Coronary vasoconstrictor effect of ghrelin is not mediated by growth hormone secretagogue receptor 1a type in dogs

Ghrelin (GHR) is a recently discovered endocrine regulatory peptide of gastrointestinal origin with multiple functions including cardiovascular effects. However, contradictory data are available on the vascular actions of GHR in different organs and species. The aim of this study was to characterize the direct effect of the peptide on the canine coronary bed and to evaluate the role of the growth hormone secretagogue receptor (GHS-R) in the effect of GHR on coronary arterioles. The presence of GHS-R1a and 1b subtypes in canine coronary arterioles was investigated using Western blotting and immunohistochemistry. Responses of coronary arterioles with spontaneous and elevated vascular tone (the latter evoked by the thromboxane mimetic agent U46619, 10⁻⁷-10⁻⁶ mol/l) to GHR (10⁻⁹-3 × 10⁻⁷ nmol/l) were recorded by video-microscopy as changes of vessel diameter. Positive immunostaining for both GHS-R subtypes was found in the wall of intramural arterioles. The microarteriographic study results showed that GHR alone could not elicit any significant effect on vessel diameter of arterioles with spontaneous tone. However, when vascular smooth muscle was preconstricted by the thromboxane mimetic agent U46619, administration of GHR induced further constriction (+31 ± 9% increase in contraction p < 0.01). This was not abolished by the specific blockade of GHS-R1a by d-Lys³-GHRP-6 (5 × 10⁻⁶ mol/l). The results suggest that GHR induces tone-dependent constriction of canine coronary arterioles which is mediated by a receptor other than GHS-R1a.     

Phosphorylation of phospholamban correlates with relaxation of coronary artery induced by nitric oxide,adenosine, and prostacyclin in the pig

The intracellular mechanisms underlying the action of the endogenous vasodilators such as NO/EDRF, adenosine, and prostacyclin acting through cGMP and cAMP, respectively, are not well understood. One important action of cyclic nucleotides in smooth muscle relaxation is to lower the cytosolic Ca²⁺ concentration by enhanced sequestration into the sarcoplasmic reticulum. The present study was undertaken to elucidate the potential role of phosphorylation of phospholamban, the regulator of sarcoplasmic reticulum Ca²⁺ pump, for the control of coronary vascular tone by NO/EDRF, adenosine, and prostacyclin. Phospholamban was identified in pig coronary artery preparations by immunofluorescence microscopy, Western blotting and in vitro phosphorylation. Segments of pig coronary artery, with either intact or denuded endothelium, were precontracted with prostaglandin F_2α (PGF_2α). In endothelium-denuded preparations 3-morpholinosydnonimine (SIN-1), 5′-N-ethylcarboxiamidoadenosine (NECA), and iloprost (ILO) caused both relaxation and phospholamban phosphorylation with the potency: SIN-1 > NECA > ILO. The regulatory myosin light chain was significantly dephosphorylated only by SIN-1. In endothelium-intact pig coronary artery, L-NAME caused additional vasoconstriction and a decrease in phospholamban phosphorylation, while phosphorylation of myosin light chain remained unchanged. An inverse relationship between phospholamban phosphorylation and vessel tone was obtained. Our findings demonstrate significant phospholamban phosphorylation during coronary artery relaxation evoked by NO, prostacyclin, and adenosine receptor activation. Because of the close correlation between phosphorylation of phospholamban and vessel relaxation, we propose that phospholamban phosphorylation is an important mechanism by which endogenous vasodilators, especially endothelial NO/EDRF, control coronary vascular smooth muscle tone. J. Cell. Biochem. 70:49–59, 1998. © 1998 Wiley-Liss, Inc.     

