BKCa compensates impaired coronary vasoreactivity through RhoA/ROCK pathway in hind-limb unweighted rats.

Previous studies have demonstrated cardiac and vascular remodeling induced by microgravity exposure. Yet, as the most important branch of vasculatures circulating the heart, the coronary artery has been seldomly studied about its adaptations under microgravity conditions. Large-conductance Ca2+-activated potassium channel (BKCa) and the Ras homolog family member A (RhoA)/Rho kinase (ROCK) pathway play key roles in control of vascular tone and mediation of microgravity-induced vascular adjustments. Therefore, we investigated the adaptation of coronary vasoreactivity to simulated microgravity and the role of BKCa and the RhoA/ROCK pathway in it. Four-week-old hind-limb unweighted (HU) rats were adopted to simulate effects of microgravity. Right coronary artery (RCA) constriction was measured by isometric force recording. The activity and expression of BKCa and the RhoA/ROCK pathway were examined by Western blot, patch-clamp recordings, and immunoprecipitation. We found HU significantly decreased RCA vasoconstriction to KCl, serotonin, and U-46619, but increased protein expression and current densities of BKCa, inhibition of which by iberiotoxin (IBTX) further decreased RCA vasoconstriction (P < 0.05). Expression of RhoA and ROCK as well as active RhoA and phosphorylation of myosin light chain (MLC) at Ser19 and MLC phosphatase target-1 at Thr696 were significantly increased by HU, and ROCK inhibitor Y-27632 exerted greater suppressing effect on HU RCA vasoconstriction than that of control (P < 0.05). BKCa opener NS1619 increased HU RCA vasoconstriction, which was blocked by both RhoA and ROCK inhibitor, similar to the effect of IBTX. These results indicate that HU impairs coronary vasoconstriction but enhances BKCa activity acting as a protective mechanism avoiding excessive decrease of coronary vasoreactivity through activation of the RhoA/ROCK pathway.-Wu, Y., Yue, Z., Wang, Q., Lv, Q., Liu, H., Bai, Y., Li, S., Xie, M., Bao, J., Ma, J., Zhu, X., Wang, Z. BKCa compensates impaired coronary vasoreactivity through RhoA/ROCK pathway in hind-limb unweighted rats.

TRPV1 channels in human skeletal muscle feed arteries: implications for vascular function.

NEW FINDINGS: What is the central question of this study? We sought to determine whether human skeletal muscle feed arteries (SFMAs) express TRPV1 channels and what role they play in modulating vascular function. What is the main finding and its importance? Human SMFAs do express functional TRPV1 channels that modulate vascular function, specifically opposing α-adrenergic receptor-mediated vasocontraction and potentiating vasorelaxation, in an endothelium-dependent manner, as evidenced by the α1 -receptor-mediated responses. Thus, the vasodilatory role of TRPV1 channels, and their ligand capsaicin, could be a potential therapeutic target for improving vascular function. Additionally, given the 'sympatholytic' effect of TRPV1 activation and known endogenous activators (anandamide, reactive oxygen species, H+ , etc.), TRPV1 channels might contribute to functional sympatholysis during exercise. To examine the role of the transient receptor potential vanilloid type 1 (TRPV1 ) ion channel in the vascular function of human skeletal muscle feed arteries (SMFAs) and whether activation of this heat-sensitive receptor could be involved in modulating vascular function, SMFAs from 16 humans (63 ± 5 years old, range 41-89 years) were studied using wire myography with capsaicin (TRPV1 agonist) and without (control). Specifically, phenylephrine (α1 -adrenergic receptor agonist), dexmedetomidine (α2 -adrenergic receptor agonist), ACh and sodium nitroprusside concentration-response curves were established to assess the role of TRPV1 channels in α-receptor-mediated vasocontraction as well as endothelium-dependent and -independent vasorelaxation, respectively. Compared with control conditions, capsaicin significantly attenuated maximal vasocontraction in response to phenylephrine [control, 52 ± 8% length-tensionmax (LTmax ) and capsaicin, 21 ± 5%LTmax ] and dexmedetomidine (control, 29 ± 12%LTmax and capsaicin, 2 ± 3%LTmax ), while robustly enhancing maximal vasorelaxation with ACh (control, 78 ± 8% vasorelaxation and capsaicin, 108 ± 13% vasorelaxation) and less clearly enhancing the sodium nitroprusside response. Denudation of the endothelium greatly attenuated the maximal ACh-induced vasorelaxation equally in the control and capsaicin conditions (∼17% vasorelaxation) and abolished the attenuating effect of capsaicin on the maximal phenylephrine response (denuded + capsaicin, 61 ± 20%LTmax ). Immunohistochemistry identified a relatively high density of TRPV1 channels in the endothelium compared with the smooth muscle of the SMFAs, but because of the far greater volume of smooth muscle, total TRPV1 protein content was not significantly attenuated by denudation. Thus, SMFAs ubiquitously express functional TRPV1 channels, which alter vascular function, in terms of α1 -receptors, in a predominantly endothelium-dependent manner, conceivably contributing to the functional sympatholysis and unveiling a therapeutic target.

