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Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) repressively regulates protein translation through phosphorylating eEF2. We previously showed that expression and activity of eEF2K are increased in isolated mesenteric arteries from spontaneously hypertensive rats (SHR) contributing to development of essential hypertension. Furthermore, we have recently shown that 7-Amino-1-cyclopropyl-3-ethyl-1,2,3,4-tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine-6-carboxamide (A484954), a selective eEF2K inhibitor, induces endothelium-dependent relaxation in isolated mesenteric arteries from SHR inducing an antihypertensive effect. In order to test the hypothesis that inhibition of eEF2K activity induces vasodilatation by suppressing sympathetic nerve activity, we examined the effects of A484954 on perivascular sympathetic nerve stimulation-induced contraction in isolated renal artery from normotensive and hypertensive rats. Electrodes were placed near the isolated renal arteries that were applied with transmural nerve stimulation (TNS). Then, contraction of the arteries was isometrically measured. A484954 inhibited TNS-induced contraction. The A484954-mediated inhibition of TNS-induced contraction was significantly prevented by N G -nitro-L-arginine methyl ester. In SHR isolated renal artery, TNS-induced contraction was enhanced compared with normotensive Wistar rats. Furthermore, A484954-mediated inhibition of TNS-induced contraction in SHR was enhanced compared with Wistar rats. In conclusion, this study demonstrates for the first time that A484954 inhibits perivascular sympathetic nerve stimulation-induced vasoconstriction at least in part perhaps through nitric oxide (NO) release from NO-operating nerve., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Reflex cardiorespiratory alterations elicited after instillation of nociceptive agents intra-arterially (i.a) are termed as 'vasosensory reflex responses'. The present study was designed to evaluate such responses produced after i.a. instillation of histamine (1 mM; 10 mM; 100 mM) and to delineate the pathways i.e. the afferents and efferents mediating these responses. Blood pressure, electrocardiogram and respiratory excursions were recorded before and after injecting saline/histamine, in a local segment of femoral artery in urethane anesthetized rats. Paw edema and latencies of responses were also estimated. Separate groups of experiments were conducted to demonstrate the involvement of somatic nerves in mediating histamine-induced responses after ipsilateral femoral and sciatic nerve sectioning (+NX) and lignocaine pre-treatment (+Ligno). In addition, another set of experiments was performed after bilateral vagotomy (+VagX) and the responses after histamine instillation were studied. Histamine produced concentration-dependent hypotensive, bradycardiac, tachypnoeic and hyperventilatory responses of shorter latencies (2-7 s) favouring the neural mechanisms in eliciting the responses. Instillation of saline (time matched control) in a similar fashion produced no response, excluding the possibilities of ischemic/stretch effects. Paw edema was absent in both hind limbs indicating that the histamine did not reach the paws and did not spill out into the systemic circulation. +NX, +VagX, +Ligno attenuated histamine-induced cardiorespiratory responses significantly. These observations conclude that instillation of 10 mM of histamine produces optimal vasosensory reflex responses originating from the local vascular bed; afferents and efferents of which are mostly located in ipsilateral somatic and vagus nerves respectively., (© 2021. The Author(s).)

Background: Some studies have suggested that patients with diabetes and foot complications have worse cardiovascular and cerebrovascular risk profiles, higher degrees of endothelial dysfunction and arterial stiffness and a higher inflammatory background than patients with diabetes without diabetic foot complications. Patients with diabetes mellitus have an alteration in the sympathovagal balance as assessed by means of heart rate variability (HRV) analysis, which is also related to the presence of endothelial dysfunction. Other studies suggest a possible role of inflammation coexisting with the alteration in the sympathovagal balance in favor of the atherosclerotic process in a mixed population of healthy subjects of middle and advanced age., Aims: The aim of this study was to evaluate the degree of alteration of sympathovagal balance, assessed by HRV analysis, in a cohort of patients with diabetes mellitus with diabetic foot and in control subjects without diabetic foot compared with a population of healthy subjects and the possible correlation of HRV parameters with inflammatory markers and endothelial dysfunction indices., Methods: We enrolled all patients with diabetic ulcerative lesions of the lower limb in the Internal Medicine with Stroke Care ward and of the diabetic foot outpatient clinic of P. Giaccone University Hospital of Palermo between September 2019 and July 2020. 4-h ECG Holter was performed. The following time domain HRV measures were analyzed: average heart rate, square root of the mean of successive differences of NN (RMSSD), standard deviation or square root of the variance (SD), and standard deviation of the means of the NN intervals calculated over a five-minute period (SDANN/5 min). The LF/HF ratio was calculated, reactive hyperemia was evaluated by endo-PAT, and serum levels of vaspine and omentin-1 were assessed by blood sample collection., Results: 63 patients with diabetic foot, 30 patients with diabetes and without ulcerative complications and 30 patients without diabetes were enrolled. Patients with diabetic ulcers showed lower mean diastolic blood pressure values than healthy controls, lower MMSE scores corrected for age, lower serum levels of omentin-1, lower RHI values, higher body weight values and comparable body height values, HF% and LF/HF ratio values. We also reported a negative correlation between the RHI value and HRV indices and the expression of increased parasympathetic activity (RMSDD and HF%) in subjects with diabetic foot and a statistically significant positive correlation with the LF/HF ratio and the expression of the sympathovagal balance., Discussion: Patients with diabetic foot show a higher degree of activation of the parasympathetic system, expressed by the increase in HF values, and a lower LF/HF ratio. Our findings may corroborate the issue that a parasympathetic dysfunction may have a possible additive role in the pathogenesis of other vascular complications in subjects with diabetic foot., (© 2021. The Author(s).)

Zinc, an abundant transition metal, serves as a signalling molecule in several biological systems. Zinc transporters are genetically associated with cardiovascular diseases but the function of zinc in vascular tone regulation is unknown. We found that elevating cytoplasmic zinc using ionophores relaxed rat and human isolated blood vessels and caused hyperpolarization of smooth muscle membrane. Furthermore, zinc ionophores lowered blood pressure in anaesthetized rats and increased blood flow without affecting heart rate. Conversely, intracellular zinc chelation induced contraction of selected vessels from rats and humans and depolarized vascular smooth muscle membrane potential. We demonstrate three mechanisms for zinc-induced vasorelaxation: (1) activation of transient receptor potential ankyrin 1 to increase calcitonin gene-related peptide signalling from perivascular sensory nerves; (2) enhancement of cyclooxygenase-sensitive vasodilatory prostanoid signalling in the endothelium; and (3) inhibition of voltage-gated calcium channels in the smooth muscle. These data introduce zinc as a new target for vascular therapeutics.

Cerebral ischemic injury exhibits both high morbidity and mortality worldwide. Traditional research of the pathogenesis of cerebral ischemic injury has focused on separate analyses of the involved cell types. In recent years, the neurovascular unit (NVU) mechanism of cerebral ischemic injury has been proposed in modern medicine. Hence, more effective strategies for the treatment of cerebral ischemic injury may be provided through comprehensive analysis of brain cells and the extracellular matrix. However, recent studies that have investigated the function of the NVU in cerebral ischemic injury have been insufficient. In addition, the metabolism and energy conversion of the NVU depend on interactions among multiple cell types, which make it difficult to identify the unique contribution of each cell type. Therefore, in the present review, we comprehensively summarize the regulatory effects and recovery mechanisms of four major cell types (i.e., astrocytes, microglia, brain-microvascular endothelial cells, and neurons) in the NVU under cerebral ischemic injury, as well as discuss the interactions among these cell types in the NVU. Furthermore, we discuss the common signaling pathways and signaling factors that mediate cerebral ischemic injury in the NVU, which may help to provide a theoretical basis for the comprehensive elucidation of cerebral ischemic injury., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