Mathematical modeling of the response of a resistive vessel to pressure

The response of small arterial vessels to internal pressure makes an essential contribution to autoregulation in the vascular bed. It is believed that free cytosolic Ca²⁺ concentration plays a pivotal role in the regulation of smooth muscle contractility and hence of the vascular lumen. A simple mathematical model of blood flow in a resistive vessel is suggested. The model is based on the experimental data obtained for cerebral arteries, but may be used for any other resistive vessel. The model not only describes the regulation of the vascular lumen by transmural pressure but also shows realistic behavior of the vessel radius and cytosolic [Ca²⁺] at different rates of pressure change. Possible variations in the radius along the vessel due to the Bayliss effect are considered.     

A model approach to in situ coronary autoregulation

Pressure and flow waveforms were recorded at the entrance of the circumflex coronary artery in anaesthetized dogs during artificial constriction and release of the aorta which caused noticeable variations in the coronary perfusion pressure. The beat-to-beat mean diastolic flow resulting from the autoregulation of the coronary bed in response to the pressure changes was analysed on the basis of a simple model. Flow variations were interpreted as the result of an active mechanism, triggered by the pressure changes and affecting the elastic behaviour of the vessels. The timing and the main characteristics of this response mechanism, after constrictions of varying duration, were evaluated and are discussed. The predicted variations in vessel distensibility and cross-sectional area were compared with data quoted in the literature, showing that the results of this procedure are compatible with those of in vitro measurements on isolated microvessels.     

Vascular smooth muscle cell stress as a determinant of cerebral artery myogenic tone

Although the level of myogenic tone (MT) varies considerably from vessel to vessel, the regulatory mechanisms through which the actual diameter set point is determined are not known. We hypothesized that a unifying principle may be the equalization of active force at the contractile filament level, which would be reflected in a normalization of wall stress or, more specifically, media stress. Branched segments of rat cerebral arteries ranging from <50 microm to >200 microm in diameter were cannulated and held at 60 mmHg with the objectives of: 1) evaluating the relationship between arterial diameter and the extent of myogenic tone, 2) determining whether differences in MT correlate with changes in cytosolic calcium ([Ca(2+)](i)), and 3) testing the hypothesis that a normalization of wall or media stress occurs during the process of tone development. The level of MT increased significantly as vessel size decreased. At 60 mmHg, vascular smooth muscle [Ca(2+)](i) concentrations were similar in all vessels studied (averaging 230 +/- 9.2 nM) and not correlated with vessel size or the extent of tone. Wall tension increased with increasing arterial size, but wall stress and media stress were similar in large versus small arteries. Media stress, in particular, was quite uniform in all vessels studied. Both morphological and calcium data support the concept of equalization of media stress (and, hence, vascular smooth muscle cell stress and force) as an underlying mechanism in determining the level of tone present in any particular vessel. The equalization of active (vascular smooth muscle cell) stress may thus explain differences in MT observed in the different-sized vessels constituting the arterial network and provide a link between arterial structure and function, in both short- and long-term (hypertension) pressure adaptation.     

Beating myocardium counteracts myogenic tone of coronary microvessels: involvement of ATP-sensitive potassium channels

Myogenic tone is intrinsic to vascular tissue and plays an important role in determining basal coronary resistance. However, the effect of the beating heart on myogenic tone is unknown. We investigated the effects of myocardium-derived vasoactive factors on the myogenic tone of coronary microvessels in the resting condition and during increased metabolism. Pressurized isolated coronary vessels (detector vessel, DV) of rabbits (n = 33, maximal inner diameter 201 +/- 8 microm) were gently placed on beating hearts of anesthetized dogs and observed with an intravital microscope equipped with a floating objective. To shut off the myocardium-derived vasoactive signals, we placed plastic film between DV and the heart. The intravascular pressure was changed from 120 to 60 cmH(2)O, and pressure-diameter curves were obtained with and without the contact of DV and the myocardium. The direct contact shifted the pressure-diameter curve upward (P < 0.05 vs. without contact), and myogenic tone was reduced by approximately 40%. When endothelium of DV was denuded, the shift persisted, but the degree of shift was reduced to 10% (P < 0.05 vs. with endothelium). The shift was abolished by glibenclamide, an ATP-sensitive potassium (K(ATP)) channel blocker. A similar upward shift was induced by rapid pacing, but the shift was not blocked by glibenclamide. We conclude that the beating myocardium counteracts myogenic tone by releasing transferable vasoactive signals that affect the endothelium and the vascular smooth muscle, and that the signals are solely mediated by the activation of K(ATP) channels, unlike the rapid pacing-induced vasoactive factors.     

