Tumor-Derived Exosomes Promote Tumor Growth Through Modulating Microvascular Hemodynamics in a Human Ovarian Cancer Xenograft Model.

OBJECTIVE: Abnormal tumor vascular network contributes to aberrant blood perfusion and reduced oxygenation in tumors, which lead to poor efficacy of chemotherapy and radiotherapy. We aimed to explore the effects of the tumor-derived exosomes (TDEs) and C188-9 (a small molecule inhibitor of signal transducer and activator of transcription 3, STAT3) on tumor microvascular hemodynamics and determine which blood flow oscillations for various frequency intervals are responsible for these changes. METHODS: Microvascular hemodynamics parameters were recorded using a PeriFlux 6000 EPOS system in tumor surface in a nude mouse subcutaneous xenograft model. Oscillations of laser Doppler flowmetry (LDF) signal were investigated by wavelet transform analysis. RESULTS: TDEs facilitated tumor growth at least partially was associated with increasing blood flow in smaller vessels with lower speed and decreasing the blood flow at larger vessels with higher speed. Lower oxyhemoglobin saturation (SO2) on tumor surface was aggravated by TDEs, and C188-9 treatment significantly alleviated this decrease. Wavelet transform spectral analysis revealed that TDEs increased the amplitude of oscillations in four frequency intervals related to endothelial (NO-dependent and -independent), myogenic and neurogenic activities, and C188-9 had no effect on this increase. CONCLUSIONS: TDEs facilitated tumor growth partially was associated with increasing blood flow in distributing vessels, reducing blood perfusion in larger vessels, and lowering SO2 on tumor surface. Enhanced vascular smooth muscle, endothelial and neurogenic activities occurred in tumor superficial zone.

Robust analysis of microcirculatory flowmotion during post-occlusive reactive hyperemia.

BACKGROUND: Flowmotion analysis of the microcirculatory blood flow is a method to extract information about the vessel regulatory function. It has previously shown promise when applied to measurements during a post-occlusive reactive hyperemia. However, the reperfusion peak and the following monotonic decline introduces false low frequencies that should not be interpreted as rhythmic vasomotion effect. AIM: To develop and validate a robust method for flowmotion analysis of post-occlusive reactive hyperemia signals. METHOD: The occlusion-induced reperfusion response contains a typical rapid increase followed by a monotonic decline to baseline. A mathematical model is proposed to detrend this transient part of the signal to enable further flowmotion analysis. The model is validated in 96 measurements on healthy volunteers. RESULTS: Applying the proposed model corrects the flowmotion signal without adding any substantial new false flowmotion components. CONCLUSION: Future studies should use the proposed method or equivalent when analyzing flowmotion during post-occlusive reactive hyperemia to ensure valid results.

Vasomotion heterogeneity and spectral characteristics in diabetic and hypertensive patients.

Vasomotion refers to the spontaneous oscillation of blood vessels within a frequency range of 0.01 to 1.6 Hz. Various disease states, including hypertension and diabetes, have been associated with alterations in vasomotion at the finger, indicating potential impairment of skin microcirculation. Due to the non-linear nature of human vasculature, the modification of vasomotion may vary across different locations for different diseases. In this study, Laser Doppler Flowmetry was used to measure blood flow motion at acupoints LU8, LU5, SP6, and PC3 among 49 participants with or without diabetes and/or hypertension. Fast Fourier Transformation was used to analyze noise type while Hilbert-Huang Transformation and wavelet analysis were applied to assess Signal Noise Ratio (SNR) results. Statistical analysis revealed that different acupoints exhibit distinct spectral characteristics of vasomotion not only among healthy individuals but also among patients with diabetes and/or hypertension. The results showed strong heterogeneity of vasomotion among blood vessels, indicating that the vasomotion measured at a certain point may not reflect the real status of microcirculation.

Vasomotion in human arteries and their regulations based on ion channel regulations: 10 years study.