New Findings: What is the topic of this review? This symposium report discusses the previously unrecognized pro-contractile role of chloride ions in rat arteries at early stages of postnatal development. What advances does it highlight? It highlights the postnatal decline in the contribution of chloride ions to regulation of arterial contractile responses and potential trophic role of sympathetic nerves in these developmental alterations., Abstract: Chloride ions are important for smooth muscle contraction in adult vasculature. Arterial smooth muscle undergoes structural and functional remodelling during early postnatal development, including changes in K + currents, Ca 2+ handling and sensitivity. However, developmental change in the contribution of Cl - to regulation of arterial contraction has not yet been explored. Here, we provide the first evidence that the role of Cl - in α 1 -adrenergic arterial contraction prominently decreases during early postnatal ontogenesis. The trophic influence of sympathetic nerves is a potential mechanism for postnatal decline of the contribution of Cl - to the vascular contraction., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Penile erection requires well-coordinated interactions between vascular and nervous systems. Penile neurovascular dysfunction is a major cause of erectile dysfunction (ED) in patients with diabetes, which causes poor response to oral phosphodiesterase-5 inhibitors. Dickkopf2 (DKK2), a Wnt antagonist, is known to promote angiogenesis. Here, using DKK2-Tg mice or DKK2 protein administration, we demonstrate that the overexpression of DKK2 in diabetic mice enhances penile angiogenesis and neural regeneration and restores erectile function. Transcriptome analysis revealed that angiopoietin-1 and angiopoietin-2 are target genes for DKK2. Using an endothelial cell-pericyte coculture system and ex vivo neurite sprouting assay, we found that DKK2-mediated juxtacrine signaling in pericyte-endothelial cell interactions promotes angiogenesis and neural regeneration through an angiopoietin-1-Tie2 pathway, rescuing erectile function in diabetic mice. The dual angiogenic and neurotrophic effects of DKK2, especially as a therapeutic protein, will open new avenues to treating diabetic ED., (© 2018 by the American Diabetes Association.)

Whether sympathetic withdrawal or endothelial dilators such as nitric oxide (NO) contributes to cold-induced vasodilation (CIVD) events is unclear. We measured blood flow and finger skin temperature (T finger ) of the index finger in nine participants during hand immersion in a water bath at 35 °C for 30 min, then at 8 °C for 30 min. Data were binned into 10 s averages for the entire 60 min protocol for laser-Doppler flux (LDF) and T finger . At baseline, T finger was 35.3 ± 0.2 °C and LDF was 227 ± 28 PU. During hand cooling, minimum T finger was 10.9 ± 0.4 °C and LDF was 15 ± 4 PU. All participants exhibited at least one CIVD event (T finger increase ≥ 1 °C), with a mean peak T finger 13.2 ± 0.8 °C and a corresponding peak LDF of 116 ± 34 PU. A Morlet mother wavelet was then used to perform wavelet analysis on the LDF signal, with frequency ranges of 0.005-0.01 Hz (endothelial NO-independent), 0.01-0.02 Hz (endothelial NO-dependent), and 0.02-0.05 Hz (neurogenic). The synchronicity of wavelet fluctuations with rising LDF coincident with CIVD events was then quantified using Auto-regressive Integrated Moving Average time-series analysis. Fluctuations in neural activity were strongly synchronized in real time with increasing LDF (stationary-r 2  = 0.73 and Ljung-box statistic > 0.05), while endothelial activities were only moderately synchronized (NO-independent r 2  = 0.15, > 0.05; NO dependent r 2  = 0.16, > 0.05). We conclude that there is a direct, real-time correlation of LDF responses with neural activity but not endothelial-mediated mechanisms. Importantly, it seems that neural activity is consistently reduced prior to CIVD, suggesting that sympathetic withdrawal directly contributes to CIVD onset.

Electrical dynamics of freshly isolated cerebral endothelium have not been determined independently of perivascular nerves and smooth muscle. We tested the hypothesis that endothelium of cerebral and skeletal muscle arteries differentially utilizes purinergic and muscarinic signaling pathways to activate endothelium-derived hyperpolarization. Changes in membrane potential ( V m ) were recorded in intact endothelial tubes freshly isolated from posterior cerebral and superior epigastric arteries of male and female C57BL/6 mice (age: 3-8 months). V m was measured in response to activation of purinergic (P2Y) and muscarinic (M 3 ) receptors in addition to small- and intermediate-conductance Ca 2+ -activated K + (SK C a /IK C a ) and inward rectifying K + (K IR ) channels using ATP (100 μmol·L -1 ), acetylcholine (ACh; 10 μmol·L -1 ), NS309 (0.01-10 μmol·L -1 ), and 15 mmol·L -1 KCl, respectively. Intercellular coupling was demonstrated via transfer of propidium iodide dye and electrical current (±0.5-3 nA) through gap junctions. With similarities observed across gender, peak hyperpolarization to ATP and ACh in skeletal muscle endothelial tubes was ~twofold and ~sevenfold higher, respectively, vs cerebral endothelial tubes, whereas responses to NS309 were similar (from resting V m ~-30 mV to maximum ~-80 mV). Hyperpolarization (~8 mV) occurred during 15 mmol·L -1 KCl treatment in cerebral but not skeletal muscle endothelial tubes. Despite weaker hyperpolarization during endothelial GPCR stimulation in cerebral vs skeletal muscle endothelium, the capability for robust SK C a /IK C a activity is preserved across brain and skeletal muscle. As vascular reactivity decreases with aging and cardiovascular disease, endothelial K + channel activity may be calibrated to restore blood flow to respective organs regardless of gender.

Sympathetic hyperactivation, a common feature of obesity and metabolic syndrome, is a key trigger of hypertension. However, some obese subjects with autonomic imbalance present a dissociation between sympathetic activity-mediated vasoconstriction and increased blood pressure. Here, we aimed to determine in a rat model of metabolic syndrome whether the endothelium endothelial nitric oxide (NO) synthase (eNOS)-NO pathway contributes to counteract the vasopressor effect of the sympathetic system. Rats were fed a high-fat and high-sucrose (HFS) diet for 15 wk. Sympathovagal balance was evaluated by spectral analysis of heart rate variability and plasmatic catecholamine measurements. Blood pressure was measured in the presence or absence of N-nitro-l-arginine methyl ester (l-NAME) to inhibit the contribution of eNOS. Vascular reactivity was assessed on isolated aortic rings in response to α 1 -adrenergic agonist. The HFS diet increased sympathetic tone, which is characterized by a higher low on the high-frequency spectral power ratio and a higher plasmatic concentration of epinephrine. Despite this, no change in blood pressure was observed. Interestingly, HFS rats exhibited vascular hyporeactivity (-23.6%) to α 1 -adrenergic receptor stimulation that was abolished by endothelial removal or eNOS inhibition (l-NAME). In addition, eNOS phosphorylation (Ser 1177 ) was increased in response to phenylephrine in HFS rats only. Accordingly, eNOS inhibition in vivo revealed higher blood pressure in HFS rats compared with control rats (147 vs. 126 mmHg for mean blood pressure, respectively). Restrain of adrenergic vasopressor action by endothelium eNOS is increased in HFS rats and contributes to maintained blood pressure in the physiological range. NEW & NOTEWORTHY Despite the fact that prohypertensive sympathetic nervous system activity is markedly increased in rats with early metabolic syndrome, they present with normal blood pressure. These observations appear to be explained by increased endothelial nitric oxide synthase response to adrenergic stimulation, which results in vascular hyporeactivity to α-adrenergic stimulation, and therefore blood pressure is preserved in the physiological range. Listen to this article's corresponding podcast at http://www.physiology.org/doi/10.1152/ajpheart.00217.2017 .