Effect of Nerve Growth Factor on Innervation of Perivascular Nerves in Neovasculatures of Mouse Cornea.

Angiogenesis, which is the generation of new vascular networks from existing blood vessels, occurs under normal and pathophysiological conditions. Perivascular nerves, which innervate mature vasculatures, maintain vascular tone and regulate tissue blood flow. However, little is known whether perivascular nerves innervate newborn blood vessels. Therefore, the aim of this study was to investigate the distribution and characterization of perivascular nerves in neovasculatures, which were generated by the mouse corneal micropocket method. Under anesthesia, a pellet containing basic fibroblast growth factor (bFGF) (100 ng/pellet) was implanted into a mouse cornea in one side of the eyeball. Nerve growth factor (NGF) was locally (2 or 20 ng) applied with the pellet, or subcutaneously (40 ng/h for 7 d) administered with an osmotic mini-pump. After the implantation, vascular endothelial cells, smooth muscle cells, and perivascular nerves in the cornea were immunohistochemically studied. Neovessels generated from existing limbal vessels were observed in pellet-implanted cornea. Immunostaining of neovasculatures showed the presence of CD31-like immunoreactive (LI) endothelial cells and α-smooth muscle actin-LI vascular smooth muscles. Perivascular nerves immunostained by protein gene product (PGP) 9.5, an axonal marker, were found in the existing limbal vessels, but they were not observed in neovasculatures. Local and subcutaneous treatment of NGF inhibits bFGF-derived angiogenesis and resulted in loop-shaped vessels that had many anastomoses, and produced innervation of PGP 9.5-LI perivascular nerves around bFGF-derived neovessels. These findings suggest that neovasculatures have no innervation of perivascular nerves, and that NGF facilitates innervations of perivascular nerves to regulate the blood flow in neovessels.

The Hydroalcoholic Extract of Leaves of Mandevilla moricandiana Induces NO-Mediated Vascular Relaxation.

