This Is MS Multiple Sclerosis Knowledge & Support Community

1: Mol Cell Biomech. 2008 Mar;5(1):1-8.Links
Role of shear stress direction in endothelial mechanotransduction.Chien S.
UCSD, La Jolla, CA, USA.

Fluid shear stress due to blood flow can modulate functions of endothelial cells (ECs) in blood vessels by activating mechano-sensors, signaling pathways, and gene and protein expressions. Laminar shear stress with a definite forward direction causes transient activations of many genes that are atherogenic, followed by their down-regulation; laminar shear stress also up-regulates genes that inhibit EC growth. In contrast, disturbed flow patterns with little forward direction cause sustained activations of these atherogenic genes and enhancements of EC mitosis and apoptosis. In straight parts of the arterial tree, laminar shear stress with a definite forward direction has anti-atherogenic effects. At branch points, the complex flow patterns with little net direction are atherogenic. Thus, the direction of shear stress has important physiological and pathophysiological effects on vascular ECs.

PMID: 18524241 [PubMed - indexed for MEDLINE]

1: Free Radic Res. 2007 Dec;41(12):1364-75. Links
Microcirculation and oxidative stress.Crimi E, Ignarro LJ, Napoli C.
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. ecrimi@partners.org

The microcirculation is a complex and integrated system, transporting oxygen and nutrients to the cells. The key component of this system is the endothelium, contributing to the local balance between pro and anti-inflammatory mediators, hemostatic balance, as well as vascular permeability and cell proliferation. A constant shear stress maintains vascular endothelium homeostasis while perturbed shear stress leads to changes in secretion of vasodilator and vasoconstrictor agents. Increased oxidative stress is a major pathogenetic mechanism of endothelial dysfunction by decreasing NO bioavailability, promoting inflammation and participating in activation of intracellular signals cascade, so influencing ion channels activation, signal transduction pathways, cytoskeleton remodelling, intercellular communication and ultimately gene expression. Targeting the microvascular inflammation and oxidative stress is a fascinating approach for novel therapies in order to decrease morbidity and mortality of chronic and acute diseases.

PMID: 18075839 [PubMed - indexed for MEDLINE]

1: Clin Hemorheol Microcirc. 2007;37(3):277-90. Links
Leukocyte involvement in the signs and symptoms of chronic venous disease. Perspectives for therapy.Boisseau MR.
Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France. m.r.boisseau@wanadoo.fr

Pain intensity in chronic venous disease varies with the stage in the clinical-etiologic-anatomic-pathophysiologic (CEAP) classification but also with patient perception, pain being by definition subjective. The venous hypertension responsible for the varicose veins and trophic changes in CVD has a variety of algogenic repercussions in which leukocytes play a particular role, notably through their ability to roll along the vessel wall. Shear stress, hypoxia and stasis activate the marginated leukocytes to shed L-selectin from their surface and express integrins, matrix metalloproteinase 9, elastase, lactoferrin and free radicals. Meanwhile the endothelium expresses adhesion molecules that permit slow rolling on E-selectin followed by adhesion and tissue transmigration. Vein wall and valve areas in particular attract mast cells, monocyte-macrophages and T lymphocytes, and undergo remodeling. Sympathetic sensory C and Adelta fibers, which wrap around cutaneous venules and are also present in the venous intima and media, are nociceptors sensitive to the pain mediators concentrated within leukocytes, such as mast cell bradykinin, responsible for visceral pain. Neuronal inflammation combined with wall remodeling intensifies symptoms. Yet no direct link has so far been shown between pain and mast cell mediator levels. Leukocyte adhesion is also associated with the increased capillary permeability that leads to edema. Antileukocyte therapies include postural rest and venotonics which alone or in combination with compression have been shown to unstick and inhibit leukocytes. The micronized purified flavonoid fraction (MPFF) protects vascular endothelium against hypoxia and reduces adhesion molecule expression. Unlike other antileukocyte therapies, venotonics do not cause neutropenia.

PMID: 17726258 [PubMed - indexed for MEDLINE

1: Ultrasound Med Biol. 2007 May;33(5):663-71. Epub 2007 Mar 26. Links
Mechanisms by which low-intensity ultrasound improve tolerance to ischemia-reperfusion injury.Bertuglia S.
CNR Institute of Clinical Physiology, Faculty of Medicine, University of Pisa, Pisa, Italy. sibert@ifc.cnr.it