Background: Impairments in macrovascular, microvascular and autonomic function are present in asymptomatic youths with clustered cardiovascular disease risk factors. This study determines the within-day reliability and between-day reliability of a single protocol to non-invasively assess these outcomes in adolescents., Methods: Forty 12- to 15-year-old adolescents (20 boys) visited the laboratory in a fasted state on two occasions, approximately 1 week apart. One hour after a standardized cereal breakfast, macrovascular function was determined via flow-mediated dilation (FMD). Heart rate variability (root mean square of successive R-R intervals; RMSSD) was determined from the ECG-gated ultrasound images acquired during the FMD protocol prior to cuff occlusion. Microvascular function was simultaneously quantified as the peak (PRH) and total (TRH) hyperaemic response to occlusion in the cutaneous circulation of the forearm via laser Doppler imaging. To address within-day reliability, a subset of twenty adolescents (10 boys) repeated these measures 90 min afterwards on one occasion., Results: The within-day typical error and between-day typical error expressed as a coefficient of variation of these outcomes are as follows: ratio-scaled FMD, 5·1% and 10·6%; allometrically scaled FMD, 4·4% and 9·4%; PRH, 11% and 13·3%; TRH, 29·9% and 23·1%; and RMSSD, 17·6% and 17·6%. The within- and between-day test-retest correlation coefficients for these outcomes were all significant (r > 0·54 for all)., Conclusion: Macrovascular, microvascular and autonomic functions can be simultaneously and non-invasively determined in adolescents using a single protocol with an appropriate degree of reproducibility. Determining these outcomes may provide greater understanding of the progression of cardiovascular disease and aid early intervention., (© 2016 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Background: Sleep-disordered breathing (SDB) after acute ischemic stroke is frequent and may be linked to stroke-induced autonomic imbalance. In the present study, the interaction between SDB and peripheral endothelial dysfunction (ED) was investigated in patients with acute ischemic stroke and at 1-year follow-up., Methods and Results: SDB was assessed by transthoracic impedance records in 101 patients with acute ischemic stroke (mean age, 69 years; 61% men; median National Institutes of Health Stroke Scale, 4) while being on the stroke unit. SDB was defined by apnea-hypopnea index ≥5 episodes per hour. Peripheral endothelial function was assessed using peripheral arterial tonometry (EndoPAT-2000). ED was defined by reactive hyperemia index ≤1.8. Forty-one stroke patients underwent 1-year follow-up (390±24 days) after stroke. SDB was observed in 57% patients with acute ischemic stroke. Compared with patients without SDB, ED was more prevalent in patients with SDB (32% versus 64%; P <0.01). After adjustment for multiple confounders, presence of SDB remained independently associated with ED (odds ratio, 3.1; [95% confidence interval, 1.2-7.9]; P <0.05). After 1 year, the prevalence of SDB decreased from 59% to 15% ( P <0.001). Interestingly, peripheral endothelial function improved in stroke patients with normalized SDB, compared with patients with persisting SDB ( P <0.05)., Conclusions: SDB was present in more than half of all patients with acute ischemic stroke and was independently associated with peripheral ED. Normalized ED in patients with normalized breathing pattern 1 year after stroke suggests a mechanistic link between SDB and ED., Clinical Trial Registration: URL: https://drks-neu.uniklinik-freiburg.de. Unique identifier: DRKS00000514., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

We evaluated the endothelial function of patients with Buerger disease using peripheral arterial tonometry test, and examined the factors that are significantly correlated with the endothelial dysfunction in these patients. We performed the peripheral arterial tonometry test in 22 patients with Buerger disease. We recorded the patients' characteristics, including ankle brachial pressure index and reactive hyperemia index, which reflect the endothelial dysfunction. We divided the patients with Buerger disease into the conservative treatment and lumbar sympathectomy group. While the reactive hyperemia index was not significantly different between these two groups, the ankle brachial pressure index was significantly different (1.12 versus 0.83, P =0.003). Furthermore, the reactive hyperemia index was significantly correlated with the ankle brachial pressure index value in the patients in the lumbar sympathectomy group ( ρ =0.848, P =0.005). Given that patients with Buerger disease show impairment of the sympathetic nervous system, we should consider the after-effects of such an impaired system on the condition of these patients. The patients treated with lumbar sympathectomy might be more appropriate to evaluate their endothelial function by a peripheral arterial tonometry test., Competing Interests: Disclosure This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors report no conflicts of interest in this work.

Objective: Angiotensin II (AngII) has been shown to regulate angiogenesis and at high pathophysiological doses to cause vasoconstriction through the AngII receptor type 1. Angiotensin 1 to 7 (Ang-(1-7)) acting through the Mas1 receptor can act antagonistically to high pathophysiological levels of AngII by inducing vasodilation, whereas the effects of Ang-(1-7) signaling on angiogenesis are less defined. To complicate the matter, there is growing evidence that a subpressor dose of AngII produces phenotypes similar to Ang-(1-7)., Approach and Results: This study shows that low-dose Ang-(1-7), acting through the Mas1 receptor, promotes angiogenesis and vasodilation similar to a low, subpressor dose of AngII acting through AngII receptor type 1. In addition, we show through in vitro tube formation that Ang-(1-7) augments the angiogenic response in rat microvascular endothelial cells. Using proteomic and genomic analyses, downstream components of Mas1 receptor signaling were identified, including Rho family of GTPases, phosphatidylinositol 3-kinase, protein kinase D1, mitogen-activated protein kinase, and extracellular signal-related kinase signaling. Further experimental antagonism of extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinase signaling inhibited endothelial tube formation and vasodilation when stimulated with equimolar, low doses of either AngII or Ang-(1-7)., Conclusions: These results significantly expand the known Ang-(1-7)/Mas1 receptor signaling pathway and demonstrate an important distinction between the pathological effects of elevated and suppressed AngII compared with the beneficial effects of AngII normalization and Ang-(1-7) administration. The observed convergence of Ang-(1-7)/Mas1 and AngII/AngII receptor type 1 signaling at low ligand concentrations suggests a nuanced regulation in vasculature. These data also reinforce the importance of mitogen-activated protein kinase/extracellular signal-related kinase signaling in maintaining vascular function., (© 2017 American Heart Association, Inc.)

Background: Takotsubo syndrome (TTS) is an acute cardiomyopathy associated with intense physical or emotional stress. The precise mechanisms of the disease remain unclear. The aim of this study was to study alterations in endothelial function, vascular compliance and structure and muscle sympathetic activity in the stable phase of the disease., Methods: In this prospective observational study, patients with TTS and controls matched for age, sex, cardiovascular risk factors and medications were recruited. Flow-mediated vasodilatation (FMD) as a measure of endothelial dysfunction was the primary endpoint. Secondary endpoints included measurements of arterial stiffness, carotid atherosclerosis, quality of life and laboratory parameters. In a subset of patients, muscle sympathetic activity was measured before and after stress tests., Results: The study included 22 TTS patients and 21 matched controls. A significant increase in endothelial dysfunction was seen in TTS compared to controls (FMD 3.4±2.4% vs. 4.8±1.9%, p=0.016). No significant differences in arterial stiffness, intima-media thickness, quality of life and laboratory markers including endothelin-1 were noted. TTS patients showed a reduced carotid total plaque area compared to controls (TPA 17.3±15.1 vs 24.7±12.8mm 2 , p=0.02). A trend of increased muscle sympathetic activity at rest was observed in TTS patients vs. controls (53.5±28.4 vs. 29.4±16.5 bursts/100 heart beats, p=0.09) with no significant differences in muscle sympathetic activity in response to stress., Conclusions: Our findings underscore the importance of endothelial dysfunction in patients with TTS which may be involved in the pathophysiology of this syndrome. CLINICALTRIALS., Gov Identifier: NCT01249599., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Rationale: Arterial endothelial cells are morphologically, functionally, and molecularly distinct from those found in veins and lymphatic vessels. How arterial fate is acquired during development and maintained in adult vessels is incompletely understood., Objective: We set out to identify factors that promote arterial endothelial cell fate in vivo., Methods and Results: We developed a functional assay, allowing us to monitor and manipulate arterial fate in vivo, using arteries isolated from quails that are grafted into the coelom of chick embryos. Endothelial cells migrate out from the grafted artery, and their colonization of host arteries and veins is quantified. Here we show that sympathetic innervation promotes arterial endothelial cell fate in vivo. Removal of sympathetic nerves decreases arterial fate and leads to colonization of veins, whereas exposure to sympathetic nerves or norepinephrine imposes arterial fate. Mechanistically, sympathetic nerves increase endothelial ERK (extracellular signal-regulated kinase) activity via adrenergic α1 and α2 receptors., Conclusions: These findings show that sympathetic innervation promotes arterial endothelial fate and may lead to novel approaches to improve arterialization in human disease., (© 2016 American Heart Association, Inc.)