Vasomotion is the oscillation of vascular tone which gives rise to flow motion of blood into an organ. As is well known, spontaneous contractile organs such as heart, GI, and genitourinary tract produce rhythmic contraction. It imposes or removes pressure on their vessels alternatively for exchange of many substances. It was first described over 150 years ago, however the physiological mechanism and pathophysiological implications are not well understood. This study aimed to elucidate underlying mechanisms and physiological function of vasomotion in human arteries. Conventional contractile force measurement, immunohistochemistry, and Western blot analysis were employed to study human left gastric artery (HLGA) and uterine arteries (HUA). RESULTS: Circular muscle of HLGA and/or HUA produced sustained tonic contraction by high K+ (50 mM) which was blocked by 2 µM nifedipine. Stepwise stretch and high K+ produced nerve-independent spontaneous contraction (vasomotion) (around 45% of tested tissues). Vasomotion was also produced by application of BayK 8644, 5-HT, prostagrandins, oxytocin. It was blocked by nifedipine (2 µM) and blockers of intracellular Ca2+ stores. Inhibitors of Ca2+ -activated Cl- channels (DIDS and/or niflumic acid) and ATP-sensitive K+ (KATP ) channels inhibited vasomotion reversibly. Metabolic inhibition by sodium cyanide (NaCN) and several neuropeptides also regulated vasomotion in KATP channel-sensitive and -insensitive manner. Finally, we identified TMEM16A Ca2+ -activated Cl- channels and subunits of KATP channels (Kir 6.1/6.2 and sulfonylurea receptor 2B [SUR2B]), and c-Kit positivity by Western blot analysis. We conclude that vasomotion is sensitive to TMEM16A Ca2+ -activated Cl- channels and metabolic changes in human gastric and uterine arteries. Vasomotion might play an important role in the regulation of microcirculation dynamics even in pacemaker-related autonomic contractile organs in humans.

Final 36-Month Outcomes from the Multicenter DynamX Study Evaluating a Novel Thin-Strut Novolimus-Eluting Coronary Bioadaptor System and Supporting Preclinical Data.

Background: The DynamX Novolimus-Eluting Coronary Bioadaptor System ( DynamX ® Bioadaptor) has uncaging elements that disengage after the resorption of the polymer coating, aiming to restore vessel function in the treated segment and to avoid long-term adverse outcomes associated with the permanent caging of the coronary artery seen with conventional stenting. Methods: This prospective, multicenter, single-arm first-in-human study enrolled 50 patients in Belgium and Italy who were treated with the DynamX Bioadaptor. Eligible patients had de novo lesions in coronary arteries measuring between 2.5 and 3.5 mm in diameter and ≤ 24 mm in length. Clinical follow-up was performed up to 36 months. This analysis includes the intention-to-treat population and is based on data available. The preclinical studies include optical coherence tomography (OCT) analyses of 5 DynamX Bioadaptors implanted in 3 mini Yucatan pigs (at 3, 12 and 24 months), and assessment of smooth muscle cell gene expression profile in 8 pigs of which each was implanted with the DynamX Bioadaptor and the Xience drug-eluting stent. To assess the gene expression profile by quantitative real-time polymerase chain reaction, animals were sacrificed at 3, 6, 9 and 12 months. Results: Target lesion failure at 36 months was 8.7% (4/46), consisting of one clinically-driven target lesion revascularization and 3 cardiac deaths (all site-reported to be unrelated to the device or procedure). There were no additional target vessel revascularization and no definite or probable scaffold thrombosis. Preclinical data confirmed late lumen enlargement (from 7.02 ± 1.31 mm 2 at baseline to 8.46 ± 1.31 mm 2 at 24 months) and identified an increased expression of contractile genes around 9 months compared to a conventional drug-eluting stent. Conclusions: The DynamX Bioadaptor demonstrated very good 36-month clinical outcomes, highlighted by the absence of target-vessel myocardial infarction and definite or probable device thrombosis, and only one target lesion revascularization up to 36 months. These data are supported by preclinical studies that showed late lumen enlargement by OCT and an increased expression of contractile genes around 9 months compared to conventional drug-eluting stents, indicating faster vessel healing. Larger clinical studies are necessary to compare outcomes against contemporary drug-eluting stents. Clinical Trial Registration: https://clinicaltrials.gov/: NCT03429894.