Inhibition of calmodulin prevents spasms in autologous arterial bypass grafts during coronary disease surgery

The tonic lability of isolated segments of the human radial artery was studied isometrically. The mechanical shock to this artery produced by its separation prior to its subsequent use as an autologous arterial bypass graft for coronary arteries provokes a persistent spasm of its smooth muscle that lasts for at least 5 h. Its tonic lability could be preserved by incubation in the presence of 0.5 mM Verapamil, which blocks Ca²⁺ channels in the membranes of smooth muscle cells. A 5-h perfusion recovered more than 20% of the initial tone. Lability of the tone could also be preserved by a 1 μM solution of Aminazine, a well-known inhibitor of calmodulin, an intracellular Ca²⁺-binding protein. In this case, a 3-h perfusion caused a 40% decrease in the tone. Hence, during the pretreatment of the radial artery for its subsequent coronary bypass grafting, the inhibition of calmodulin can be efficacious in preventing intra-and postoperative complications that can be produced by the spasm of arterial grafts.     

Molecular Linkage of TRP Proteins to Smooth Muscle Receptor-Operated Ca2+-Permeable Cationic Channels

The molecular mechanisms underlying Ca²⁺ entry evoked by cell surface receptors in smooth muscle have long been enigmatic, but an important breakthrough has been made by recent investigations on mammalian homologues of Drosophila transient receptor potential (TRP) protein. There is now growing evidence that TRPC6 plays an integrative role in vascular tone regulation, Ca²⁺ entry channels activated by the sympathetic nerve stimulation, vasoactive peptides, and mechanosensitive mechanisms. Other TRPC isoforms, such as TRPC1 and TRPC4 (and perhaps TRPC5), are also expressed abundantly in smooth muscle and may contribute to muscle contraction, cell proliferation, and cholinergic control of the gut motility. This paper briefly overviews the current knowledge about these TRP proteins in smooth muscle physiology.     

Communication between endothelial and smooth muscle cells

Vascular endothelial cells play a fundamental role in the control of vascular tone, and therefore in the control of local blood flow, by releasing various contracting (endothelin, prostaglandins) and relaxing (prostacycline, NO) factors. An additional mechanism involving the hyperpolarization of the vascular smooth muscle cells is observed mainly in the coronary vascular bed and in the periphery. This phenomenon was attributed to an elusive endothelial factor called endothelium-derived hyperpolarizing factor (EDHF). This mechanism is now better understood. It involves first an increase in the endothelial intracellular concentration of calcium, the activation of endothelial potassium channels and the resulting hyperpolarization of the endothelial cells. The hyperpolarization of the endothelial cells is transmitted to the smooth muscle cells by different pathways. This hyperpolarization propagates along the vessels not only via the smooth muscle cells but also via the endothelial cells. Therefore, the endothelial layer can also be considered as a conducting tissue. The discovery of specific inhibitors of the endothelial cell hyperpolarization allows the assessment of the contribution of EDHF-mediated responses in the control of vascular tone.     