Vagus nerve stimulation (VNS), a method for activating cholinergic anti-inflammatory pathways, could suppress endothelial activation and minimize tissue injury during inflammation. The aim of this study was to investigate the effects of chronic VNS on endothelial impairments and the inflammatory profile in ovariectomized (OVX) rats. Sprague-Dawley rats (7-8 months old) were randomly assigned to the following four groups: sham-OVX, OVX, OVX+sham-VNS, and OVX+VNS. Throughout the experimental period, the OVX+VNS group received VNS for 3h (20.0 Hz, 1.0 mA, and 10.00 ms pulse width) at the same time every other day. After 12 weeks of VNS, blood samples and thoracic aortas were collected for further analyses. Light microscopy and electron microscopy analyses showed that chronic VNS prevented endothelial swelling, desquamation and even necrosis in the OVX rats. In addition, it obviously improved endothelial function in the OVX rats by restoring the endothelial nitric oxide synthase (e-NOS) and serum endothelin-1 level. Increased expression of cell adhesion molecules (VCAM-1, ICAM-1 and E-selectin) in the thoracic aortas and increases in the levels of circulating cytokines (TNF-α, IL-6, MCP-1, and CINC/KC) were also observed in the OVX rats. Chronic VNS significantly restored these detrimental changes partly by increasing the ACh concentrations in vascular walls and blocking NF-κB pathway activity. The results of this in vivo study have shown that the administration of chronic VNS during, in the early stage of estrogen deficiency, protects OVX rats from endothelial impairments and the inflammatory profile. These findings indicate that activation of the vagus nerve could be a promising supplemental therapy for reducing the risks of suffering from further CVDs in postmenopausal women., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Metabolic activity of cells within a neurovascular unit is among the factors determining structural and functional integritY of the blood-brain barrier and the an- giogenesis process. in order to verify the hypothesis about the role Of g1YcolYtic activity in the perivascula astroglialcells associated with lactate release in the development of functioning of cerebral microvessel endothelial cells, we have used a three-component model of the brain neurovascular unit in vitro. The cells o f n o n -en d o th elia l o rig in w ere in c u b a te d in th e p rese n ce o f m o d u la to rs o f la c ta te pro d u c n ago ni glu c ose ta a G ly c o s o) , bas t h e oe t a n t a at- blocker of monocarboxylate transporters MCTlprCT and recepltiors of3Ctate0produasan (2-donisyoflactate G e8 breceptor) Iasa estbishe vthat that te suppression of lactate production and transport, prdc o1,adrcpin(C-O-Aa n (2gdoxysgflucoase as a glycolysis inhibitor), transport (phloretin as a sukr of lacaroduto transport , aswellasastimultionof3lactate receptors in astroglial cells, lead to aberrant development of endothelial layer, ther by u g g e tin t h efor atio o f anti ngi gencmi roen ircm ent for cerebral endothelium due to inappropriate lactate-m ediated effects. KeYw.ords:-n-eur-ovascular unit; metabolism; glYcolysis; lactate.

We studied the vascular endothelial vasomotor function in healthy young individuals, depending on the type of character accentuation, levels of neuroticism, depression and anxiety. It is shown that the types of character accentuation effect on endothelial vasomotor function in healthy men and women. Personality characteristics of a person can be a significant risk factor for disease, the pathogenesis of which is the starting element of endothelial vasomotor dysfunction.

The review analyzws the literature on the pathological alterations of endothelium, smooth muscle and vasomotor innervation of arterial vessels in animal modes of type 1 diabetes mellitus. Particular attention is paid t the analysis of mechanisms of diabetic abnormalities in the light of modern knowledge on the functioning of the main components of the vascular wall.

Objective: The aim of present study was to test the hypothesis that activation of receptor for advanced glycation end products (RAGE) pathway contributes to aortic remodeling and endothelial dysfunction in sinoaortic denervated (SAD) rats., Methods and Results: Experiment 1: 8 weeks after sinoaortic denervation, aortas were removed for measurement of AGE/RAGE pathway. Sinoaortic denervation in rats resulted in enhanced activity of aldose reductase, reduced activity of glyoxalase 1, accumulation of methylglyoxal and AGE, and upregulated expression of RAGE in aortas. Experiment 2: 5 weeks after sinoaortic denervation, the rats received intraperitoneal injections of 500 μg soluble RAGE (sRAGE) daily for 3 weeks. Treatment of SAD rats with sRAGE attenuated aortic remodeling, marked by reduction in AW/length, wall thickness, proliferation of SMC, and collagen deposition, and improvement of endothelial function. Treatment of SAD rats with sRAGE abated aortic oxidative stress, marked by reduction in formation of malondialdehyde, reactive oxygen species, superoxide, peroxynitrite and 3-nitrotyrosine, and enhancement of ratio of GSH/GSSG. Treatment of SAD rats with sRAGE attenuated aortic mitochondrial dysfunction. Treatment of SAD rats with sRAGE suppressed aortic NFκB nuclear translocation and inflammation. Treatment of SAD rats with sRAGE restored aortic NO formation through upregulating eNOS and dimethylarginine dimethylaminohydrolase-2 and downregulating protein arginine methyltransferase-1., Conclusion: Activated RAGE contributed to aortic remodeling and endothelial dysfunction in SAD rats, possibly via induction of oxidative stress and inflammation, impairment of mitochondrial function, and reduction in NO bioavailability., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Systemic microvascular complications are related to the presence of diabetic neuropathy. This study investigated the associations of blood flow oscillations with peripheral neuropathy in 25 controls and 3 diabetic groups including clinical (24), subclinical (27) and without neuropathy (26). Laser Doppler skin perfusion was transformed into three low-frequency subintervals corresponding to endothelial, neurogenic and myogenic vasomotor controls. The average vasomotion was significantly reduced in clinical neuropathy group and characterized by endothelial and neural but not smooth muscle-related changes. The normalized spectrums revealed a relative increase of myogenic and decrease of neurogenic activity in subclinical neuropathy group. The myogenic component showed a statistically inverse correlation with postural fall in systolic blood pressure (r = -0.32, p < 0.01). The diabetic patients with decreased low-frequency vasomotor responses were associated with increased odds ratio of peripheral neuropathy [odds ratio = 3.51 (95% confidence interval = 1.19-10.31), p = 0.02]. This study elucidated possible interaction between impaired microvascular flow motion and diabetic peripheral neuropathy. The vasomotor changes of skin microcirculation could be detected even in the absence of overt cardiovascular dysfunction.

Introduction.  Low-energy shockwave therapy (LESWT) has been shown to improve erectile function in patients suffering from diabetes mellitus (DM)-associated erectile dysfunction (ED). However, the underlying mechanism remains unknown. Aim.  The aim of this study is to investigate whether LESWT can ameliorate DM-associated ED in a rat model and examine the associated changes in the erectile tissues. Methods.  Newborn male rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine (EdU; 50 mg/kg) for the purpose of tracking endogenous mesenchymal stem cells (MSCs). Eight weeks later, eight of these rats were randomly chosen to serve as normal control (N group). The remaining rats were injected intraperitoneally with 60 mg/kg of streptozotocin (STZ) to induce DM. Eight of these rats were randomly chosen to serve as DM control (DM group), whereas another eight rats were subject to shockwave (SW) treatment (DM+SW group). Each rat in the DM+SW group received 300 shocks at energy level of 0.1 mJ/mm(2) and frequency of 120/minute. This procedure was repeated three times a week for 2 weeks. Another 2 weeks later, all 24 rats were evaluated for erectile function by intracavernous pressure (ICP) measurement. Afterward, their penile tissues were examined by histology. Main Outcome Measures.  Erectile function was measured by ICP. Neuronal nitric oxide synthase (nNOS)-positive nerves and the endothelium were examined by immunofluorescence staining. Smooth muscle and MSCs were examined by phalloidin and EdU staining, respectively. Results.  STZ treatment caused a significant decrease in erectile function and in the number of nNOS-positive nerves and in endothelial and smooth muscle contents. These DM-associated deficits were all partially but significantly reversed by LESWT. MSCs (EdU-positive cells) were significantly more numerous in DM+SW than in DM rats. Conclusion.  LESWT can partially ameliorate DM-associated ED by promoting regeneration of nNOS-positive nerves, endothelium, and smooth muscle in the penis. These beneficial effects appear to be mediated by recruitment of endogenous MSCs. Qiu X, Lin G, Xin Z, Ferretti L, Zhang H, Lue TF, and Lin C-S. Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model. J Sex Med 2013;10:738-746., (© 2012 International Society for Sexual Medicine.)