Spectral analysis of laser speckle contrast imaging and infrared thermography to assess skin microvascular reactive hyperemia.

BACKGROUND: Post-occlusive reactive hyperemia (PORH) test with signal spectral analysis coupled provides potential indicators for the assessment of microvascular functions. OBJECTIVE: The objective of this study is to investigate the variations of skin blood flow and temperature spectra in the PORH test. Furthermore, to quantify the oscillation amplitude response to occlusion within different frequency ranges. MATERIALS AND METHODS: Ten healthy volunteers participated in the PORH test and their hand skin temperature and blood flow images were captured by infrared thermography (IRT) and laser speckle contrast imaging (LSCI) system, respectively. Extracted signals from selected areas were then transformed into the time-frequency space by continuous wavelet transform for cross-correlation analysis and oscillation amplitude response comparisons. RESULTS: The LSCI and IRT signals extracted from fingertips showed stronger hyperemia response and larger oscillation amplitude compared with other areas, and their spectral cross-correlations decreased with frequency. According to statistical analysis, their oscillation amplitudes in the PORH stage were obviously larger than the baseline stage within endothelial, neurogenic, and myogenic frequency ranges (p < 0.05), and their quantitative indicators of oscillation amplitude response had high linear correlations within endothelial and neurogenic frequency ranges. CONCLUSION: Comparisons of IRT and LSCI techniques in recording the reaction to the PORH test were made in both temporal and spectral domains. The larger oscillation amplitudes suggested enhanced endothelial, neurogenic, and myogenic activities in the PORH test. We hope this study is also significant for investigations of response to the PORH test by other non-invasive techniques.

Lymphatic microcirculation profile in the progression of hypertension in spontaneously hypertensive rats.

OBJECTIVE: The contractile behavior of collecting lymphatic vessels occurs in essential hypertension in response to homeostasis, suggesting a possible role for microcirculation. We aimed to clarify the nature of the lymphatic microcirculation profile in spontaneously hypertensive rats (SHRs) and normotensive controls. METHODS: The vasomotion of collecting lymphatic vessels in eight- and thirteen-week-old SHRs and age-matched Wistar-Kyoto rats (WKYs, n = 4 per group) was visualized by intravital video and VasTrack. The lymphatic vasomotion profile (frequency and amplitude) and contractile parameters (contraction fraction and total contractility activity index) were compared. Plasma nitrite/nitrate levels were assessed by the Griess reaction, and plasma endothelin-1 was measured by enzyme-linked immunosorbent assay. RESULTS: WKYs and SHRs differed in the vasomotion of collecting lymphatic vessels. Both eight- and thirteen-week-old WKYs revealed a high-amplitude pumping pattern, whereas a low-amplitude pattern was observed in SHRs. Moreover, compared with age-matched WKYs, SHRs exhibited deteriorated output and reflux capability and lost the ability to regulate collecting lymphatic vasomotion. Additionally, the chemistry complements the microcirculatory lymphatic profile as demonstrated by an increase in plasma nitrite, nitrate, and endothelin-1 in SHRs. ET-1 inhibitor meliorated the lymphatic contractile capability in SHRs partially through regulating frequency of lymphatic vasomotion. CONCLUSIONS: We used an intravital lymphatic imaging system to observe that SHRs exhibit an impaired collecting lymphatic vasomotion profile and deteriorated contractility and reflux.

Vasomotion analysis of speed resolved perfusion, oxygen saturation, red blood cell tissue fraction, and vessel diameter: Novel microvascular perspectives.