The effects of vasoactivity and hypoxic pulmonary hypertension on extralobar pulmonary artery biomechanics

Loss of large artery compliance is an emerging novel predictor of cardiovascular mortality. Hypoxia-induced pulmonary hypertension (HPH) has been shown to decrease extralobar pulmonary artery (PA) compliance in the absence of smooth muscle cell (SMC) tone and to increase SMC tone in peripheral PAs. We sought to determine the impact of HPH on extralobar PA tone and the impact of SMC activation on extralobar PA biomechanics. To do so, C57BL6 mice were exposed to 0 (CTL) or 10 days (HPH) of hypoxia and isolated vessel tests were performed on extralobar PAs using either a physiological saline solution (PSS), a vasoconstrictor (U46619), two vasodilators (SNP and Y27632) or calcium free medium (relaxant solution; VBRS). The vasodilators and relaxant solution had no effect on extralobar artery diameter suggesting that basal SMC tone is essentially zero in CTL conditions and does not increase with HPH. HPH caused narrowing, decreased circumferential stretch (λ; p<0.0001), decreased local area compliance (C_A; p<0.0005) and increased incremental elastic modulus (E_inc; p<0.05) in the normal tone state (with PSS). In both CTL and HPH conditions, SMC activation decreased E_inc (p<0.0005) but also increased wall thickness (p<0.05) such that changes in C_A with SMC constriction were minimal; only in HPH PAs was a significant decrease with SMC constriction observed (p<0.05). Our results demonstrate that 10 days of hypoxia does not increase extralobar PA SMC tone and that HPH-induced decreases in compliance are caused by narrowing, wall thickening and increases in modulus, not persistent vasoconstriction.     

Haemodynamics and wall remodelling of a growing cerebral aneurysm: a computational model

We have developed a computational simulation model for investigating an often postulated hypothesis connected with aneurysm growth. This hypothesis involves a combination of two parallel and interconnected mechanisms: according to the first mechanism, an endothelium-originating and wall shear stress-driven apoptotic behavior of smooth muscle cells, leading to loss of vascular tone is believed to be important to the aneurysm behavior. Vascular tone refers to the degree of constriction experienced by a blood vessel relative to its maximally dilated state. All resistance and capacitance vessels under basal conditions exhibit some degree of smooth muscle contraction that determines the diameter, and hence tone, of the vessel. The second mechanism is connected to the arterial wall remodeling. Remodeling of the arterial wall under constant tension is a biomechanical process of rupture, degradation and reconstruction of the medial elastin and collagen fibers. In order to investigate these two mechanisms within a computationally tractable framework, we devise mechanical analogues that involve three-dimensional haemodynamics, yielding estimates of the wall shear stress and pressure fields and a quasi-steady approach for the apoptosis and remodeling of the wall. These analogues are guided by experimental information for the connection of stimuli to responses at a cellular level, properly averaged over volumes or surfaces. The model predicts aneurysm growth and can attribute specific roles to the two mechanisms involved: the smooth muscle cell-related loss of tone is important to the initiation of aneurysm growth, but cannot account alone for the formation of fully grown sacks; the fiber-related remodeling is pivotal for the latter.     

Exploring Arterial Smooth Muscle Kv7 Potassium Channel Function using Patch Clamp Electrophysiology and Pressure Myography

Contraction or relaxation of smooth muscle cells within the walls of resistance arteries determines the artery diameter and thereby controls flow of blood through the vessel and contributes to systemic blood pressure. The contraction process is regulated primarily by cytosolic calcium concentration ([Ca²⁺]_cyt), which is in turn controlled by a variety of ion transporters and channels. Ion channels are common intermediates in signal transduction pathways activated by vasoactive hormones to effect vasoconstriction or vasodilation. And ion channels are often targeted by therapeutic agents either intentionally (e.g. calcium channel blockers used to induce vasodilation and lower blood pressure) or unintentionally (e.g. to induce unwanted cardiovascular side effects).Kv7 (KCNQ) voltage-activated potassium channels have recently been implicated as important physiological and therapeutic targets for regulation of smooth muscle contraction. To elucidate the specific roles of Kv7 channels in both physiological signal transduction and in the actions of therapeutic agents, we need to study how their activity is modulated at the cellular level as well as evaluate their contribution in the context of the intact artery.The rat mesenteric arteries provide a useful model system. The arteries can be easily dissected, cleaned of connective tissue, and used to prepare isolated arterial myocytes for patch clamp electrophysiology, or cannulated and pressurized for measurements of vasoconstrictor/vasodilator responses under relatively physiological conditions. Here we describe the methods used for both types of measurements and provide some examples of how the experimental design can be integrated to provide a clearer understanding of the roles of these ion channels in the regulation of vascular tone.     

