Regulation Of Vascular Reactivity Research Articles

Arachidonic Acid Metabolites in Neurologic Disorders.

Arachidonic acid (ARA) is essential for the fluidity, selective permeability, and flexibility of the cell membrane. It is an important factor for the function of all cells, particularly in the nervous system, immune system, and vascular endothelium. ARA is the second most common polyunsaturated fatty acid in the phospholipids of the nerve cell membrane after docosahexaenoic acid. ARA metabolites have many kinds of physiologic roles. The major action of ARA metabolites is the promotion of the acute inflammatory response, mediated by the production of pro-inflammatory mediators such as PGE2 and PGI2, followed by the formation of lipid mediators, which have pro-resolving effects. Another important action of ARA derivatives, especially COX, is the regulation of vascular reactivity through PGs and TXA2. There is significant involvement of ARA metabolites in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and neuropsychiatric disorders. ARA derivatives also make an important contribution to acute stroke, global ischemia, subarachnoid hemorrhage, and anticoagulation-related hemorrhagic transformation. In this review, we have discussed experimental and human study results of neurologic disorders related to ARA and its metabolites in line with treatment options.

A Study on the Role of K Channels in Regulation of Vascular Reactivity in Diabetic Rats

Abstract Background: Diabetes Mellitus (DM) is a major interna-tional health problem characterized by an absolute or relative deficiency in the production or action of insulin, which results in hyperglycemia. Unfortunately, long term insulin adminis-tration in patients with DM results in insulin resistance. In this work, a novel therapeutic strategy of one of the ATP sensitive K channel opener KATP openers called Nicorandil was tried as an adjuvant agent in ameliorating CVD in exper-imentally-induced type I DM in rats. Aim of Study: The present study was designed to elucidate possible role of K channels in glucose homeostasis and regulation of the vascular reactivity in diabetic rats. Material and Methods: Fifty adult male albino rats were used in this investigation, divided into following groups control: Non-diabetic (C), diabetic (D), diabetic insulin treated (D + I), diabetic nicorandil treated (D + N) and diabetic insulin and nicorandil treated (D + I + N). Blood samples were collected for estimation of Fasting Blood Glucose (FBG) and (HbA1c), and vascular reactivity was examined using different vasoactive agents. Results: Type 1 DM resulted in substantial alterations in biochemical variables, as fasting blood glucose level, HbA1c, ABP and vascular reactivity. In our study there is significant decrease in fasting blood glucose level, (HbA1c) in both diabetic insulin (D + I) treated group and diabetic insulin and nicorandil (D + I + N) treated group in compared with the diabetic group, but with insignif-icant change between the two groups. There was significant improvement in vascular reactivity in diabetic insulin (D + I) treated group, diabetic nicorandil (D + N) treated group and diabetic insulin and nicorandil (D + I + N) treated group in compared with the diabetic (D) non treated group, but with insignificant change between insulin and nicorandil (D + I + N) treated group and non-diabetic (C) group. Conclusion: Nicorandil can be used as an adjuvant therapy in diabetic rats to improve vascular reactivity.

Abstract 447: Essential Role of Stromal Interaction Molecule 1 in Heart Failure

Background: Stromal interacting molecule 1 (STIM1) is a calcium sensor in the endoplasmic reticulum (ER). We previously reported that STIM1 plays opposing roles in vascular smooth muscle cells (SMC) vs. endothelial cell in the regulation of vascular reactivity. However, the role of SMC STIM1 in heart failure is yet to be determined. Methods and Results: We utilize control (C57/Bl6) and mice lacking STIM1 specifically in SMC (Stim1 SMC-/- ). We subjected all mice to left anterior descending coronary artery (LAD) permanent occlusion for 3 weeks. We performed echocardiography before the LAD ligation and 3 week after. In the end, we sacrificed mice and harvested the heart for biochemical and histology studies. The heart weight, collagen, and infarct area were significantly augmented in control mice subjected to LAD occlusion. The diastolic (Ejection fraction) and systolic functions (fractional shortening) were significantly compromised in control mice subjected to LAD occlusion. Interestingly, the cardiac hypertrophy, the collagen content, the infarct area, the ejection fraction, and the fraction shortening were protected in Stim1 SMC-/- mice subjected to LAD occlusion. The protective effect of STIM1 disruption in SMC involved the reduction in ER stress activation, the autophagy, and apoptosis mechanisms. Conclusion: Our results indicate that the disruption of STIM1 in SMC protects the heart against chronic ischemia through the inhibition of ER stress, autophagy, and apoptosis.