In order to study the mechanisms of development of pathological changes in children living in contaminated areas and chronically exposed to radionuclides as a result of exposure through the food chain, studied the vegetative homeostasis and thermographic study endothelium-dependent vascular reactions with occlusive tests. Showed signs of dysregulation of the autonomic nervous system dysfunction, the secretory activity of the endothelium and increased secretion of substances endothelial origin.

The role of endothelial and neural factors as modulators of neurogenic- and noradrenaline-induced vasoconstriction was examined in healthy pig internal mammary artery (IMA). Tetrodotoxin-, guanethidine-sensitive electrical field stimulation (EFS)-, and noradrenaline-elicited contractions were significantly diminished by prazosin (n=8, P<0.001) and less so by rauwolscine, indicating functional α₁- and α₂-adrenoceptor-mediated noradrenergic innervation of the IMA. Endothelium removal reduced neurogenic (n=8, P<0.01) but augmented noradrenaline responses (n=8, P<0.01), suggesting the release of two endothelium-dependent factors with opposite effects. In the presence of endothelium, neurogenic and exogenous noradrenaline vasoconstrictions were enhanced by L-NOArg (n=7, P<0.05 and P<0.01 respectively) and ODQ (n=7, both P<0.05); in denuded arteries, nNOS inhibition with N(ω)-propyl-L-arginine increased neurogenic contraction (n=7, P<0.05). Western blotting indicated the presence of neural and endothelial origin NO (n=6, P<0.001). Tetraethylammonium (n=9, P<0.001), iberiotoxin (n=7, P<0.001) and 4-aminopyridine (n=8, P<0.01) enhanced vasoconstrictions revealing a modulatory role of big conductance Ca²⁺-activated K⁺ (BK(Ca)) and voltage-dependent K⁺ (K(v)) channels in noradrenergic responses. Bosentan pretreatment (n=8, P<0.05) suggested endothelin-1 as the inferred contractile neurogenic endothelial-dependent factor. Indomethacin-induced inhibition involved a muscular prostanoid (n=9, P<0.05), functionally and immunologically localized, and derived from cyclooxygenase (COX)-1 and COX-2, as revealed by Western blots (n=5, P=0.1267). Thus, noradrenergic IMA contractions are controlled by contractile prostanoid activation and endothelin-1 release, and offset by BK(Ca) and K(v) channels and neural and endothelial NO. These results help clarify the mechanisms of vasospasm in IMA, as the preferred vessel for coronary bypass., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In patients with spinal cord injury (SCI), somatosympathetic reflexes produce exaggerated decreases in skin blood flow below the lesion. This hypoperfusion appears to result from an increased responsiveness of cutaneous arterial vessels to neural activation. Here we investigated the mechanisms that underlie SCI-induced enhancement of neurovascular transmission in a cutaneous vessel, the rat tail artery. Isometric contractions of arterial segments from T11 spinal cord transected and sham-operated rats were compared 6 wk postoperatively. SCI more than doubled the amplitudes of contractions of arteries in response to moderate frequencies of nerve stimulation (0.1 to 1 Hz). In arteries from SCI rats, but not those from sham-operated rats, the L-type Ca(2+) channel blocker nifedipine (1 μM) reduced the amplitudes of nerve-evoked contractions. Furthermore, while the sensitivity to the agonists phenylephrine (α(1)-adrenoceptor selective) and clonidine (α(2)-adrenoceptor selective) did not differ significantly between arteries from SCI and sham-operated rats, nifedipine had a greater inhibitory effect on contractions to both agents in arteries from SCI rats. Although sensitivity to clonidine was unchanged, SCI selectively reduced the contribution of postjunctional α(2)-adenceptors to nerve-evoked contractions. In arteries from unoperated rats, the L-type channel agonist BAY K 8644 (0.1 μM) produced a similar enhancement of nerve-evoked contraction to that produced by SCI and also selectively reduced the contribution of α(2)-adrenceptors to these responses. Together the findings demonstrate that the SCI-induced enhancement of neurovascular transmission in the rat tail artery can largely be accounted for by an increased contribution of L-type Ca(2+) channels to activation of the vascular smooth muscle.

The pulmonary vasculature is innervated by specific subsets of sympathetic, parasympathetic, and sensory nerve fibers. In contrast to most other organs, innervation density is highest at large-caliber vessels and decreases toward the periphery, and reactivity to vasoactive compounds also changes along the course. In some species, such as the experimentally widely used rodents rat and mouse, autonomic efferent (sympathetic and parasympathetic) perivascular axons barely reach beyond the lung hilus, whereas in humans this innervation extends to small intrapulmonary vessels. Throughout, the most distal arterioles (i.e., intraacinar arteries equipped with an incomplete coat of intermediate cells instead of a full muscular wall) are devoid of innervation. Altogether, 10 vasoactive substances (3 small molecular transmitters and 7 neuropeptides) at minimum have been identified in various combinations (cotransmission) in pulmonary vascular axons. Analysis of this "neurochemical coding" has been provided only for the guinea pig so far, but not for humans or for animal species commonly used for pulmonary vascular research. Sympathetic pulmonary vascular neurons are reflexively activated via arterial chemoreceptors when arterial Po(2) is lowered and adapt the pulmonary vasculature to this condition of increased pulmonary blood flow by α(1)-adrenoreceptor-mediated increase in vascular impedance primarily at large vessels. In contrast, neither they nor other nerve fibers play a role in the local hypoxic vasoconstriction triggered by low alveolar Po(2), which serves to match perfusion to ventilation. The major potential role of the pulmonary vascular innervation, autonomic and sensory, lies in the pronounced trophic activities of its transmitters.

The influence of the sympathetic nervous system (SNS) upon vascular resistance is more profound in muscles comprised predominately of low-oxidative type IIB vs. high-oxidative type I fiber types. However, within muscles containing high-oxidative type IIA and IIX fibers, the role of the SNS on vasomotor tone is not well established. The purpose of this study was to examine the influence of sympathetic neural vasoconstrictor tone in muscles composed of different fiber types. In adult male rats, blood flow to the red and white portions of the gastrocnemius (Gast(Red) and Gast(White), respectively) and the soleus muscle was measured pre- and postdenervation. Resistance arterioles from these muscles were removed, and dose responses to α₁-phenylephrine or α₂-clonidine adrenoreceptor agonists were determined with and without the vascular endothelium. Denervation resulted in a 2.7-fold increase in blood flow to the soleus and Gast(Red) and an 8.7-fold increase in flow to the Gast(White). In isolated arterioles, α₂-mediated vasoconstriction was greatest in Gast(White) (∼50%) and less in Gast(Red) (∼31%) and soleus (∼17%); differences among arterioles were abolished with the removal of the endothelium. There was greater sensitivity to α(1)-mediated vasoconstriction in the Gast(White) and Gast(Red) vs. the soleus, which was independent of whether the endothelium was present. These data indicate that 1) control of vascular resistance by the SNS in high-oxidative, fast-twitch muscle is intermediate to that of low-oxidative, fast-twitch and high-oxidative, slow-twitch muscles; and 2) the ability of the SNS to control blood flow to low-oxidative type IIB muscle appears to be mediated through postsynaptic α₁- and α₂-adrenoreceptors on the vascular smooth muscle.