Natural products extracted from plants represent a valuable source of new bioactive substances. Many studies describe the potential of plant products for the treatment of cardiovascular diseases. Species of the Mandevilla genus have been studied for their biological activities, mainly as antioxidant, anti-inflammatory, and vasorelaxant. However, the phytochemical and pharmacological profiles of Mandevilla moricandiana have not been investigated yet. The aim of this study was to evaluate the vasodilator effect of the hydroalcoholic extract of the leaves of M. moricandiana, as well as its chemical profile. Chemical analysis and quantification of major compounds were performed by HPLC analysis. Total flavonoid content was quantified based on rutin equivalents, and major compounds were identified based on HPLC-DAD-MS analysis. M. moricandiana leaf extract-induced vasodilation was investigated in rat aortic rings precontracted with phenylephrine. The total flavonoids were quantified as 3.25 ± 0.11 % w/w of the hydroalcoholic leaf extract, and HPLC-DAD-MS allowed for the identification of luteolin and quercetin glycosides. The maximal relaxant effect of the hydroalcoholic leaf extract was 86.07 ± 1.68 % at a concentration of 30 µg/mL (p < 0.05; n = 6). The concentration of hydroalcoholic extract of the leaves of M. moricandiana necessary to reduce phenylephrine-induced contractions of the endothelium-intact aorta by 50 % was 0.82 ± 0.10 µg/mL. M. moricandiana leaf extract-induced vasodilation was abolished in aortas pretreated with NG-nitro-L-arginine methyl ester and 1H-[1,2,4]oxadiazolo-[4,3-α]quinoxalin-1-one. In addition, diphenhydramine partially inhibited the effect of the hydroalcoholic extract of the leaves of M. moricandiana. Thus, M. moricandiana-induced relaxation depends on the endothelium and on the activation of the nitric oxide/cyclic GMP pathway, with the involvement of endothelial histamine H1 receptors. Luteolin and quercetin glycosides seem to contribute to the extract activity.

Ryanodine-induced vasoconstriction of the gerbil spiral modiolar artery depends on the Ca2+ sensitivity but not on Ca2+ sparks or BK channels.

BACKGROUND: In many vascular smooth muscle cells (SMCs), ryanodine receptor-mediated Ca2+ sparks activate large-conductance Ca2+-activated K+ (BK) channels leading to lowered SMC [Ca2+]i and vasodilation. Here we investigated whether Ca2+ sparks regulate SMC global [Ca2+]i and diameter in the spiral modiolar artery (SMA) by activating BK channels. METHODS: SMAs were isolated from adult female gerbils, loaded with the Ca2+-sensitive flourescent dye fluo-4 and pressurized using a concentric double-pipette system. Ca2+ signals and vascular diameter changes were recorded using a laser-scanning confocal imaging system. Effects of various pharmacological agents on Ca2+ signals and vascular diameter were analyzed. RESULTS: Ca2+ sparks and waves were observed in pressurized SMAs. Inhibition of Ca2+ sparks with ryanodine increased global Ca2+ and constricted SMA at 40 cmH2O but inhibition of Ca2+ sparks with tetracaine or inhibition of BK channels with iberiotoxin at 40 cmH2O did not produce a similar effect. The ryanodine-induced vasoconstriction observed at 40 cmH2O was abolished at 60 cmH2O, consistent with a greater Ca2+-sensitivity of constriction at 40 cmH2O than at 60 cmH2O. When the Ca2+-sensitivity of the SMA was increased by prior application of 1 nM endothelin-1, ryanodine induced a robust vasoconstriction at 60 cmH2O. CONCLUSIONS: The results suggest that Ca2+ sparks, while present, do not regulate vascular diameter in the SMA by activating BK channels and that the regulation of vascular diameter in the SMA is determined by the Ca2+-sensitivity of constriction.

Expression Patterns of HIF-1α Under Hypoxia in Vascular Smooth Muscle Cells of Venous Malformations.