Regulation of arterial reactivity by concurrent signaling through the E-prostanoid receptor 3 and angiotensin receptor 1

Prostaglandin E2 (PGE2), a cyclooxygenase metabolite that generally acts as a systemic vasodepressor, has been shown to have vasopressor effects under certain physiologic conditions. Previous studies have demonstrated that PGE2 receptor signaling modulates angiotensin II (Ang II)-induced hypertension, but the interaction of these two systems in the regulation of vascular reactivity is incompletely characterized. We hypothesized that Ang II, a principal effector of the renin-angiotensin-aldosterone system, potentiates PGE2-mediated vasoconstriction. Here we demonstrate that pre-treatment of arterial rings with 1nM Ang II potentiated PGE2-evoked constriction in a concentration dependent manner (AUC-Ang II 2.778±2.091, AUC+Ang II 22.830±8.560, ***P<0.001). Using genetic deletion models and pharmacological antagonists, we demonstrate that this potentiation effect is mediated via concurrent signaling between the angiotensin II receptor 1 (AT1) and the PGE2 E-prostanoid receptor 3 (EP3) in the mouse femoral artery. EP3 receptor-mediated vasoconstriction is shown to be dependent on extracellular calcium in combination with proline-rich tyrosine kinase 2 (Pyk2) and Rho-kinase. Thus, our findings reveal a novel mechanism through which Ang II and PGE2 regulate peripheral vascular reactivity.

Role of miR-124 and miR-141 in the regulation of vascular reactivity and the relationship to RhoA and Rac1 after hemorrhage and hypoxia

Recent studies show that hypoxia can alter expression levels of microRNAs (miRNAs). Whether hypoxia or hemorrhage-induced vascular hyporeactivity is related to miRNAs and the underlying mechanisms of this process is not clear. Using hypoxia-treated superior mesenteric arteries (SMAs) and vascular smooth muscle cells (VSMCs) of rats that underwent hemorrhage, we observed the regulatory effects of miR-124/miR-141 on vascular reactivity, the relationship of these miRNAs to RhoA and Rac1, and the mutual regulation of miR-124 and miR-141. The contractile responses of SMAs and VSMCs showed an increase in early stages and a decrease in late stages of hypoxia and hemorrhage. Forty-five miRNAs appeared to have been significantly changed in SMAs after hypoxia, and miR-124 and miR-141 underwent the most change. Overexpressed miR-124 or miR-141 and their antisenses appeared to alter both vascular reactivity and expression of the proteins RhoA and Rac1 after hypoxia. miR-124 inhibited Rac1 by acting at the Rac1 mRNA 3'-untranslated region (UTR), but it led to an increase in RhoA by inhibiting miR-141. miR-141 inhibited RhoA by acting at the RhoA mRNA 3'-UTR, but it led to an increase in Rac1 by inhibiting miR-124. Further study found that miR-124 inhibited miR-141 via transcription factor early growth response gene-1 (Egr-1), whereas miR-141 inhibited miR-124 via transcription of nuclear factor erythroid 2-related factor 2 (Nrf-2). These results suggest that miR-124 and miR-141 participate in the regulation of vascular reactivity after hypoxia and hemorrhage by regulating expression of the RhoA and Rac1 proteins, and in doing so, miR-124 and miR-141 are mutually regulated. These findings provide potential targets for restoring vascular function as part of the treatment protocol for hemorrhagic shock and some other critical illness.