BACKGROUND: Vasomotion is the spontaneous oscillation in vascular tone in the microcirculation and is believed to be a physiological mechanism facilitating the transport of blood gases and nutrients to and from tissues. So far, Laser Doppler flowmetry has constituted the gold standard for in vivo vasomotion analysis. MATERIALS AND METHODS: We applied vasomotion analysis to speed-resolved perfusion, oxygen saturation, red blood cell tissue (RBC) tissue fraction, and average vessel diameter from five healthy individuals at rest measured by the newly developed Periflux 6000 EPOS system over 10 minutes. Magnitude scalogram and the time-averaged wavelet spectra were divided into frequency intervals reflecting endothelial, neurogenic, myogenic, respiratory, and cardiac function. RESULTS: Recurrent high-intensity periods of the myogenic, neurogenic, and endothelial frequency intervals were found. The neurogenic activity was considerably more pronounced for the oxygen saturation, RBC tissue fraction, and vessel diameter signals, than for the perfusion signals. In a correlation analysis we found that changes in perfusion in the myogenic, neurogenic, and endothelial frequency intervals precede changes in the other signals. Furthermore, changes in average vessel diameter were in general negatively correlated to the other signals in the same frequency intervals, indicating the importance of capillary recruitment. CONCLUSION: We conclude that vasomotion can be observed in signals reflecting speed resolved perfusion, oxygen saturation, RBC tissue fraction, and vessel diameter. The new parameters enable new aspects of the microcirculation to be observed.

Vascular origins of low-frequency oscillations in the cerebrospinal fluid signal in resting-state fMRI: Interpretation using photoplethysmography.

In vivo mapping of cerebrovascular oscillations in the 0.05-0.15 Hz remains difficult. Oscillations in the cerebrospinal fluid (CSF) represent a possible avenue for noninvasively tracking these oscillations using resting-state functional MRI (rs-fMRI), and have been used to correct for vascular oscillations in rs-fMRI functional connectivity. However, the relationship between low-frequency CSF and vascular oscillations remains unclear. In this study, we investigate this relationship using fast simultaneous rs-fMRI and photoplethysmogram (PPG), examining the 0.1 Hz PPG signal, heart-rate variability (HRV), pulse-intensity ratio (PIR), and the second derivative of the PPG (SDPPG). The main findings of this study are: (a) signals in different CSF regions are not equivalent in their associations with vascular and tissue rs-fMRI signals; (b) the PPG signal is maximally coherent with the arterial and CSF signals at the cardiac frequency, but coherent with brain tissue at ~0.2 Hz; (c) PIR is maximally coherent with the CSF signal near 0.03 Hz; and (d) PPG-related vascular oscillations only contribute to ~15% of the CSF (and arterial) signal in rs-fMRI. These findings caution against averaging all CSF regions when extracting physiological nuisance regressors in rs-fMRI applications, and indicate the drivers of the CSF signal are more than simply cardiac. Our study is an initial attempt at the refinement and standardization of how the CSF signal in rs-fMRI can be used and interpreted. It also paves the way for using rs-fMRI in the CSF as a potential tool for tracking cerebrovascular health through, for instance, the potential relationship between PIR and the CSF signal.

Sensing of Microvascular Vasomotion Using Consumer Camera.

In this paper, we will introduce a method for observing microvascular waves (MVW) by extracting different images from the available images in the video taken with consumer cameras. Microvascular vasomotion is a dynamic phenomenon that can fluctuate over time for a variety of reasons and its sensing is used for variety of purposes. The special device, a side stream dark field camera (SDF camera) was developed in 2015 for the medical purpose to observe blood flow from above the epidermis. However, without using SDF cameras, smart signal processing can be combined with a consumer camera to analyze the global motion of microvascular vasomotion. MVW is a propagation pattern of microvascular vasomotions which reflects biological properties of vascular network. In addition, even without SDF cameras, MVW can be analyzed as a spatial and temporal pattern of microvascular vasomotion using a combination of advanced signal processing with consumer cameras. In this paper, we will demonstrate that such vascular movements and MVW can be observed using a consumer cameras. We also show a classification using it.