Bindarit Inhibits Human Coronary Artery Smooth Muscle Cell Proliferation,Migration and Phenotypic Switching

Bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs) synthesis, reduces neointimal formation in animal models of vascular injury and recently has been shown to inhibit in-stent late loss in a placebo-controlled phase II clinical trial. However, the mechanisms underlying the efficacy of bindarit in controlling neointimal formation/restenosis have not been fully elucidated. Therefore, we investigated the effect of bindarit on human coronary smooth muscle cells activation, drawing attention to the phenotypic modulation process, focusing on contractile proteins expression as well as proliferation and migration. The expression of contractile proteins was evaluated by western blot analysis on cultured human coronary smooth muscle cells stimulated with TNF-α (30 ng/mL) or fetal bovine serum (5%). Bindarit (100–300 µM) reduced the embryonic form of smooth muscle myosin heavy chain while increased smooth muscle α-actin and calponin in both TNF-α- and fetal bovine serum-stimulated cells. These effects were associated with the inhibition of human coronary smooth muscle cell proliferation/migration and both MCP-1 and MCP-3 production. The effect of bindarit on smooth muscle cells phenotypic switching was confirmed in vivo in the rat balloon angioplasty model. Bindarit (200 mg/Kg/day) significantly reduced the expression of the embryonic form of smooth muscle myosin heavy chain, and increased smooth muscle α-actin and calponin in the rat carodid arteries subjected to endothelial denudation. Our results demonstrate that bindarit induces the differentiated state of human coronary smooth muscle cells, suggesting a novel underlying mechanisms by which this drug inhibits neointimal formation.     

Regulation of Vascular Smooth Muscle Relaxation by the Endothelium in Health and in Diabetes (with a Focus on Endothelium-Derived Hyperpolarizing Factor)

Amongst its wide repertoire of functions, the vascular endothelium plays a pivotal role in the regulation of vascular smooth muscle tone and ultimately tissue perfusion. In healthy vessels, the endothelium exerts a vasodilator influence on the underlying smooth muscle cells. In diabetes mellitus, endothelium-dependent vasodilation is impaired in various vascular beds and may contribute to the increased vascular tone and reduced tissue perfusion, which are features of this disease. There are regional variations in the extent of endothelial vasodilator dysfunction in diabetes, and the basis for this variation has yet to be resolved. The complement of vasodilators involved in endothelium-dependent relaxation varies in different vascular beds. In larger arteries and conduit vessels, the role of nitric oxide (NO) has been the focus of human and animal studies on diabetes. Small arteries and arterioles are important in the local regulation of tissue perfusion, and in many of these, another endothelial vasodilator, endothelium-derived hyperpolarizing factor (EDHF), plays an increasingly prominent role in overall endothelium-dependent relaxation. Surprisingly few studies have explored the influence of diabetes on EDHF; however, there is emerging evidence from a diverse range of vascular beds that the actions of EDHF are seriously compromised in diabetes. Vascular disease remains the leading cause of morbidity and mortality associated with diabetes mellitus. A better understanding of the regional differences and mechanisms involved in endothelial function and dysfunction in small arteries may reveal new strategies to aid in the prevention and/or therapeutic management of the vascular complications of diabetes mellitus.     