Protein markers related to vascular responsiveness after hemorrhagic shock in rats

BackgroundVascular hyporesponsiveness is an important pathophysiological feature of some critical conditions such as hemorrhagic shock. Many proteins and molecules are involved in the regulation of the pathologic process, however the mechanism has still remained unclear. Our study was intended to look for the related protein markers involved in the regulation of vascular reactivity after hemorrhagic shock. MethodsDifferential in-gel electrophoresis and tandem mass spectrometry were applied to quantify the differences of protein expression in the superior mesenteric arteries from hemorrhagic shock and normal rats. ResultsA total of 2317 differentially expressed protein spots in the superior mesenteric arteries of rats before and after hemorrhagic shock were found, and 146 protein spots were selected for tandem mass spectrometry identification. Thirty-seven differentially expressed proteins were obtained, including 3 uncharacterized proteins and 34 known proteins. Among them, heat shock protein beta-1 and calmodulin were the known proteins involved in the occurrence of vascular hyporesponsiveness. Bioinformatics analysis results showed that 18 proteins were related to vasoconstriction, 11 proteins may be involved in other vascular functions such as regulation of angiogenesis and endothelial cell proliferation. ConclusionsThe changes of vascular responsiveness after hemorrhagic shock in rats may be associated with the upregulation or downregulation of previously mentioned protein expressions. These findings may provide the basis for understanding and further study of the mechanism and treatment targets of vascular hyporeactivity after shock.

Rho kinase acts as a downstream molecule to participate in protein kinase Cε regulation of vascular reactivity after hemorrhagic shock in rats.

Our previous study demonstrated that Rho kinase and protein kinase C (PKC) played important parts in the regulation of vascular reactivity after shock. Using superior mesenteric arteries (SMAs) from hemorrhagic shock rats and hypoxia-treated vascular smooth muscle cells (VSMCs), relationship of PKCε regulation of vascular reactivity to Rho kinase, as well as the signal transduction after shock, was investigated. The results showed that inhibition of Rho kinase with the Rho kinase-specific inhibitor Y-27632 antagonized the PKCε-specific agonist carbachol and highly expressed PKCε-induced increase of vascular reactivity in SMAs and VSMCs, whereas inhibition of PKCε with its specific inhibitory peptide did not antagonize the Rho kinase agonist (U-46619)-induced increase of vascular reactivity in SMAs and VSMCs. Activation of PKCε or highly expressed PKCε upregulated the activity of Rho kinase and the phosphorylation of PKC-dependent phosphatase inhibitor 17 (CPI-17), zipper interacting protein kinase (ZIPK), and integrin-linked kinase (ILK), whereas activation of Rho kinase increased only CPI-17 phosphorylation. The specific neutralization antibodies of ZIPK and ILK antagonized PKCε-induced increases in the activity of Rho kinase, but CPI-17 neutralization antibody did not antagonize this effect. These results suggested that Rho kinase takes part in the regulation of PKCε on vascular reactivity after shock. Rho kinase is downstream of PKCε. Protein kinase Cε activates Rho kinase via ZIPK and ILK; CPI-17 is downstream of Rho kinase.

Differential role for stromal interacting molecule 1 in the regulation of vascular function.

We determined the in vivo role of stromal-interacting molecule 1 (STIM1) in the regulation of vascular function using endothelial cell (EC)- and smooth-muscle (SM)-specific knockout mice. Systolic blood pressure and glucose levels were similar in all mice (Stim1(SMC-/-), Stim1(SMC-/+), Stim1(EC-/-), Stim1(EC-/+)), but body weight was reduced in Stim1(EC-/-) and Stim1(SMC-/-) mice. The contraction of arteries in response to phenylephrine was significantly reduced in Stim1(SMC-/-) mice only. However, contraction to thromboxane and KCl was similar in all groups. The endothelium-dependent relaxation (EDR) was impaired in Stim1(EC-/+) and drastically reduced in Stim1(EC-/-) mice while the endothelium-independent vasorelaxation was similar among all groups. Acute downregulation of STIM1 in arteries reduced EDR and the contractile response to phenylephrine, while the contractile response to thromboxane was not affected. NADPH oxidase activity was increased only in Stim1(EC-/+) and Stim1(EC-/-) mice. Calcium (Ca(2+)) entry in endothelial cells stimulated with thrombin and histamine had the pharmacological features of store-operated Ca(2+) entry (SOCE) and was dependent on STIM1 expression. We conclude that STIM1 plays opposing roles in vascular smooth muscle vs. endothelial cells in the regulation of vascular reactivity.