Hypoxic Conditions Promote Rhythmic Contractile Oscillations Mediated by Voltage-Gated Sodium Channels Activation in Human Arteries.

Arterial smooth muscle exhibits rhythmic oscillatory contractions called vasomotion and believed to be a protective mechanism against tissue hypoperfusion or hypoxia. Oscillations of vascular tone depend on voltage and follow oscillations of the membrane potential. Voltage-gated sodium channels (Nav), responsible for the initiation and propagation of action potentials in excitable cells, have also been evidenced both in animal and human vascular smooth muscle cells (SMCs). For example, they contribute to arterial contraction in rats, but their physiopathological relevance has not been established in human vessels. In the present study, we investigated the functional role of Nav in the human artery. Experiments were performed on human uterine arteries obtained after hysterectomy and on SMCs dissociated from these arteries. In SMCs, we recorded a tetrodotoxin (TTX)-sensitive and fast inactivating voltage-dependent INa current. Various Nav genes, encoding α-subunit isoforms sensitive (Nav 1.2; 1.3; 1.7) and resistant (Nav 1.5) to TTX, were detected both in arterial tissue and in SMCs. Nav channels immunostaining showed uniform distribution in SMCs and endothelial cells. On arterial tissue, we recorded variations of isometric tension, ex vivo, in response to various agonists and antagonists. In arterial rings placed under hypoxic conditions, the depolarizing agent KCl and veratridine, a specific Nav channels agonist, both induced a sustained contraction overlaid with rhythmic oscillations of tension. After suppression of sympathetic control either by blocking the release of catecholamine or by antagonizing the target adrenergic response, rhythmic activity persisted while the sustained contraction was abolished. This rhythmic activity of the arteries was suppressed by TTX but, in contrast, only attenuated by antagonists of calcium channels, Na+/Ca2+ exchanger, Na+/K+-ATPase and the cardiac Nav channel. These results highlight the role of Nav as a novel key element in the vasomotion of human arteries. Hypoxia promotes activation of Nav channels involved in the initiation of rhythmic oscillatory contractile activity.

Oscillations and concentration dynamics of brain tissue oxygen in neonates and adults.

The brain is a metabolically demanding organ and its health directly depends on brain oxygen dynamics to prevent hypoxia and ischemia. Localized brain tissue oxygen is characterized by a baseline level combined with spontaneous oscillations. These oscillations are attributed to spontaneous changes of vascular tone at the level of arterioles and their frequencies depend on age. Specifically, lower frequencies are more typical for neonates than for adults. We have built a mathematical model which analyses the diffusion abilities of oxygen based on the frequency of source brain oxygen oscillations and neuronal demand. We have found that a lower frequency of spontaneous oscillations of localized brain tissue oxygen can support higher amplitudes of oxygen concentration at areas distant from a source relative to oscillations at higher frequencies. Since hypoxia and ischemia are very common events during early development and the neurovascular unit is underdeveloped in neonates, our results indicate that lower frequency oxygen oscillations can represent an effective passive method of neonatal brain protection against hypoxia. These results can have a potential impact on future studies aiming to find new treatment strategies for brain ischemia.

Endothelin receptor A and p66Shc regulate spontaneous Ca2+ oscillations in smooth muscle cells controlling renal arterial spontaneous motion.