Objectives: Submandibular vasodilatory responses are impaired in male streptozotocin-diabetic rats. However, the effects of diabetes on submandibular vascular reactivity in female rats have not been examined. The purpose of this study was to determine whether there are gender differences in the effects of diabetes on parasympathetic vasodilatation in the rat submandibular gland., Methods: Diabetes was induced using streptozotocin, and vascular responses (calculated as the % increase in submandibular vascular conductance) to parasympathetic stimulation (1-10 Hz) were measured using laser-Doppler flowmetry. To estimate the relative contributions of nitric oxide (NO), prostacyclin (PGI2) and endothelium-derived hyperpolarizing factor (EDHF), vascular conductance was measured before and after inhibition of cyclooxygenase (COX) and NO synthase (NOS)., Results: Frequency-dependent increases in blood flow were observed in both male and female rats, but the contribution of EDHF was greater in females than in males. Further, PGI2 appeared to play a role only in males. Vasodilatory responses were diminished in all diabetic animals, and when compared with their respective controls the degree of impairment was similar in males and females. However, in diabetic males inhibition of COX and NOS had little or no effect, whereas inhibition of NO, but not COX, resulted in a further significant decrease in vascular responses in diabetic females., Conclusions: Parasympathetic vasodilatation in the rat submandibular gland is diminished equally in diabetic males and females. However, in males diabetes predominantly impairs PGI2- and NO-dependent vasodilatation, whereas in females the contribution of EDHF-mediated pathways are affected and NO-dependent vasodilatation is preferentially maintained., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Escalating evidence indicates that disturbed flow patterns, characterized by the presence of retrograde and oscillatory shear stress, induce a proatherogenic endothelial cell phenotype; however, the mechanisms underlying oscillatory shear profiles in peripheral conduit arteries are not fully understood. We tested the hypothesis that acute elevations in muscle sympathetic nerve activity (MSNA) are accompanied by increases in conduit artery retrograde and oscillatory shear. Fourteen healthy men (25 +/- 1 yr) performed three sympathoexcitatory maneuvers: graded lower body negative pressure (LBNP) from 0 to -40 Torr, cold pressor test (CPT), and 35% maximal voluntary contraction handgrip followed by postexercise ischemia (PEI). MSNA (microneurography; peroneal nerve), arterial blood pressure (finger photoplethysmography), and brachial artery velocity and diameter (duplex Doppler ultrasound) in the contralateral arm were recorded continuously. All maneuvers elicited significant increases in MSNA total activity from baseline (P < 0.05). Retrograde shear (-3.96 +/- 1.2 baseline vs. -8.15 +/- 1.8 s(-1), -40 LBNP, P < 0.05) and oscillatory shear index (0.09 +/- 0.02 baseline vs. 0.20 +/- 0.02 arbitrary units, -40 LBNP, P < 0.05) were progressively augmented during graded LBNP. In contrast, during CPT and PEI, in which MSNA and blood pressure were concomitantly increased (P < 0.05), minimal or no changes in retrograde and oscillatory shear were noted. These data suggest that acute elevations in MSNA are associated with an increase in conduit artery retrograde and oscillatory shear, an effect that may be influenced by concurrent increases in arterial blood pressure. Future studies should examine the complex interaction between MSNA, arterial blood pressure, and other potential modulatory factors of shear rate patterns.

In humans, exercise training and moderate to high levels of physical activity are protective against cardiovascular disease. In fact they are 40% more protective than predicted based on the changes in traditional risk factors (blood lipids, hypertension, diabetes etc.) that they cause. In this review, we highlight the positive effects of exercise on endothelial function and the autonomic nervous system. We also ask if these effects alone, or in combination, might explain the protective effects of exercise against cardiovascular disease that appear to be independent of traditional risk factor modification. Our goal is to use selected data from our own work and that of others to stimulate debate on the nature and cause of the 'risk factor gap' associated with exercise and physical activity.

The discovery of endothelial-derived relaxing factor, and later nitric oxide (NO), as a biologically active substance led to intense focus on the vascular endothelium as a major site of physiological regulation and pathophysiological dysfunction. NO is clearly a potent vasodilator and plays a key role in establishing both whole body and regional "vascular tone". In this context, skeletal muscle and human skin have the remarkable capacity to increase their blood flow 50-100-fold and this increase is caused almost exclusively by local vasodilation. In general, the mechanisms responsible for these vasodilator phenomena have been poorly understood. In the early 1990s, investigators started to ask if NO might explain the "unexplained" vasodilator responses seen in skeletal muscle and skin. They also asked how "NO tone" interacted with "sympathetic tone" and whether NO can override the vasoconstrictor responses normally generated when sympathetic nerves release norepinephrine. Surprisingly, it was found that NO plays only a modest (non-obligatory) role in exercise hyperemia, reactive hyperemia and the neurally mediated rise in skin blood flow during whole body heat stress. By contrast, NO plays a major role in the skeletal muscle vasodilator responses to mental stress and the skin dilator responses to local heating. In animals, but not humans, NO can limit the ability of the sympathetic nerves to cause vasoconstriction in exercising muscles. Thus the role of NO in two of the most extreme dilator responses seen in nature is limited and in muscle the sympathetic nerves can restrain the dilation to defend arterial blood pressure.

The localisation and function of noradrenergic perivascular innervation of the radial artery were examined in a porcine model. Through immunohistochemical techniques, we explored the possible existence of dopamine beta-hydroxylase and choline-acetyltransferase in the nerve fibres supplying the radial artery. Arterial rings suspended in organ baths were used to isometrically record tension in functional tests designed to determine the vasoconstriction response to electrical field stimulation (EFS) or exogenous noradrenaline. Morphological studies revealed the presence of noradrenergic, but not cholinergic, nerve fibres in the tunica adventitia and adventitia-media boundary of the artery wall. EFS-elicited frequency-dependent contractions (EF(50)=3.37+/-0.19 Hz and E(max)=87.7+/-3.8%; n=47) were abolished by tetrodotoxin. The contractile effect was markedly reduced by guanethidine, phentolamine and prazosin and slightly inhibited by rauwolscine, but unaltered by propranolol, atropine, bosentan or capsaicine. Endothelium removal increased EFS-evoked contractions but the addition of L-NOArg, ODQ or indomethacin had no effect. Pre-incubation with tetraethylammonium and 4-aminopyridine, but not glibenclamide, enhanced these neurogenic responses. SOD and apocynin reduced EFS-elicited responses at low frequencies. Exposure of the arterial rings to the same agents did not affect the noradrenaline concentration-response curves except for the alpha-adrenoceptor antagonists. These results led to the conclusions that neurogenic contractions in the pig radial artery are predominantly mediated by noradrenaline released from periarterial adrenergic nerves. This neurogenic vasoconstriction is modulated by a non-NO, non-prostanoid endothelium-dependent relaxing factor and by Ca(2+)-activated and voltage-dependent K(+) channels.

The nervous and vascular systems are both exquisitely branched and complicated systems and their proper development requires careful guidance of nerves and vessels. The recent realization that common ligand-receptor pairs are used in guiding the patterning of both systems has prompted the question of whether similar signaling pathways are used in both systems. This review highlights recent progress in our understanding of the similarities and differences in the intracellular signaling mechanisms downstream of semaphorins, ephrins and vascular endothelial growth factor in neurons and endothelial cells during neural and vascular development. We present evidence that similar intracellular signaling principles underlying cytoskeletal regulation are used to control neural and vascular guidance, although the specific molecules used in neurons and endothelial cells are often different.