Differential role for STIM1 in the regulation of vascular function (851.7)

Background: The aim of this study was to determine the role of stromal interacting molecule‐1 (STIM1) in the regulation of vascular function using tissue‐specific STIM1 knockout mice either in endothelial cells or in smooth muscle cells.Methods &amp;amp; results: We used male C57/BL6 homozygous and heterozygous mice lacking STIM1 specifically in either smooth muscle cells (STIM1SMC‐/‐, STIM1SMC‐/+) or in endothelial cells (STIM1EC‐/‐, STIM1EC‐/+). Systolic blood pressure and glucose levels were similar in all mice, but body weight was significantly reduced in STIM1EC‐/‐ and STIM1SMC‐/‐ mice. The contraction of resistance and conductance arteries in response to phenylephrine was significantly reduced in STIM1SMC‐/‐ mice only. However, contraction to thromboxane and potassium chloride was similar in all groups. The endothelium‐dependent relaxation was significantly impaired in STIMEC‐/+ and drastically reduced in STIM1EC‐/‐ mice while the endothelium‐independent vasorelaxation was similar among all groups. Acute down regulation of STIM1 in resistance arteries reduced endothelium‐dependent relaxation to acetylcholine and the contractile response to phenylephrine, while the contractile response to thromboxane was not affected. NADPH oxidase activity was only increased in STIMEC‐/+ and STIMEC‐/‐ mice. Calcium Ca2+ entry in microvascular endothelial cells stimulated with thrombin and histamine, two vasoactive compounds that cause NO production, had the pharmacological features of store‐operated Ca2+ entry (SOCE) and was dependent on STIM1 expression.Conclusions: STIM1 plays opposing roles in vascular smooth muscle vs. endothelial cells in the regulation of vascular reactivity. We conclude that STIM1 is a critical factor in the basic mechanisms of vascular endothelium‐dependent relaxation and the contractility in response to sympathetic activity but not in the intrinsic contractility of smooth muscle.

Role of non-MLC20 phosphorylation pathway in the regulation of vascular reactivity during shock

BackgroundStudies have shown that shock-induced vascular hyporeactivity is associated with the decrease in 20-kDa myosin light chain (MLC20) phosphorylation. Whether and how a non-MLC20 phosphorylation pathway participates in the regulation of vascular reactivity after shock is not known. MethodsWith superior mesentery artery (SMA) obtained from rats in hemorrhagic shock and hypoxia-treated SMA, the regulatory effect of platelet-derived growth factor (PDGF) on vascular reactivity and the roles of caldesmon, 27-kDa heat shock protein (HSP27), extracellular signal–regulated protein kinase (Erk), and p38 mitogen–activated protein kinase (MAPK), the main molecules that are involved in the non-MLC20 phosphorylation pathway of the regulation of smooth-muscle contraction, were investigated. ResultsPDGF (40–100 ng/mL) increased the vascular reactivity after shock in a dose-dependent manner, whereas it did not increase the MLC20 phosphorylation in a dose-dependent manner. PDGF with concentration more than 60 ng/mL did not further increase the MLC20 phosphorylation, whereas upregulated the phosphorylation of HSP27, Erk, and p38MAPK, and the activity of myosin adenosine triphosphatase in SMAs, and downregulated the phosphorylation of caldesmon. p38MAPK antagonist, SB203580, not only antagonized PDGF-induced increase in the phosphorylation of HSP27, but also antagonized PDGF-induced decrease in the phosphorylation of caldesmon, whereas Erk antagonist, PD98059, only antagonized PDGF-induced decrease in the phosphorylation of caldesmon. ConclusionsThese findings suggested that a non-MLC20 phosphorylation pathway participated in the regulation of vascular reactivity after shock. Caldesmon- and HSP27-mediated change in myosin adenosine triphosphatase activity and Erk and p38MAPK played an important role in this process. These findings may provide some potential targets for the treatment of vascular hyporeactivity after shock.