Adaptor protein p66Shc is overexpressed in smooth muscle cells of renal resistance vessels of hypertensive salt-sensitive rats and is involved in the regulation of renal vascular tone. We applied 2-photon laser scanning fluorescence microscopy to analyze spontaneous dynamic fluctuations in intracellular calcium concentrations ([Ca2+]i) in smooth muscle cells embedded in the walls of freshly isolated renal resistance arteries. The amplitude, number of events, and frequency of spontaneous [Ca2+]i oscillations triggered by endogenously released endothelin-1 were recorded in smooth muscle cells of the renal arteries. Endothelin receptor A antagonist BQ123 dramatically reduced the amplitude and frequency of spontaneous Ca2+ events, producing marked inhibition of renal vessels spontaneous motion. Spontaneous Ca2+ fluctuations in smooth muscle cells of p66Shc knockout (p66ShcKO) rats had significantly higher amplitude than in control rats. The frequency of spontaneous [Ca2+]i oscillations did not change in p66ShcKO rats, suggesting that p66Shc expression did not affect endothelin-1 release from resident endothelial cells. Acute application of endothelin-1 revealed significantly elevated production of the total [Ca2+]i in p66ShcKO rats. Spontaneous cytosolic Ca2+ oscillations in smooth muscle cells of renal vessels mediate their spontaneous motion via the endothelin-1/endothelin receptor A pathway. p66Shc decreases the amplitude of individual changes in [Ca2+]i, which mitigates the spontaneous motion of renal vessels.-Palygin, O., Miller, B. S., Nishijima, Y., Zhang, D. X., Staruschenko, A., Sorokin, A. Endothelin receptor A and p66Shc regulate spontaneous Ca2+ oscillations in smooth muscle cells controlling renal arterial spontaneous motion.

Synchronous vasomotion of skin microvessels at acupoints on the twelve main meridians of beagle dogs.

BACKGROUND/PURPOSE: Synchronous microvascular vasomotion was detected at acupoints in our previous human study. This present study aimed to characterize the skin microvascular vasomotion at acupoints on the twelve meridians of beagle dogs. MATERIALS AND METHODS: Two acupoints were selected on each meridian and exactly located at the rosy red spots by an electrochemical color-appearing method, where the electrical resistance was measured. The skin blood flow at acupoints was recorded by laser Doppler flowmetry (LDF), and microvascular vasomotion was analyzed according to LDF waveforms. RESULTS: The skin electrical resistance at acupoints was significantly lower than that at control non-acupoints. The LDF waveforms at acupoints were sinusoidal, which showed the synchronization of the microvascular vasomotion. The spectral analysis revealed that the vasomotion frequencies at acupoints on the same meridian were identical but not among different meridians, and the frequencies on the twelve main meridians displayed a constant order. CONCLUSION: The skin microvascular vasomotion is synchronous at acupoints of beagle dogs and has a specific frequency along the meridian, and the electrochemical color-appearing method is a feasible strategy for the precise and visual location of acupoints. The study provides evidence for the universality of synchronous vasomotion of skin microvessels at acupoints.

Effects of Psychological Stress on Vascular Physiology: Beyond the Current Imaging Signal.

PURPOSE OF REVIEW: This review describes the effects of psychological stress on the physiology of the entire vascular system, from individual cellular components to macrovascular and microvascular responses, and highlights the importance of the vascular system in the context of current limitations in cardiac imaging for evaluation of the cardiovascular response to mental stress. RECENT FINDINGS: The physiological responses that mediate vascular changes are based on evolutionary needs, but there is increasing evidence that the long-term consequences of psychological stress can precipitate the development and progression of cardiovascular disease (CVD). While there is an extensive body of literature describing localized physiological responses or overt cardiovascular manifestations, often framed within the organ-specific scope of cardiovascular imaging, there has not been a comprehensive description of the global vascular effects of psychological stress. Given the global nature of these processes, targeted cardiovascular imaging modalities may be insufficient. Here we approach the vascular response to mental stress systematically, describing the effects on the endothelium, vascular smooth muscle, and adventitia. We then address the mental stress effects on large vessels and the microvascular compartment, with a discussion of the role of microvascular resistance in the pathophysiology of mental stress-induced myocardial ischemia. Vascular responses to psychological stress involve complex physiological processes that are not fully characterized by routine cardiovascular imaging assessments. Future research incorporating standardized psychological assessments targeted toward vascular mechanisms of stress responses is required to guide the development of behavioral and therapeutic interventions.

Coronary vasomotion and exercise-induced adaptations in coronary artery disease patients: A systematic review and meta-analysis.