PURPOSE: The molecular pathophysiology of venous malformations (VMs), which are a type of vascular malformation, is poorly understood. Until now, it is known that VM lesions are related to the process of angiogenesis. Because angiogenesis is induced under hypoxic conditions, hypoxia is thought to be important in VM lesion formation. Therefore, we examined the implications of hypoxia on the biological behavior of VM vascular smooth muscle cells (VSMCs). In doing so, we investigated the expression patterns of hypoxia-inducible factor-1α (HIF-1α), which plays a key role in hypoxia-induced angiogenesis, to provide a further understanding of the molecular mechanisms involved in VM. METHODS: Vascular smooth muscle cells from 5 normal veins and 5 VM lesions were cultured under moderate hypoxic conditions (3% O2, 5% CO2). The effects of hypoxia on HIF-1α expression were measured by immunocytochemical staining, reverse transcription-polymerase chain reaction, and real-time reverse transcription-polymerase chain reaction. RESULTS: Overall, the expression of HIF-1α in cells was high after exposure to hypoxia for 6 or 12 hours, but decreased after 24 hours of hypoxia. HIF-1α expression in VM VSMCs was 2 times higher than that in normal VSMCs. Immunocytochemically, HIF-1α was mainly located in the nucleus and the intensity in VM VSMCs was stronger after 6 and 12 hours of hypoxia when compared to the expression pattern of HIF-1α in VSMCs from normal tissue. This suggested that VM tissue is more susceptible to the effects of hypoxia than normal tissue. CONCLUSIONS: These results indicate that the high expression of HIF-1α in VM VSMCs under hypoxic conditions could be an important factor for stimulating downstream angiogenesis in VM. Furthermore, the results of this investigation could provide the basis for future studies of VM pathophysiology, and ultimately lead to the development of new therapeutic approaches.

Augmented dilation to nitric oxide in uterine arteries from rats with type 2 diabetes: implications for vascular adaptations to pregnancy.

Pre-existing diabetes increases the risk of maternal and fetal complications during pregnancy, which may be due to underlying maternal vascular dysfunction and impaired blood supply to the uteroplacental unit. Endothelial dysfunction and reduced vascular smooth muscle responsiveness to nitric oxide (NO) are common vascular impairments in type 2 diabetes (T2D). We hypothesized that uterine arteries from diabetic rats would have reduced vascular smooth muscle sensitivity to NO compared with nondiabetic rats due to impairment in the NO/soluble guanylate cyclase (sGC)/cGMP signaling pathway. Uterine arteries from pregnant Goto-Kakizaki (GK; model of T2D) and Wistar (nondiabetic) rats were studied in a wire myograph. GK nonpregnant uterine arteries had reduced responses to ACh and sodium nitroprusside (SNP) but increased responses to propylamine propylamine NONOate and greater sensitivity to sildenafil compared with Wistar nonpregnant arteries. In late pregnancy, Wistar rats had reduced uterine vascular smooth muscle responsiveness to SNP, but GK rats failed to show this adaptation and had reduced expression of sGC compared with the nonpregnant state. GK rats had a smaller litter size (13.9 ± 0.48 vs. 9.8 ± 0.75; P < 0.05) and a greater number of resorptions compared with Wistar controls (0.8 ± 0.76% vs. 19.9 ± 6.06%; P < 0.05). These results suggest that uterine arteries from rats with T2D show reduced sensitivity of uterine vascular smooth muscle sGC to NO. During pregnancy, the GK uterine vascular smooth muscle fails to show relaxation responses similar to those of arteries from nondiabetic rats.

Modeling secondary messenger pathways in neurovascular coupling.

Neurovascular coupling is the well-documented link between neural stimulation and constriction or dilation of the surrounding vasculature. Glial cells mediate this response via their unique anatomy, which connects neurons to arterioles. It is believed that calcium transients and the release of secondary messengers by these cells influence the vascular response. We present a model of intracellular calcium dynamics in an astrocyte (glial cell) and show that stable oscillatory behaviour is possible under certain conditions. We then couple this to a novel model for the relationship between calcium concentration and the production of vasoactive secondary messengers through a fatty-acid intermediate. The two secondary messengers modelled are epoxyeicosatrienoic and 20-hydroxyeicosatetraenoic acids (EET and 20-HETE, respectively). These secondary messengers are produced on different time scales, and we show how this supports the observation that the vasculature dilates rapidly in response to neural stimulation, before returning to baseline levels on a slower time scale.

[Hepatic structure remodeling after an experimental pulmonary trunk stenosis and following its operative correction].