Postshock mesenteric lymph drainage ameliorates vascular reactivity and calcium sensitivity through RhoA

BackgroundVascular hyporeactivity plays an important role in the pathogenesis of severe shock. Previous studies have shown that postshock mesenteric lymph (PSML) blockage ameliorates the vascular reactivity and calcium sensitivity, and RhoA is involved in the regulation of vascular reactivity after hemorrhagic shock. Therefore, the present study tested whether small GTPase RhoA mediates the improvement of the vascular reactivity and calcium sensitivity in superior mesenteric artery (SMA) of rats with PSML drainage. Materials and methodsThe hemorrhagic shock model (blood pressure to 40 ± 2 mm Hg) was established, and PSML was drained from immediate hypotension for 3 h, after which SMA was isolated, and the vascular reactivity and calcium sensitivity were tested in the presence of RhoA agonist (U-46619) or inhibitor (C3 transferase). The protein expressions of small GTPase RhoA and phospho-RhoA were also examined in SMA. ResultsThe hemorrhagic shock resulted in a significant decrease in the SMA reactivity and calcium sensitivity, which was enhanced by the application of U-46619 to the SMA. In contrast, the PSML drainage ameliorated the deleterious effect of the hemorrhagic shock on the SMA. This beneficial effect of the PSML drainage was abolished by C3 transferase. Western blotting revealed that the expressions of the RhoA and phospho-RhoA in SMA tissue obtained from the shock group were significantly decreased, and the PSML drainage markedly enhanced these protein expressions. ConclusionsRhoA is an important contributor to the PSML drainage-induced amelioration of the vascular reactivity and calcium sensitivity in rats with hemorrhagic shock.

Effects of Interleukin-1β on Vascular Reactivity After Lipopolysaccharide-induced Endotoxic Shock in Rabbits and Its Relationship With PKC and Rho Kinase

Calcium desensitization plays a critical role in the occurrence of vascular hyporeactivity after shock. Interleukin (IL)-1β participates in the regulation of vascular reactivity via both nitric oxide (NO)-dependent and NO-independent mechanisms. However, the specific NO-independent pathway remains to be established. The issue of whether IL-1β modulates vascular reactivity via regulation of calcium sensitivity in the NO-independent mechanism is unclear. In the current study, effects of IL-1β on vascular calcium sensitivity and its relationship with PKC and Rho kinase were investigated in vivo and in vitro using a rabbit model of lipopolysaccharide (LPS)-induced endotoxic shock and superior mesenteric arteries (SMAs), respectively. The calcium sensitivity profile of SMAs displayed a biphasic change after LPS-induced endotoxic shock (significant increase at 0.5 hour and 1 hour after LPS administration and marked decrease after 2 hours) and was negatively related to changes in serum IL-1β. The IL-1 receptor antagonist, IL-1ra (4 μg/mL), partly reversed LPS-induced calcium desensitization. In vitro incubation with IL-1β (50-200 ng/mL) reduced the calcium sensitivity of SMAs and suppressed the activities of Rho kinase and PKC and the phosphorylation of 20-kDa myosin light chain. These effects of IL-1β were shown to be regulated by the PKC agonist, phorbol 12-myristate 13-acetate, and Rho kinase agonist and antagonist, angiotensin II, and Y-27632, respectively. Our results collectively suggest that IL-1β participates in vascular hyporeactivity after endotoxic shock via regulation of vascular calcium sensitivity. Moreover, this regulatory effect of IL-1β seems closely related to downregulation of the activities of PKC and Rho kinase.