BACKGROUND: Exercise can improve coronary blood flow in a healthy heart, but the vascular response of patients with coronary artery disease (CAD) is different. The aim of this study was to systematically review the chronic effects of exercise on coronary arterial function in CAD patients. MATERIALS AND METHODS: Six electronic databases (PubMed, ScienceDirect, "Scopus," Web of Science, EMBASE, and Google Scholar) covering publications from 1986 to 2019 were systematically searched with related keywords. Studies were included if they investigated changes in blood flow and coronary artery diameter in response to chronic exercise training in patients with CAD. A total of 5421 studies were assessed for quality and outcomes, and finally five studies met criteria for inclusion. For metaanalysis, the results of the studies were pooled using the randomeffects model. The heterogeneity between the studies was checked using I 2 index. RESULTS: The total sample population consisted of 108 CAD patients. According to the findings of this study, coronary artery function in adaptation with exercise showed that a period of exercise leads to statistically significant improvement in coronary flow velocity reserve (z = 3.15, P = 0.002; standardized mean difference [SMD] =2.33, 95% confidence interval [CI]: 0.88-3.78) (containing six trials). In addition, vasodilatory response of coronary arteries in response to endothelium-independent vasodilator nitroglycerin was investigated in three studies (containing four trials). A meta-analysis showed that performing chronic aerobic exercises did not make a significant change in the endothelium-independent vasodilator (z = 0.83, P = 0.40; SMD = -0.36, 95% CI: -1.21-0.49). CONCLUSION: Based on the results of the present study, aerobic exercises improve the endothelial function of coronary arteries and thereby the vascular vasomotion function, while the results of this meta-analysis showed no change in arterial smooth muscle's function by chronic aerobic exercises. This study reflects the lack of high- and medium-quality reports about the chronic effects of anaerobic and resistance exercises and the various methods of aerobic exercise on cardiovascular function.

Stimulation history affects vasomotor responses in rat mesenteric arterioles.

Resistance vessels regulate blood flow by continuously adjusting activity of the wall smooth muscle cells. These cells integrate a variety of stimuli from blood, endothelium, autonomic nerves, and surrounding tissues. Each stimulus elicits an intracellular signaling cascade that eventually influences activation of the contractile machinery. The characteristic time scale of each cascade and the sharing of specific reactions between cascades provide for complex behavior when a vessel receives multiple stimuli. Here, we apply sequential stimulation with invariant concentrations of vasoconstrictor (norepinephrine/methoxamine) and vasodilator (SNAP/carbacol) to rat mesenteric vessels in the wire myograph to show that (1) time elapsed between addition of two vasoactive drugs and (2) the sequence of addition may significantly affect final force development. Furthermore, force oscillations (vasomotion) often appear upon norepinephrine administration. Using computational modeling in combination with nitric oxide (NO) inhibition/NO addition experiments, we show that (3) amplitude and number of oscillating vessels increase over time, (4) the ability of NO to induce vasomotion depends on whether it is applied before or after norepinephrine, and (5) emergence of vasomotion depends on the prior dynamical state of the system; in simulations, this phenomenon appears as "hysteresis." These findings underscore the time-dependent nature of vascular tone generation which must be considered when evaluating the vasomotor effects of multiple, simultaneous stimuli in vitro or in vivo.

Enhanced nitric oxide signaling amplifies vasorelaxation of human colon cancer feed arteries.