Recent studies show that low-intensity ultrasound (US) increases endothelial nitric oxide (NO) levels in different models both in vitro and in vivo. Ischemia-reperfusion (I/R) injury is characterized by endothelial cell dysfunction, mainly as a result of altered shear stress responses associated with vasoconstriction, reduced capillary perfusion and excessive oxidative stress. This review provides an overview of the microvascular effects of low-intensity US and suggests that US exposure can be a method to provide tolerance to I/R damage. The hamster cheek pouch, extensively used in studies of I/R-induced injury, has been characterized in terms of changes of arteriolar diameter, flow and shear stress. The low-intensity US exposure reduces vasoconstriction and leukocyte adhesion and increases capillary perfusion during postischemic reperfusion. These effects may be the result of enhanced fluctuations in shear stress exerted by the flowing blood on the vessel wall. The fluctuations in turn are due to mechanical perturbations arising from the difference in acoustical impedance between the endothelial cells and the vessel content. We believe that periodic pulses of US may also cause a sustained reduction of oxidative stress and an enhanced endothelial NO level by increasing oscillatory shear stress during postischemic reperfusion. Low-intensity US exposure may represent a safe and novel important therapeutic target for patients with acute coronary syndromes and for treatment of chronic myocardial ischemia.

PMID: 17383799 [PubMed - indexed for MEDLINE]

1: World J Surg. 2007 Apr;31(4):733-43. Links
Effect of low shear stress on permeability and occludin expression in porcine artery endothelial cells.Conklin BS, Vito RP, Chen C.
Sections of Leukocyte Biology and Nutrition, Department of Pediatrics, Baylor College of Medicine, Children's Nutrition Research Center, 1100 Bates, Suite 6014, Houston, Texas 77030, USA.

INTRODUCTION: Although both fluid shear stress and mass transport of atherogenic substances into the vascular wall are known to be important factors in atherogenesis, there has been little research on the effect of shear stress on vascular permeability. Therefore, the effects of shear stress on the permeability of arteries and the expression of the endothelial cell tight junction molecule occludin, an important regulator of vascular permeability, were investigated. METHODS: Porcine carotid arteries were perfusion cultured ex vivo with low (1.5 dyne/cm(2)) or physiologic (15 dyne/cm(2)) shear stress and 100 mmHg pressure for 24 hours. Subsequently, 20 nm gold particles in solution were infused into the lumen of vessels at 100 mmHg for 30 minutes. Frozen sections were then cut and stained for gold particles. Image analysis was used to determine the density of the particles in the vessel walls. The expression of endothelial cell occludin mRNA and protein were determined using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. RESULTS: Permeability results showed a 2.8-fold increase in the apparent permeability of vessels cultured with low versus physiologic shear stress. RT-PCR and Western blotting results showed significant decreases in occludin mRNA and protein expression at 12 and 24 hours in vessels cultured with low versus physiologic shear stress. CONCLUSIONS: These results demonstrate that low shear stress increases vascular permeability in porcine carotid arteries, possibly owing to decreased occludin expression. These results may have implications in the preferential formation of atherosclerotic vascular disease adjacent to branches and bifurcations where low mean shear stresses may occur.

PMID: 17372666 [PubMed - indexed for MEDLINE]

1: Shi Yan Sheng Wu Xue Bao. 2003 Apr;36(2):85-90.Links
[Inhibition of vascular smooth muscle cell proliferation by non-steroidal anti-inflammatory drugs][Article in Chinese]


Wang YQ, Brooks G, Harper J, Li YQ, Zhu CB, Yuan WZ, Wu XS.
College of Life Science, Hunan Normal University, Changsha 410081.

Abnormal vascular smooth muscle cell (VSMC) proliferation is known to play an important role in the pathogenesis of atherosclerosis, restenosis and instent stenosis. Recent studies suggest that salicylates, in addition to inhibiting cyclooxygenase activity, exert an antiproliferative effect on VSMC growth both in vitro and in vivo. However, whether all non-steroidal anti-inflammatory drugs (NSAID) exert similar antiproliferative effects on VSMCs, and do so via a common mechanism of action, remains unknown. In the present study, we demonstrated that the NSAIDs, aspirin, ibuprofen and sulindac induced a dose-dependent inhibition of proliferation in rat A10 VSMCs (IC50 = 1666 mumol/L, 937 mumol/L and 520 mumol/L, respectively). These drugs did not show significant cytotoxic effects as determined by LDH release assay, even at the highest concentrations tested (aspirin, 5000 mumol/L; ibuprofen, 2500 mumol/L; and sulindac, 1000 mumol/L). Flow cytometric analyses showed that a 48 h exposure of A10 VSMCs to ibuprofen (1000 mumol/L) and sulindac (750 mumol/L) led to a significant G1 arrest (from 68.7 +/- 2.0% of cells in G1 to 76.6 +/- 2.2% and 75.8 +/- 2.2%, respectively, p < 0.05). In contrast, aspirin (2500 mumol/L) failed to induce a significant G1 arrest (68.1 +/- 5.2%). Clearer evidence of a G1 block was obtained by treatment of cells with the mitotic inhibitor, nocodazole (40 ng/ml), for the final 24 h of the experiment. Under these conditions, aspirin still failed to induce a G1 arrest (from 25.9 +/- 10.9% of cells in G1 to 19.6 +/- 2.3%) whereas ibuprofen and sulindac led to a significant accumulation of cells in G1(51.8% +/- 17.2% and 54.1% +/- 10.6%, respectively, p < 0.05). These results indicate that ibuprofen and sulindac inhibit VSMC proliferation by arresting the cell cycle in the G1 phase whereas the effect of aspirin appears to be independent of any special phase of the cell cycle. Irrespective of mechanism, our results suggest that NSAIDs might be of benefit to the treatment of vascular proliferative disorders.