Angiotensin II is known to potentiate vasoconstriction induced by electrical field stimulation (EFS), but the underlying mechanisms for this potentiation are not fully understood. This study was designed to investigate the role of superoxide anion in the potentiation effects of angiotensin II. Contraction of rat mesenteric arterial segments was induced by perivascular nerve stimulation with EFS, and superoxide production was measured with lucigenin-enhanced chemiluminescence. Extracellular signal-regulated kinase (ERK) phosphorylation was determined in cultured smooth muscle cells with Western blot. Angiotensin II concentration dependently potentiated the contraction of rat mesenteric arteries to EFS, which is frequency-dependent. This potentiation was blunted by an angiotensin AT(1) receptor antagonist (2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid, CV-11974), NAD(P)H oxidase inhibitor (apocynin), superoxide dismutase (SOD) and its mimetic tiron, but not affected by angiotensin AT(2) receptor antagonist and inhibitors of xanthine oxidase, cytochrome P450, and cyclooxygenase. Angiotensin II increased superoxide production by mesenteric arteries, which was blunted by angiotensin AT(1) receptor antagonist CV-11974, and NAD(P)H oxidase inhibitor apocynin. Superoxide generating compound pyrogallol mimicked the effects of angiotensin II. Tyrosine kinase inhibitor (tyrphostin A25) and mitogen-activated protein kinase (MAPK)/ERK inhibitors (1,4-diamino-2,3-dicyano-1,4-bis [2-aminophenylthio]butadiene (U 0126)) inhibited angiotensin II- and pyrogallol-induced potentiation of EFS-induced contraction, while inactive forms of these inhibitors did not show any inhibitory effects. In cultured smooth muscle cells from mesenteric arteries, angiotensin II and superoxide similarly induced ERK phosphorylation. These results showed that superoxide mediated angiotensin II-induced potentiation of contractile response to EFS and tyrosine kinase-MAPK/ERK activation was involved.

Background: Sirolimus inhibits endothelial cell proliferation in vitro, but although the sirolimus-eluting stent (SES) is widely used because of the very low rates of in-stent restenosis, the influence of SES on coronary endothelial vasomotor function in humans is not well known., Methods and Results: The present study included 21 patients treated with SES, and 12 patients treated with conventional bare metal stent (BMS). Endothelium-dependent vasomotor function was evaluated 6 months after stent implantation, using intracoronary acetylcholine infusion. Changes in diameter at the 5-mm proximal and distal edges of the stent, and at the control segment were assessed by quantitative coronary angiography. To evaluate native endothelial function, an intracoronary acetylcholine test was performed before stenting. In the 21 SES patients acetylcholine infusion at 10(-8) mol/L and 10(-7) mol/L produced significant vasoconstriction in the proximal stent segment (-11.3+/-10.3%, and -14.1+/-11.3%, respectively) and the distal stent segment (-13.7+/-9.3%, and -17.5+/-12.5%, respectively). In contrast, in the 12 BMS patients, acetylcholine infusion at the same concentrations did not produce a vasoconstrictive response in the proximal stent segment (5.0+/-8.2% and 4.9+/-9.1%, respectively) or the distal stent segment (4.2+/-7.6% and 5.1+/-7.7%, respectively). Intracoronary nitroglycerin induced a similar grade of vasodilation in the peri-stent area in both groups. Local endothelial function before SES implantation showed no vasoconstrictive response., Conclusions: In contrast to vasodilation in BMS patients, SES implantation in the peri-stent area resulted in a vasoconstrictive response to acetylcholine. SES implantation may impair endothelial function in humans.

Adiponectin, an adipocyte-derived protein, has been shown to have vasculoprotective effects. This study examined the possible relationship between coronary vasomotor function and the transcardiac gradient of adiponectin, reflecting adiponectin utilization and/or accumulation in the coronary vascular bed. The epicardial diameter and blood flow response of the left anterior descending coronary artery to intracoronary infusions of ACh was analyzed in 108 consecutive subjects who had a normal coronary angiogram and left ventriculogram. Adiponectin levels were measured by ELISA in plasma obtained from the aortic root (Ao) and the anterior interventricular vein (AIV). Adiponectin levels in the AIV were lower than levels in the Ao. In multivariate linear regression analysis, the transcardiac gradient of adiponectin (Ao - AIV levels) showed a positive correlation with increases in epicardial coronary diameter and coronary blood flow in response to ACh that was independent of traditional coronary risk factors. The transcardiac gradient of adiponectin was not significantly associated with the coronary dilator response to isosorbide dinitrate and the coronary flow response to sodium nitroprusside. In other groups of patients with coronary spastic angina (n = 41) or microvascular angina (n = 32) who had impaired coronary vasomotor responses, there was no significant gradient of adiponectin between the Ao and AIV. The transcardiac gradient of adiponectin may modulate endothelial vasomotor function in large and resistance coronary arteries and may play a role in the pathogenesis of diseases presenting with coronary vasomotor dysfunction.

Humans are active creatures, yet physical activity and activity tolerance decline over the life span. One prevailing theme in the literature to account for a portion of the reduced activity tolerance with aging is the observation that the capacity to augment blood flow to skeletal muscle may be impaired with advancing age. This dysfunction may be due to adaptations in the structure or function of their microvascular networks, which collectively determine blood flow resistance. The intent of this review is to present the current knowledge of structure and function of microvascular networks from skeletal muscle with special regard to how these may adapt to, or persist through, the aging process. Skeletal muscles are supplied by an intricate branching network of arterioles and venules. The consistency of findings among available studies suggests that the overall arteriolar and venular network branching topology establishes early in development and varies little, if at all, over the life span. Microvascular networks are not a series of functionally isolated segmental branches. Rather, these networks transmit and communicate vasomotor signals along their lengths and among their branches. Current evidence suggests that aging is associated with a decrement in the capacity of upstream vessels to respond to downstream vasodilation and signals transmitted cell-to-cell along the vascular wall.

Brain perfusion is tightly coupled to neuronal activity, is commonly used to monitor normal or pathological brain function, and is a direct reflection of the interactions that occur between neuronal signals and blood vessels. Cerebral blood vessels at the surface and within the brain are surrounded by nerve fibers that originate, respectively, from peripheral nerve ganglia and intrinsic brain neurons. Although of different origin and targeting distinct vascular beds, these "perivascular nerves" fulfill similar roles related to cerebrovascular functions, a major one being to regulate their tone and, therein, brain perfusion. This utmost function, which underlies the signals used in functional neuroimaging techniques and which can be jeopardized in pathologies such as Alzheimer's disease, stroke, and migraine headache, is thus regulated at several levels. Recently, new insights into our understanding of how neural input regulate cerebrovascular tone resulted in the rediscovery of the functional "neurovascular unit." These remarkable advances suggest that neuron-driven changes in vascular tone result from interactions that involve all components of the neurovascular unit, transducing neuronal signals into vasomotor responses not only through direct interaction between neurons and vessels but also indirectly via the perivascular astrocytes. Neurovascular coupling is thus determined by chemical signals released from activated perivascular nerves and astrocytes that alter vascular tone to locally adjust perfusion to the spatial and temporal changes in brain activity.

Vascular sympathetic innervation is an important determinant of blood pressure and blood flow. The mechanisms that determine vascular sympathetic innervation are not well understood. Recent studies indicate that vascular endothelial cells (EC) express semaphorin 3A, a repulsive axon guidance cue. This suggests that EC would inhibit the growth of axons to blood vessels. The present study tests this hypothesis. RT-PCR and Western analyses confirmed that rat aortic vascular ECs expressed semaphorin 3A as well as other class 3 semaphorins (sema 3s). To determine the effects of EC-derived sema 3 on sympathetic axons, axon outgrowth was assessed in cultures of neonatal sympathetic ganglia grown for 72 h in the absence and presence of vascular EC. Nerve growth factor-induced axon growth in the presence of ECs was 50 +/- 4% (P < 0.05) of growth in the absence of ECs. ECs did not inhibit axon growth in the presence of an antibody that neutralized the activity of sema 3 (P > 0.05). RT-PCR and Western analyses also indicated that sema 3s were expressed in ECs of intact arteries. To assess the function of sema 3s in arteries, sympathetic ganglia were grown in the presence of arteries for 72 h, and the percentage of axons that grew toward the artery was determined: 44 +/- 4% of axons grew toward neonatal carotid arteries. Neutralization of sema 3s or removal of EC increased the percentage of axons that grew toward the artery (71 +/- 8% and 72 +/- 8%, respectively). These data indicate that vascular EC-derived sema 3s inhibit sympathetic axon growth and may thus be a determinant of vascular sympathetic innervation.