Changes in the liver were studied in 25 puppies with experimental pulmonary trunk stenosis of 6-12 months duration and 10 animals after the elimination of this defect. Control group included 10 dogs of the corresponding age. A complex of histological, morphometric, electron microscopic and immunohistochemical methods was used. During the modeling of pulmonary trunk stenosis, the resistance of hepatic afferent vessels to hepatic blood flow was increased due to the venous-arterial and venous-venous reactions. In the arteries, the bundles of smooth myocytes (SM) of the intimal muscle were formed together with the musculo-elastic sphincters, polypoid cushions, while in the branches of the portal vein, the intimal SM bundles and the valves appeared. In the efferent veins, the muscular elevations were hypertrophied. In all the vessels the thickening of the walls was observed, and in the media of the arteries, there were signs of sclerosis and the increased expression of alpha-smooth muscle actin (alpha-SMA). Hepatocytes demonstrated marked ultrastructural changes: mitochondrial matrix swelling, partial destructions of their cristae, dilation of endoplasmic reticulum cisterns. After the elimination of the defect, previously formed vascular adaptation reactions were found to disappear, the tone of the blood vessels in the liver decreased, causing the regression of hypertrophic changes of their media. The number of the arterial blood vessels with intimal muscle, sphincters and cushions decreased. The expression of alpha-SMA in the media of the arteries was also reduced. In hepatic efferent veins, the muscular elevations became attenuated. The dystrophic changes in hepatocytes regressed at both light-microscopic and the ultrastructural level.

Chronic hypoxia upregulates pulmonary arterial ASIC1: a novel mechanism of enhanced store-operated Ca2+ entry and receptor-dependent vasoconstriction.

Acid-sensing ion channel 1 (ASIC1) is a newly characterized contributor to store-operated Ca(2+) entry (SOCE) in pulmonary vascular smooth muscle (VSM). Since SOCE is implicated in elevated basal VSM intracellular Ca(2+) concentration ([Ca(2+)](i)) and augmented vasoconstriction in chronic hypoxia (CH)-induced pulmonary hypertension, we hypothesized that ASIC1 contributes to these responses. To test this hypothesis, we examined effects of the specific pharmacologic ASIC1a inhibitor, psalmotoxin 1 (PcTX1), on vasoconstrictor and vessel wall [Ca(2+)](i) responses to UTP and KCl (depolarizing stimulus) in fura-2-loaded, pressurized small pulmonary arteries from control and CH (4 wk at 0.5 atm) Wistar rats. PcTX1 had no effect on basal vessel wall [Ca(2+)](i), but attenuated vasoconstriction and increases in vessel wall [Ca(2+)](i) to UTP in arteries from control and CH rats; normalizing responses between groups. In contrast, responses to the depolarizing stimulus, KCl, were unaffected by CH exposure or PcTX1. Upon examining potential Ca(2+) influx mechanisms, we found that PcTX1 prevented augmented SOCE following CH. Exposure to CH resulted in a significant increase in pulmonary arterial ASIC1 protein. This study supports a novel role of ASIC1 in elevated receptor-stimulated vasoconstriction following CH which is likely mediated through increased ASIC1 expression and SOCE.

Effect of SWL on renal hemodynamics: could a change in renal artery contraction-relaxation responses be the cause?