PMID: 12858504 [PubMed - indexed for MEDLINE]

Nees focuses on the role of the smaller vessels and their endothelium, as opposed to the venous valves, as the starting point for CVI.

The venular endothelium possesses a unique property, which gives it a specific role in the development of CVI. It is, unlike the endothelium of other vessels, a contractile tissue actively regulating the width of its intercellular gaps. Especially inflammatory mediators open these gaps [11,12].

Opening of the venular gaps leads to an outflow of blood and plasma components to the surrounding interstitial tissues and forms the microscopic correlate to the oedema observed clinically. Thrombogenic factors, e.g. tissue factors, induce interstitial inflammation and thrombosis, which spread to the venular lumen, possibly via the open gaps, reducing or cutting off perfusion. This inflammation may maintain the opening of the venular gaps, thus resulting in a circulus vitiosus, a chronic situation. Thrombocytes, polymorphonuclear granulocytes, T-lymphocytes, and monocytes are attracted to the site of inflammation and secrete aggressive oxidative or hydrolytic enzymes. Due to the reduced blood flow and damage in the venular endothelium they are insufficiently diluted [11].

This scenario may also occur in the vasa venorum, i.e. the supply vessels of the larger veins [13]. This is especially relevant for the promotion to the later stages of CVI. Microthrombi and inflammation of the venules, in the direct neighbourhood of the larger veins, may compromise the normal metabolism of venous wall structures, e.g. of the venous valves, eventually leading to their destruction. Histological evaluation of veins from later stages of CVI supports this hypothesis [14,15].

It remains still unclear which factors lead to an opening of the venular gaps in the first place. Hypotheses include immunological attacks of unknown origin, hypoxia, nutritive or toxic causes, infections, and acquired or genetic metabolic factors [7,11,16].

In an attempt to find causative forms of therapy for CVI, Nees et al. evaluated the influence of horse-chestnut seeds extracts (HCSE) on the contractility of the venular endothelial cells [11]. They examined the permeability of guinea pig venular endothelium to water applied under pressure (hydraulic conductivity). Application of polymorphonuclear granulocytes and activated thrombocytes to the endothelial cells increased their hydraulic conductivity by a factor of approximately 15 vs. control. This reflected the opening of the endothelial gaps, which could also be observed directly by scanning electron microscopy.

The parallel addition of HCSE inhibited the increase in conductivity in a dose dependant manner and almost completely in a concentration of 0.01 or 0.1 mg/ml (depending on extract used). The addition of the extracts, ten minutes after the polymorphonuclear granulocytes and thrombocytes, even restituted the increased conductivity almost to baseline values. These effects were observed and verified also by scanning electron microscopy. These findings were replicable also in human venular endothelium [Nees, personal communication].

HCSE required the presence of and probably the binding to serum proteins to show an effect (serum proteins alone did not show any effect and were used as a negative control). Possibly serum concentrations of free HCSE in man do not correspond to therapeutic efficacy [11].

Conclusion
We conclude that in early stages of CVI, when the veins and their wall structures have not yet suffered any permanent damage, pharmacological methods may be sufficient to interact with the disease process. Closure of the venular endothelial gaps interrupts the circulus vitiosus. If venules and surrounding tissues have not yet been permanently damaged they have a chance to regenerate.

Also in the later stages of CVI, HCSE may still close the venular endothelial gaps and thus can reduce oedema to some extent, as shown in Study #2 (Figure 1). At this time, however, the disease process has already involved the larger veins, with irreversible damage.

Adequate therapy in this stage of CVI is compression. It increases blood velocity by mechanically reducing the cross-section of the larger veins. Additionally the increased perivascular pressure inhibits the outflow of blood and plasma factors from the endothelial venular gaps, which reduces contact with tissue factor and thus the initial steps of coagulation and thrombosis [11,17,18].

Nevertheless compression cannot restitute destroyed venous structures, but remains a mainly symptomatic therapy. Especially when taking into account the reduced quality of life under compression therapy, patients in the early stages of CVI should be offered pharmacological treatment rather than to wait until the only help is compression.