Role of Orai1 and L-type CaV1.2 channels in Endothelin-1 mediated coronary contraction under ischemia and reperfusion

Ischemia and Reperfusion (I/R) injuries are associated with coronary artery hypercontracture. They are mainly originated by an exacerbated response to agonists released by endothelium such as Endothelin (ET-1), involving the alteration in intracellular calcium handling. Recent evidences have highlighted the implication of Store-Operated Calcium Channels (SOCC) in intracellular calcium homeostasis in coronary artery. However, little is known about the role of SOCC in the regulation of coronary vascular tone under I/R.The aim of this study was to evaluate the role of SOCC and l-type Ca²⁺ channels (LTCC) in coronary artery vasoconstriction originated by ET-1 in I/R. We used Left Anterior Descendent coronary artery (LAD) rings, isolated from Wistar rats, to study the contractility and intracellular Ca²⁺ concentration ([Ca²⁺]_i) under a simulated I/R protocol. We observed that responses to high-KCL induced depolarization and caffeine-induced Ca²⁺ release are attenuated in coronary artery under I/R. Furthermore, ET-1 addition in ischemia promotes transient and small rise of [Ca²⁺]_i and coronary vascular tone. Meanwhile, these effects are significantly potentiated during reperfusion. The resulting ET-1-induced vasoconstrictions and [Ca²⁺]_i increase were abolished by; GSK-7975A and gadolinium, inhibitors of SOCC; and nifedipine a widely used inhibitor of LTCC. Interestingly, using in situ Proximity Ligation Assay (PLA) in isolated coronary smooth muscle cells we found significant colocalization of LTCC Ca_V1.2 isoform with Orai1, the pore forming subunit of SOCC, and TRPC1 under I/R.Our data suggest that hypercontraction of coronary artery induced by ET-1 after I/R involves the co-activation of LTCC and SOCC, which colocalize significantly in the sarcolemma of coronary smooth muscle cells.     

Organ blood flow and vessels of microcirculatory bed in fish

Information on density of fish capillary network and its permeability, peculiarities of geometry, morphology, and ultrastructure of vessels of microcirculation bed—arterioles, venules, capillaries—is presented. A great attention is paid to vasomotor reactions and their participation in redistribution of blood. Nervous and humoral mechanisms of control of tone of the vessel smooth muscle wall and voluminous blood flow are considered. Effects of environmental factors on processes of microcirculation in fish are discussed.     

Molecular and cellular basis of the regulation of lymphatic contractility and lymphatic absorption

Lymphatic absorption is a highly regulated process driven by both an extrinsic mechanism (external force) and an intrinsic mechanism (lymphatic vessel contractility). The lymphatic muscle is a specialized smooth muscle with unique mechanical properties. To understand the molecular mechanism and relative contribution of smooth muscle contraction in lymphatic absorption, we analyzed mice with a smooth muscle-specific deletion of Mylk, a critical gene for smooth muscle contraction. Interestingly, the knockout mice were significantly resistant to anesthesia reagents. Upon injection in the feet with FITC-dextran, the mutant mice displayed a 2-fold delay of the absorption peak in the peripheral circulation. Examining the ear lymphatic vessels of the mutant mice revealed a reduction in the amount of fluid in the lumens of the lymphangions, suggesting an impairment of lymph formation. The Mylk-deficient lymphatic muscle exhibited a significant reduction of peristalsis and of myosin light chain phosphorylation in response to depolarization. We thus concluded that MLCK and myosin light chain phosphorylation are required for lymphatic vessel contraction. Lymphatic contractility is not an exclusive requirement for lymphatic absorption, and external force appears to be necessary for absorption.     

Measuring vessel length in vascular plants: can we divine the truth? History,theory, methods,and contrasting models

Key message

The Cohen method of measuring vessel-length distributions is much more accurate than the DD algorithm on integer values, which should be abandoned. More research is needed to get the real distribution of vessel length.