The aim of this study was to reveal the effect of shock wave lithotripsy (SWL) on renal artery contraction-relaxation responses and the relation of this effect with renal hemodynamics. Twenty-four rabbits are divided into six different groups. The first two groups evaluated as the control groups. After isolating the kidneys, we applied phenylephrine (Ph) and acetylcholine (Ach) in the first group and sodium nitroprusside (SNP) and histamine (H) in the second group. In the third, fourth, fifth and sixth groups, 14.5 kV shock wave (SW) was focused on the left kidneys. We adjusted the number of shocks to a total of 500, 1,500, and 3,000 SW, in the third, fourth and fifth groups, respectively. After isolating the kidneys, Ph, Ach was given in groups 3, 4 and 5. In the sixth group, to get the SNP and the H responses, 3,000 shocks modality was utilized. Marked contractile responses were obtained by phenylephrine in the control group. In kidneys that were exposed to 500 shocks SWL procedures, a decrease in contractile responses and hence, in perfusion pressures in different concentrations of phenylephrine was noted. However, a notable change in relaxation responses occurred after 3,000-shock applications. No difference in relaxation responses to nitroprusside, a direct vasodilating agent, was observed in any group, compared to the control group. Another cause of deterioration of renal hemodynamics after SWL can be attributed to the reduction in renal artery contraction-relaxation responses that result in the vascular smooth muscle and endothelial damage.

Sympathetic innervation does not contribute to glycerol release in ischemic flaps.

BACKGROUND: Extracellular glycerol as detected by microdialysis has been used as a surrogate marker for (ischemic) tissue damage and cellular membrane breakdown in the monitoring of free microvascular musculocutaneous flaps. One confounding factor for glycerol as a marker of ischemic cell damage is the effect of lipolysis and associated glycerol release as induced by sympathetic signalling alone. We hypothesized that extracellular glycerol concentrations in a microvascular flap with sympathetic innervation would be confounded by intact innervation per se as compared to denervated flap. Clinical relevance is related to the use of both free and pedicled flaps in reconstructive surgery. We tested the hypothesis in an experimental model of microvascular musculocutaneal flaps. METHODS: Twelve pigs were anesthetized and mechanically ventilated. Two identical rectus abdominis musculocutaneal flaps were raised for the investigation. In the A-flaps the adventitia of the artery and accompanying innervation was carefully stripped, while in the B-flaps it was left untouched. Flap ischemia was induced by clamping both vessels for 60 minutes. The ischemia was confirmed by measuring tissue oxygen pressure, while extracellular lactate to pyruvate ratio indicated the accompanying anaerobic metabolism locally. RESULTS: Intramuscular and subcutaneal extracellular glycerol concentrations were measured by microdialysate analyzer. Contrary to our hypothesis, glycerol concentrations were comparable between the two ischemia groups at 60 minutes (p = 0.089, T-test). CONCLUSIONS: In this experimental model of vascular flap ischemia, intact innervation of the flap did not confound ischemia detection by glycerol. Extrapolation of the results to clinical setting warrants further studies.

[Role of cooperation of myogenic response and sensitiveness of endothelia to shear stress of change inadjusting of organ blood stream].

In the review we analyze a counteraction of two mechanogenic mechanisms that control vascular hydraulic resistance: 1) myogenic response, and 2) ability of vascular endothelium to change the smooth muscle tone in responce to changes of wall shear stress. We showed that this counteraction provides an adequate blood supple of organs, autoregulation of organ blood flow and stability of the vascular system.

Transforming growth factor-beta 1 induces angiogenesis in vitro via VEGF production in human airway smooth muscle cells.

