/11 F); and Q4: HEI &gt; 66.0 (n=26; 13 M/13 F). Endothelium-dependent vasodilation was determined by forearm blood flow (FBF) (via plethysmography) responses to intra-arterial infusion of acetylcholine (ACh: 4.0, 8.0, and 16.0 μg/100 mL tissue/min) and sodium nitroprusside (NTP: 1.0, 2.0, and 4.0 μg/100 mL tissue/min). There were no significant differences in endothelium-dependent vasodilation across the HEI-2015 score quartiles. FBF blood responses to ACh were remarkably similar between Q1 (5.1±0.2 to 13.0±0.7 mL/100 mL tissue/min), Q2 (4.3±0.2 to 12.1±0.7 mL/100 mL tissue/min), Q3 (4.4±0.2 to 13.0±0.7 mL/100 mL tissue/min) and Q4 (4.5±0.2 to 14.4±0.6 mL/100 mL tissue/min). Moreover, HEI scores were not significantly associated with the vasodilator response to either ACh (r=0.15, P=0.13) or NTP (r=-0.04; P=0.72). In summary, although diet quality determined by HEI-2015 score has been shown to be associated with increased risk of cardiovascular disease and events, HEI-2015 was not associated endothelial function in mid-life and older adults. Given the established experimental and pathophysiological evidence linking between diet, endothelial vasodilator function and cardiovascular risk, HEI-2015 score is not a sensitive dietary indicator/biomarker of vascular function.