Mitogen-activated protein kinases regulate vascular reactivity after hemorrhagic shock through myosin light chain phosphorylation pathway

Vascular hyporeactivity played an important role in many critical illness including shock or sepsis, but the mechanisms are incompletely understood. The objective of the present study was to investigate the roles of major mitogen-activated protein kinases (MAPKs extracellular signal-regulated kinase [ERK], p38 MAPK, and jun NH2-terminal kinase [JNK]) on vascular reactivity and the mechanisms. With superior mesenteric arteries from hemorrhagic shock rats, the role of p38 MAPK, ERK, and JNK in the regulation of vascular reactivity following shock and their relationship to myosin light chain (MLC20) phosphorylation-dependent pathway was observed. ERK, p38 MAPK, and JNK activities in superior mesenteric arteries were increased at early shock and decreased at late shock. Stimulation of MAPKs with angiotensin II (AngII) increased the vascular reactivity, calcium sensitivity, and MLC20 phosphorylation. The increasing effect of AngII on vascular reactivity was antagonized by ERK, p38 MAPK, and JNK inhibitors, while the effect of AngII on calcium sensitivity was only blocked by ERK and p38 MAPK inhibitor, but not by JNK inhibitor. AngII increased the activity of protein kinase C-dependent phosphatase inhibitor of 17-kD (CPI17), integrin-linked kinase (ILK), and zipper-interacting protein kinase (ZIPK), The effect of AngII on CPI17 was blocked by ERK and p38 MAPK inhibitor, while the effect of AngII on ILK and ZIPK was only blocked by ERK inhibitor. MAPKs participated in the regulation of vascular reactivity during shock. ERK and p38 MAPK is mainly through ILK, ZIPK, and CPI17-mediated MLC20 phosphorylation-dependent pathway, while JNK may be involved in the regulation of vascular reactivity by other mechanisms.

RhoA/Rho-Kinase and Nitric Oxide in Vascular Reactivity in Rats with Endotoxaemia

RhoA/Rho-kinase (RhoA/ROK) pathway promotes vasoconstriction by calcium sensitivity mechanism. LPS causes nitric oxide (NO) overproduction to induce vascular hyporeactivity. Thus, we tried to examine the role of RhoA/ROK and NO in the regulation of vascular reactivity in different time-point of endotoxaemia. Male Wistar rats were intravenously infused for 10 min with saline or E. coli endotoxin (lipopolysaccharide, LPS, 10 mg/kg) and divided to five groups (n = 8 in each group): (i) Control, sacrificed at 6 h after saline infusion; (ii) LPS1h, sacrificed at 1 h after LPS infusion; (iii) LPS2h, sacrificed at 2 h after LPS infusion; (iv) LPS4h, sacrificed at 4 h after LPS infusion; and (v) LPS6h, sacrificed at 6 h after LPS infusion. LPS1h and LPS2h were regarded as early endotoxaemia, whereas LPS4h and LPS6h were regarded as late endotoxaemia. Indeed, our results showed that LPS reproduced a biphasic hypotension and sustained vascular hyporeactivity to noradrenaline (NA) in vivo. Interestingly, this hyporeactivity did not occur in ex vivo during early endotoxaemia. This could be due to increases of aortic RhoA activity (n = 5, P<0.05) and myosin phosphatase targeting subunit 1 phosphorylation (n = 3, P<0.05). In addition, pressor response to NA and vascular reactivity in early endotoxaemia were inhibited by ROK inhibitor, Y27632. Furthermore, plasma bradykinin was increased at 10 min (24.6±13.7 ng/mL, n = 5, P<0.05) and aortic endothelial NO synthase expression was increased at 1 h (+200%. n = 3, P<0.05) after LPS. In late endotoxaemia, the vascular hyporeactivity was associated with aortic inducible NO synthase expression (n = 3, P<0.05) and an increased serum NO level (n = 8, P<0.05). Thus, an increased RhoA activity could compensate vascular hyporeactivity in early endotoxaemia, and the large NO production inhibiting RhoA activity would lead to vascular hyporeactivity eventually.