Increase in size and number of bronchial blood vessels as well as hyperaemia are factors that contribute to airway wall remodelling in patients with chronic airway diseases, such as asthma and chronic obstructive pulmonary diseases (COPD). Expression of transforming growth factor beta 1 (TGF-beta 1), a multifunctional cytokine as well as vascular endothelial growth factor (VEGF), a key angiogenic molecule, has been shown in the inflammed airways in patients with chronic airway diseases. TGF-beta 1 has been implicated in the regulation of extracellular matrix, leading to airway remodelling in patients with chronic airway diseases. However, the role of TGF-beta 1 in regulating VEGF expression in patients with chronic airway diseases, as well as the underlying mechanisms are not yet well established. We investigated whether TGF-beta 1 stimulates VEGF expression in vitro and hence could influence vascular remodelling. Cultured human airway smooth muscle cells (HASMC) were serum deprived for 60 h before incubation with 5ng/ml of TGF-beta 1 for different time points. Control cells received serum-free culture medium. TGF-beta 1 treatment resulted in time dependent HASMC cell proliferation with maximal values for DNA biosynthesis at 24 h and cell number at 48 h. Northern blot analysis of VEGF mRNA expression showed increased levels in cells treated with TGF-beta 1 for 4 to 8 h. TGF-beta 1 also induced a time-dependent release of VEGF proteins in the conditioned medium after 48 h of treatment. Furthermore, the ability of HASMC-released VEGF proteins to induce human umbilical vein endothelial cells proliferation was inhibited by VEGF receptor antagonist, confirming that TGF-beta 1 induced VEGF was biologically active. We conclude that TGF-beta 1 in addition to an extracellular matrix regulator also could play a key role in bronchial angiogenesis and vascular remodelling via VEGF pathway in asthma.

Vascular smooth muscle phenotypic diversity and function.

The control of force production in vascular smooth muscle is critical to the normal regulation of blood flow and pressure, and altered regulation is common to diseases such as hypertension, heart failure, and ischemia. A great deal has been learned about imbalances in vasoconstrictor and vasodilator signals, e.g., angiotensin, endothelin, norepinephrine, and nitric oxide, that regulate vascular tone in normal and disease contexts. In contrast there has been limited study of how the phenotypic state of the vascular smooth muscle cell may influence the contractile response to these signaling pathways dependent upon the developmental, tissue-specific (vascular bed) or disease context. Smooth, skeletal, and cardiac muscle lineages are traditionally classified into fast or slow sublineages based on rates of contraction and relaxation, recognizing that this simple dichotomy vastly underrepresents muscle phenotypic diversity. A great deal has been learned about developmental specification of the striated muscle sublineages and their phenotypic interconversions in the mature animal under the control of mechanical load, neural input, and hormones. In contrast there has been relatively limited study of smooth muscle contractile phenotypic diversity. This is surprising given the number of diseases in which smooth muscle contractile dysfunction plays a key role. This review focuses on smooth muscle contractile phenotypic diversity in the vascular system, how it is generated, and how it may determine vascular function in developmental and disease contexts.

The phosphorylation motif at serine 225 governs the localization and function of sphingosine kinase 1 in resistance arteries.

OBJECTIVE: The purpose of this study was to characterize a phosphorylation motif at serine 225 as a molecular switch that regulates the pressure-dependent activation of sphingosine kinase 1 (Sk1) in resistance artery smooth muscle cells. METHODS AND RESULTS: In isolated hamster gracilis muscle resistance arteries, pressure-dependent activation/translocation of Sk1 by ERK1/2 was critically dependent on its serine 225 phosphorylation site. Specifically, expression of Sk1(S225A) reduced resting and myogenic tone, resting Ca(2+), pressure-induced Ca(2+) elevations, and Ca(2+) sensitivity. The lack of function of the Sk1(S225A) mutant could not be entirely overcome by forced localization to the plasma membrane via a myristoylation/palmitylation motif; the membrane anchor also significantly inhibited the function of the wild-type Sk1 enzyme. In both cases, Ca(2+) sensitivity and myogenic tone were attenuated, whereas Ca(2+) handling was normalized/enhanced. These discrete effects are consistent with cell surface receptor-mediated effects (Ca(2+) sensitivity) and intracellular effects of S1P (Ca(2+) handling). Accordingly, S1P(2) receptor inhibition (1 micromol/L JTE013) attenuated myogenic tone without effect on Ca(2+). CONCLUSIONS: Translocation and precise subcellular positioning of Sk1 is essential for full Sk1 function; and two distinct S1P pools, proposed to be intra- and extracellular, contribute to the maintenance of vascular tone.

Inhaled nickel nanoparticles alter vascular reactivity in C57BL/6 mice.