Circulatory systems of vertebrate and invertebrate metazoans are very different. Large vessels of invertebrates are constituted of spaces and lacunae located between the basement membranes of endodermal and mesodermal epithelia, and they lack an endothelial lining. Myoepithelial differentation of the coelomic cells covering hemal spaces is a frequent event, and myoepithelial cells often form microvessels in some large invertebrates. There is no phylogenetic theory about the origin of the endothelial cells in vertebrates. We herein propose that endothelial cells originated from a type of specialized blood cells, called amoebocytes, that adhere to the vascular basement membrane. The transition between amoebocytes and endothelium involved the acquisition of an epithelial phenotype. We suggest that immunological cooperation was the earliest function of these protoendothelial cells. Furthermore, their ability to transiently recover the migratory, invasive phenotype of amoebocytes (i.e., the angiogenic phenotype) allowed for vascular growth from the original visceral areas to the well-developed somatic areas of vertebrates (especially the tail, head, and neural tube). We also hypothesize that pericytes and smooth muscle cells derived from myoepithelial cells detached from the coelomic lining. As the origin of blood cells in invertebrates is probably coelomic, our hypothesis relates the origin of all the elements of the circulatory system with the coelomic wall. We have collected from the literature a number of comparative and developmental data supporting our hypothesis, for example the localization of the vascular endothelial growth factor receptor-2 ortholog in hemocytes of Drosophila or the fact that circulating progenitors can differentiate into endothelial cells even in adult vertebrates.

Blood vessels and nerves are structurally similar complex branched systems. Their guidance must be exquisitely regulated to ensure proper wiring of both networks. Recent results showed that specialized endothelial cells, resembling axonal growth cones, form the tips of growing capillaries. These endothelial tip cells guide outgrowing capillaries in response to gradients of extracellular matrix-bound vascular endothelial growth factor. Several axon guidance molecules, including Semaphorins, Netrins, Ephrins and Slits, have also been implicated in vessel pathfinding and network formation. In particular, Semaphorin3E and its receptor plexinD1 in addition to the Netrin receptor UNC5B have recently been shown to direct endothelial tip cell navigation.

Objectives: Endothelial dysfunction is a new pathway in cardiovascular disease (CVD) development. Psychosocial factors have been little studied in relation to endothelial function, although they may interact via associations with the autonomic nervous system (ANS). The purpose of this review is to propose a model by which psychosocial factors are related to CVD development through interactions between the ANS and vascular endothelium., Methods: The literature supporting an interaction between the ANS and endothelium in healthy and disease states is reviewed. Potential mechanisms linking the two systems are explored as a pathway for CVD development., Results: Endothelial dysfunction and impaired cardiovascular ANS regulation are both markers for increased CVD risk. Sympathetic nerves and vascular endothelial cells share a functional antagonism in healthy states to maintain appropriate blood vessel tone. Alterations in sympathetic activity and endothelial cell function are both observed early in the development of CVD and may result from an inability to maintain the functional antagonism. Impairments in either ANS regulation or endothelial function may contribute to further disease development by evoking maladaptive changes in the opposing system., Conclusions: Although interactions between cardiovascular ANS regulation and endothelial function are likely involved in CVD development, further research is needed to determine whether ANS and endothelium interactions are a plausible pathway linking psychosocial factors with increased CVD risk.

Background: Nasal vasculature and seromucous glands are exposed to complex mechanisms influenced by external as well as internal stimuli. In addition to classic and peptidergic neurotransmitters, Nitric oxide (NO) was increasingly found to be important in the control of various physiological functions. NO regulates nasal immunology, influences macrophages activity and has antiviral and bacteriostatic properties. The aim of this study was to detect the localization of nitric oxide synthases (NOS) I and III in the normal human nasal mucosa with immunoelectron microscopical techniques., Methods: Specimens of non-inflamed inferior turbinates from 35 patients who required nasal surgery were fixed in phosphate-buffered glutaraldehyde. After dehydration, incubation in unicryl and polymerization ultrathin sections were cut. Primary antibodies against NOS I and III were applied and the immunocomplexes were visualized by an immunocytochemical staining-technique using a gold-labeled antibody. Immunostained structures were photodocumented by using a transmission electron microscope., Results: NOS-immunoreactive nerve fibers were mainly colocated in parasympathetic nerves in the adventitia of arterial vessels and in periglandular axons. Electron microscopy showed that NOS-positive axons were in close contact with acinus cells. A strong NOS III-immunoreactivity was found in endothelial cells of capillaries near the glands as well as in arterial vessels. Furthermore, immunoreaction products were deposited throughout the cytoplasm of fibroblasts., Conclusions: Nitric oxide in nerval fibers, seromucous glands and endothelial cells of capillaries and arterial vessels suggests that NO takes part in the regulation of physiological processes of the human nasal mucosa. NO was colocalized in parasympathetic nerves and plays a role in the neurotransmission and neuromodulation of the vascular tone and glandular secretion. Arteries showed a distinctly developed nitric innervation and endothelial accumulation. The NO production in axons of the adventitia and in the endothelium of arteries demonstrated that these vessels are influenced by a dual NO system. Mainly NO could act on these structures with vasodilatory effects. Finally NO would be able to influence the functions of perivascular fibroblasts.

The interaction between the endothelium and purinergic perivascular nerves was investigated by measuring the changes in amplitude of excitatory junction potential (EJP) of smooth muscle cells in hamster mesenteric arteries (100-350 microm). Uridin-5'-triphosphate (UTP) (100 microM) applied to endothelium-intact preparations evoked a hyperpolarization of 17.0 +/- 0.7 mV (n=46). During this hyperpolarization, the amplitude of electrically evoked EJPs was inhibited to about 50% of that of the control. In endothelium-denuded preparations, UTP (100 microM) neither hyperpolarized the smooth muscle nor inhibited the amplitude of the EJP. Neither a nitric oxide (NO) synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME) (100 microM), nor a cyclooxygenase inhibitor, indomethacin (1 microM), had an effect on the UTP-evoked hyperpolarization and inhibition of the electrically evoked EJP. The UTP-evoked membrane hyperpolarization and inhibition of the EJP amplitude was antagonized by the P2Y receptor antagonist, cibacron blue (100 microM). Endothelium-derived hyperpolarizing factor (EDHF)-mediated hyperpolarization was inhibited by either adventitial or intimal application of apamin (0.1 micro and charybdotoxin (0.1 microM). However, the EJP inhibition was still present. In apamin- and charybdotoxin-treated preparations, focal application of adenosine 5'-triphosphate (ATP) (10 mM) evoked a depolarization of 15.5 +/- 1.3 mV (n=15). This postjunctional response was not modified by UTP (15.3 +/- 1.7 mV, n=4, P>0.05). These results suggest that exogenously applied UTP activates P2Y receptors of endothelium to release endothelium-derived factors, which in turn inhibit ATP release from purinergic nerves., (Copyright 2003 Elsevier Science B.V.)

We review the evidence for a genetic basis of the cardiovascular and renal stress response. A bio-behavioral model of stress-induced hypertension is presented that explains how repeated exposure to stress in combination with genetic susceptibility might lead to the development of hypertension. In this model, we focus on three underlying physiological systems that mediate the stress response of the heart, vasculature and kidney: the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the endothelial system (ES). We then review the evidence for a genetic influence on cardiovascular reactivity to psychological stress and stress-induced sodium retention using data from twin and family studies and a limited number of candidate gene studies. Finally, by describing the underlying physiological systems of our model and their genetic underpinning we emphasize the importance of inclusion of genetic measurements in any future studies testing the reactivity hypothesis.