Angiopoietins regulate vascular reactivity after haemorrhagic shock in rats through the Tie2-nitric oxide pathway

Vascular reactivity shows biphasic changes after severe trauma or shock. Our aim was to elucidate the mechanisms of biphasic-changed vascular reactivity after haemorrhagic shock by observing the regulation of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) on it. Haemorrhagic-shock Sprague-Dawley rats, hypoxia-treated superior mesenteric arteries (SMAs) with intact endothelia, and a cell mixture of vascular smooth muscle cells (VSMCs) and vascular endothelial cells (VECs) were adopted to evaluate the regulatory effects of Ang-1 and Ang-2 on vascular reactivity and their relationship to Tie2 (receptor tyrosine kinase)-Akt-endothelial nitric oxide synthase (eNOS) and Tie2-extracellular signal-regulated kinase (Erk)-inducible nitric oxide synthase (iNOS) signal pathways. Ang-1 expression, Tie2 phosphorylation, and nitric oxide (NO) release were increased at early shock. Exogenous Ang-1 maintained the vascular reactivity of SMAs after early hypoxia. Tie2-blocking antibody and the antagonists of Akt and eNOS antagonized Ang-1-induced maintenance in vascular reactivity and a slight release in NO at the early stage of shock. Ang-2 expression, Tie2 phosphorylation, and NO release were greatly increased at late shock, but exogenous Ang-2 further decreased the vascular reactivity of SMAs after late hypoxia. Tie2-blocking antibody and the antagonists of Erk and iNOS andtagonized the Ang-2-induced decrease in vascular reactivity and a large release of NO at the late stage of shock. Ang-1 and Ang-2 participated in the regulation of vascular reactivity after haemorrhagic shock. Ang-1 was mainly responsible for the hyperreactivity at early shock through the Tie2-Akt-eNOS pathway and an appropriate amount of NO release. Ang-2 was mainly responsible for the hyporeactivity at late shock through the Tie2-Erk-iNOS pathway and the release of a large amount of NO.

Propofol regulation of vascular reactivity is mediated via TRP channels

Transient receptor potential channels, TRPA1 and TRPV1 are known to play a major role in pain and inflammatory pathways. Recent evidences have shown that general anesthetics can either directly or indirectly sensitize these channels. Similarly studies have also implicated cross‐talk between these channels which plays an immense role in regulating these channels. Propofol, an intravenous anesthetic, causes hypotension when administered to patients during surgery. Our main objective was to determine the role of these channels in the regulation of vascular reactivity while further demonstrating Propofol mediates vasodilation through TRPA1/TRPV1 signaling. Using high‐fidelity microtip transducer catheter, changes in mean arterial pressure were recorded in C57BL6 and TRPA1(−/−) mice. Propofol induced a dose‐dependent depressor response which was blunted in TRPA1(−/−) mice and was further attenuated in TRPA1(−/−) mice in the presence of a specific TRPV1 antagonist SB366791. Isometric‐tension studies in endothelium intact and denuded aortic rings from TRPA1(−/−)mice in presence/absence of SB366791 illustrated a role for TRPA1/TRPV1. Furthermore propofol elicited robust relaxation in isolated coronary microvessel from controls which was blunted in the presence of SB366791 and in vessels from TRPA1(−/−)mice. In conclusion, Propofol mediated regulation of vascular reactivity occurs in part via combined TRPA1/TRPV1 mediated signaling.

Changes of extracellular signal-regulated kinase activity following hemorrhagic shock and its role in regulation of vascular reactivity