BACKGROUND: The use of nanoparticles (NPs) in technological applications is rapidly expanding, but the potential health effects associated with NP exposure are still largely unknown. Given epidemiological evidence indicating an association between inhaled ambient ultrafine particles and increased risk of cardiovascular disease morbidity and mortality, it has been suggested that exposure to NPs via inhalation may induce similar cardiovascular responses. METHODS: Male C57BL/6 mice were exposed via whole-body inhalation to either filtered air (FA) or nickel hydroxide (NH) NPs (100, 150, or 900 µg/m(3)) for 1, 3, or 5 consecutive days (5 h/day). At 24-h post-exposure, vascular function in response to a vasoconstrictor, phenylephrine (PE), and a vasodilator, acetylcholine (ACh), was measured in the carotid artery. RESULTS: Carotid arteries from mice exposed to all concentrations of NH-NPs showed statistically significant differences in graded doses of PE-induced contractile responses compared with those from FA mice. Similarly, vessels from NH-NP-exposed mice also demonstrated impaired vasorelaxation following graded doses of ACh as compared with FA mice. CONCLUSIONS: These results suggest that short-term exposure to NH-NPs can induce acute endothelial disruption and alter vasoconstriction and vasorelaxation. These findings are consistent with other studies assessing vascular tone and function in the aorta, coronary, and mesenteric vessels from mice exposed to motor vehicular exhaust and concentrated ambient particles.

[Pathomorphological characteristics of various portions of the aorta and pulmonary artery in coarctation in babies of the first month of life].

A total of 554 case and autopsy records were clinically and morphologically analyzed. There was aortic coarctation (AC) in 47 cases, including 32 cases in babies aged less than 1 month. Pathomorphologic changes in the aorta and pulmonary artery in AC are a dynamic process and reflect the signs of increased vascular permeability, damaged muscle elements, and formed minor vessels. It may be suggested that such changes reflect impaired vascular blood flow at the sites of AC, which should be kept in mind in the early diagnosis and prediction of complications.

[Changes of ultrastructure of the capillary endotheliocytes of ischemized and nonaffected muscular tissue after transplantation of human hemopoietic stem cells of fetal liver in experiment in vivo].

In experiment was investigated ultrastructure of the capillaries endothelial cells and histological peculiarities of muscular tissue on various stages after transplantation of hemopoietic stem cells of fetal liver (HSCFL). There was proved, that in ischemic environment HSCFL stimulate processes of angiogenesis, and in the case of transplantation into intact muscular tissue they are differentiating into the tissue macrophages, not interfering with muscular tissue structure.

Endothelial function in patients with atrial fibrillation.

Atrial fibrillation (AF) is the most common heart arrhythmia and is associated with poor outcomes. The adverse effects of AF are mediated through multiple pathways, including endothelial dysfunction, as measured by flow-mediated dilatation. Flow-mediated dilatation has demonstrated endothelial dysfunction in several conditions and is associated with poor outcomes including mortality, yet can be improved with medical therapy. It is thus a useful tool in assessing endothelial function in patients. Endothelial dysfunction is present in patients with AF and is associated with poor outcomes. These patients are generally older and have other co-morbidities such as hypertension, hypercholesterolaemia and diabetes. The precise process by which AF is affiliated with endothelial damage/dysfunction remains elusive. This review explores the endothelial structure, its physiology and how it is affected in patients with AF. It also assesses the utility of flow mediated dilatation as a technique to assess endothelial function in patients with AF. Key MessagesEndothelial function is affected in patients with atrial fibrillation as with other cardiovascular conditions.Endothelial dysfunction is associated with poor outcomes such as stroke, myocardial infarction and death, yet is a reversible condition.Flow-mediated dilatation is a reliable tool to assess endothelial function in patients with atrial fibrillation.Patients with atrial fibrillation should be considered for endothelial function assessment and attempts made to reverse this condition.