Inadequate perfusion of solid cancer tissue results in low local nutrient and oxygen levels and accumulation of acidic waste products. Previous investigations have focused primarily on tumor blood vessel architecture, and we lack information concerning functional differences between arteries that deliver blood to solid cancer tissue versus normal tissue. Here, we use isometric myography to study resistance-sized arteries from human primary colon adenocarcinomas and matched normal colon tissue. Vasocontraction of colon cancer feed arteries in response to endothelin-1 and thromboxane stimulation is attenuated compared with normal colon arteries despite similar wall dimensions and comparable contractions to arginine vasopressin and K+-induced depolarization. Acetylcholine-induced vasorelaxation and endothelial NO synthase expression are increased in colon cancer feed arteries compared with normal colon arteries, whereas vasorelaxation to exogenous NO donors is unaffected. In congruence, the differences in vasorelaxant and vasocontractile function between colon cancer feed arteries and normal colon arteries decrease after NO synthase inhibition. Rhythmic oscillations in vascular tone, known as vasomotion, are of lower amplitude but similar frequency in colon cancer feed arteries compared with normal colon arteries. In conclusion, higher NO synthase expression and elevated NO signaling amplify vasorelaxation and attenuate vasocontraction of human colon cancer feed arteries. We propose that enhanced endothelial function augments tumor perfusion and represents a potential therapeutic target. NEW & NOTEWORTHY Local vascular resistance influences tumor perfusion. Arteries supplying human colonic adenocarcinomas show enhanced vasorelaxation and reduced vasocontraction mainly due to elevated nitric oxide-mediated signaling. Rhythmic oscillations in tone, known as vasomotion, are attenuated in colon cancer feed arteries.

MAGnesium-based bioresorbable scaffold and vasomotor function in patients with acute ST segment elevation myocardial infarction: The MAGSTEMI trial: Rationale and design.

AIM: Use of a Bioresorbable Scaffolds (BRS) either in clinical practice or in the setting of an acute myocardial infarction (MI) is controversial. Despite an overall high rate of thrombosis, vascular healing response following BRS implantation tend to superiority as compared to metallic drug-eluting stent in ST-segment elevation myocardial infarction (STEMI) patients. We sought to compare the in-stent/scaffold vasomotion between metallic BRS and sirolimus eluting stent (SES) at 12-month angiographic follow-up in the setting of patients with STEMI treated by primary PCI. STUDY DESIGN: This is an investigator-driven, prospective, multicenter, randomized, single blind, two-arm, controlled trial (ClinicalTrials.gov number: NCT03234348). This trial will randomize ~148 patients 1:1 to SES or BRS. Primary end-point is the in-stent/scaffold change in mean lumen diameter after nitroglycerin administration at 12-month angiographic follow-up. Besides, patient-oriented combined endpoint of all-cause death, any MI, and any revascularization, together with scaffold/stent thrombosis rate and device-oriented endpoint of cardiac death, target vessel (TV)-MI and TVR at 1 year will be also evaluated. Clinical follow-up will be scheduled yearly up to 5 years. CONCLUSION: This trial will shed light on the vascular vasomotion following BRS implantation in the complex scenario of STEMI.

Autonomic control of cardiovascular adjustments associated with orthostasis in the scansorial snake Boa constrictor.

Orthostatic hypotension is a phenomenon triggered by a change in the position or posture of an animal, from a horizontal to a vertical head-up orientation, characterised by a blood pooling in the lower body and a reduction in central and cranial arterial blood pressure (PA). This hypotension elicits systemic vasoconstriction and tachycardia, which generally reduce blood pooling and increase PA Little is known about the mediation and importance of such cardiovascular adjustments that counteract the haemodynamic effects of orthostasis in ectothermic vertebrates, and some discrepancies exist in the information available on this subject. Thus, we sought to expand our knowledge on this issue by investigating it in a more elaborate way, through an in vivo pharmacological approach considering temporal circulatory changes during head-up body inclinations in unanaesthetised Boa constrictor To do so, we analysed temporal changes in PA, heart rate (fH) and cardiac autonomic tone associated with 30 and 60 deg inclinations, before and after muscarinic blockade with atropine, double blockade with atropine and propranolol, and α1-adrenergic receptor blockade with prazosin. Additionally, the animals' fH variability was analysed. The results revealed that, in B. constrictor: (1) the orthostatic tachycardia is initially mediated by a decrease in cholinergic tone followed by an increase in adrenergic tone, a pattern that may be evolutionarily conserved in vertebrates; (2) the orthostatic tachycardia is important for avoiding an intense decrease in PA at the beginning of body inclinations; and (3) α1-adrenergic orthostatic vasomotor responses are important for the maintenance of PA at satisfactory values during long-term inclinations.