Objective To investigate the changes of extracellular signal-regulated kinase (ERK) activity and its role in regulation of vascular reactivity following hemorrhagic shock. Methods In 72 SD rats, the hemorrhagic shock model was adopted, the activity of ERK in the superior mesenteric artery ( SMA) of rats after shock was measured, and the vascular reactivity of SMA after shock was observed. The effect of altered ERK activity on the regulation of vascular reactivity of SMA after shock was investigated.Results After shock, the activity of ERK in SMA was increased about 2. 6 folds as compared to normal group ( P ＜0. 01) , and it reached the peak at 30 min after shock. The activity of ERK 2 h after shock was reduced to 56. 1 % of normal group ( P ＜ 0. 05 ). At the same time, the vascular reactivity of SMA was also increased at early shock and decreased at late shock. Angiotensin II ( AngII) increased the activity of ERK to 1. 9 folds as compared to shock 2-h group (P ＜0. 01) , and AngII also increased the vascular reactivity of SMA at 2 h shock. PD98059, the ERK antagonist, antagonized the effect of AngII on ERK activity and vascular reactivity of the SMA. Conclusion ERK may play an important role in the regulation of vascular reactivity after hemorrhagic shock. Key words: Hemorrhagic shock;  Extracellular signal-regulated kinase;  Vascular reactivity

Differential placental caveolin-1 gene expression in women with pre-eclampsia

BackgroundPre-eclampsia (PE) affects 2–7% of pregnant women and is thought to be associated with structural/functional alterations in the placental and maternal vasculature. The main component of caveolae, caveolin-1 (Cav-1) has...

Óxido nítrico e sistema cardiovascular: ativação celular, reatividade vascular e variante genética

Nitric oxide (NO), primarily identified as an endothelium-derived relaxing factor, is a free radical that signals different biological processes. The identification of NO synthase (NOS) isoforms and the subsequent characterization of the mechanisms of cell activation of the enzymes permitted the partial understanding of both the physiological interactions and of the mechanisms of the diseases in which NO is involved. Mainly expressed in the vascular endothelium, the endothelial NOS isoform (eNOS) plays an important role in the regulation of vascular reactivity and in the development and progression of atherosclerosis. The purpose of this review is to contextualize the reader about the eNOS structure and its mechanisms of cell activation. In view of the advances in molecular biology, we will also address the known mechanisms of gene expression regulation and the role of variants on the genetic code of eNOS associated with cardiovascular phenotypes. Although the importance of NO as an atheroprotective molecule is recognized, our focus will be the review of the literature on NO and its participation in the modulation of the muscle vasodilatation phenotype.

The mechanism by which RhoA regulates vascular reactivity after hemorrhagic shock in rats

RhoA, an important member of the Rho family of GTPases, has been implicated in many cellular processes. Our pilot study found that RhoA participated in the regulation of vascular reactivity after shock, but the mechanism was incompletely understood. Whether RhoA regulates vascular reactivity through the Rho kinase-myosin light-chain phosphatase (MLCP) and Rac1-p21-activated kinase (PAK)-myosin light-chain kinase (MLCK) signaling pathway needs investigation. With isolated, superior mesenteric arteries from hemorrhagic-shock rats and hypoxia-treated vascular smooth muscle cells (VSMCs), the effects of U-46619 (RhoA agonist) and C3 transferase (RhoA antagonist) on vascular reactivity, and the relationship to the Rho kinase-MLCP and Rac1-PAK-MLCK signaling pathways were observed. The vascular reactivity of the superior mesenteric artery and the contractile response of VSMCs to norepinephrine after prolonged hemorrhagic shock and hypoxia (2 h) were significantly decreased. Activation of RhoA with U-46619 significantly increased shock or hypoxia-induced decreased vascular reactivity. These effects of U-46619 were abolished by Y-27632 (Rho kinase inhibitor) and PDGF (Rac1 stimulator). Y-27632 had a stronger antagonistic effect than PDGF. U-46619 increased the activity of Rho kinase and MLCK, enhanced the phosphorylation of 20-kDa myosin light chain, and decreased the activity of Rac1, PAK, and MLCP in VSMCs after hypoxia. Y-27632-antagonized U-46619 induced the decrease of MLCP activity and the increase of 20-kDa myosin light chain phosphorylation. PDGF-antagonized U-46619 induced decrease of PAK activity and increase of MLCK activity. RhoA has an important role in the regulation of vascular reactivity after hemorrhagic shock. The Rho kinase-MLCP and Rac1-PAK-MLCK signal pathways participate in the regulatory process of RhoA. Rho kinase-MLCP may be the main signaling pathway by which RhoA regulates vascular reactivity.