Abstract

Scientists have been measuring the vessel length of plants for more than 50 years. The method involves infusing stem or segments with a visible substance that completely fills vessels cut open at the infusion surface. The number of infused vessels is then quantified versus distance from the infusion surface. A theoretical model is then used to convert the counts of infused vessels to a vessel length distribution. Over the years the methods and theory have changed greatly. The purpose of this review is to give the reader an understanding of why vessel length is important and to provide a theoretical basis for selection of the best method and theory to arrive at vessel length data.     

The Relationships between Polymorphisms in Genes Encoding the Growth Factors TGF-β1, PDGFB,EGF, bFGF and VEGF-A and the Restenosis Process in Patients with Stable Coronary Artery Disease Treated with Bare Metal Stent

Background

Neointima forming after stent implantation consists of vascular smooth muscle cells (VSMCs) in 90%. Growth factors TGF-β1, PDGFB, EGF, bFGF and VEGF-A play an important role in VSMC proliferation and migration to the tunica intima after arterial wall injury. The aim of this paper was an analysis of functional polymorphisms in genes encoding TGF-β1, PDGFB, EGF, bFGF and VEGF-A in relation to in-stent restenosis (ISR).

Materials and Methods

265 patients with a stable coronary artery disease (SCAD) hospitalized in our center in the years 2007–2011 were included in the study. All patients underwent stent implantation at admission to the hospital and had another coronary angiography performed due to recurrence of the ailments or a positive result of the test assessing the coronary flow reserve. Angiographically significant ISR was defined as stenosis >50% in the stented coronary artery segment. The patients were divided into two groups–with angiographically significant ISR (n = 53) and without significant ISR (n = 212). Additionally, the assessment of late lumen loss (LLL) in vessel was performed. EGF rs4444903 polymorphism was genotyped using the PCR-RFLP method whilst rs1800470 (TGFB1), rs2285094 (PDGFB) rs308395 (bFGF) and rs699947 (VEGF-A) were determined using the TaqMan method.

Results

Angiographically significant ISR was significantly less frequently observed in the group of patients with the A/A genotype of rs1800470 polymorphism (TGFB1) versus patients with A/G and G/G genotypes. In the multivariable analysis, LLL was significantly lower in patients with the A/A genotype of rs1800470 (TGFB1) versus those with the A/G and G/G genotypes and higher in patients with the A/A genotype of the VEGF-A polymorphism versus the A/C and C/C genotypes. The C/C genotype of rs2285094 (PDGFB) was associated with greater LLL compared to C/T heterozygotes and T/T homozygotes.

Conclusions

The polymorphisms rs1800470, rs2285094 and rs6999447 of the TGFB1, PDGFB and VEGF-A genes, respectively, are associated with LLL in patients with SCAD treated by PCI with a metal stent implantation.     

Enzymatic changes in myosin regulatory proteins may explain vasoplegia in terminally ill patients with sepsis

The current study was conducted with the hypothesis that failure of maintenance of the vascular tone may be central to failure of the peripheral circulation and spiralling down of blood pressure in sepsis. Namely, we examined the balance between expression of myosin light chain (MLC) phosphatase and kinase, enzymes that regulate MLCs dephosphorylation and phosphorylation with a direct effect on pharmacomechanical coupling for smooth muscle relaxation and contraction respectively. Mechanical recordings and enzyme immunoassays of vascular smooth muscle lysates were used as the major methods to examine arterial biopsy samples from terminally ill sepsis patients. The results of the present study provide evidence that genomic alteration of expression of key regulatory proteins in vascular smooth muscles may be responsible for the relentless downhill course in sepsis. Down-regulation of myosin light chain kinase (MLCK) and up-regulation of MLCK may explain the loss of tone and failure to mount contractile response in vivo during circulation. The mechanical studies demonstrated the inability of the arteries to develop tone when stimulated by phenylephrine in vitro. The results of our study provide indirect hint that control of inflammation is a major therapeutic approach in sepsis, and may facilitate to ameliorate the progressive cardiovascular collapse.