Laminar Shear, but Not Oscillatory Shear, Has a Synergistic Effect with Thrombin Stimulation on Tissue Factor Expression in HUVEC (original) (raw)
Related papers
2000
Shortterm exercise training increases ACh-induced relaxation and eNOS protein in porcine pulmonary arteries. J Appl Physiol 90: [1102][1103][1104][1105][1106][1107][1108][1109][1110] 2001.-We tested the hypothesis that shortterm exercise (STEx) training and the associated increase in pulmonary blood flow during bouts of exercise cause enhanced endothelium-dependent vasorelaxation in porcine pulmonary arteries and increased expression of endothelial cell nitric oxide synthase (eNOS) and superoxide dismutase-1 (SOD-1) protein. Mature, female Yucatan miniature swine exercised 1 h twice daily on a motorized treadmill for 1 wk (STEx group, n ϭ 7); control pigs (Sed, n ϭ 6) were kept in pens. Pulmonary arteries were isolated from the left caudal lung lobe, and vasomotor responses were determined in vitro. Arterial tissue from the distal portion of this pulmonary artery was processed for immunoblot analysis. Maximal endothelium-dependent (ACh-stimulated) relaxation was greater in STEx (71 Ϯ 5%) than in Sed (44 Ϯ 6%) arteries (P Ͻ 0.05), and endothelium-independent (sodium nitroprusside-mediated) responses did not differ. Sensitivity to ACh was not altered by STEx training. Immunoblot analysis indicated a 3.9-fold increase in eNOS protein in pulmonary artery tissue from STEx pigs (P Ͻ 0.05) with no change in SOD-1 or glyceraldehyde-3-phosphate dehydrogenase protein levels. We conclude that STEx training enhances AChstimulated vasorelaxation in pulmonary arterial tissue and that this adaptation is associated with increased expression of eNOS protein.
Reactive oxygen species as therapeutic targets in pulmonary hypertension
Therapeutic Advances in Respiratory Disease, 2013
Pulmonary hypertension (PH) is characterized by a progressive elevation of pulmonary arterial pressure due to alterations of both pulmonary vascular structure and function. This disease is rare but life-threatening, leading to the development of right heart failure. Current PH treatments, designed to target altered pulmonary vascular reactivity, include vasodilating prostanoids, phosphodiesterase-5 inhibitors and endothelin-1 receptor antagonists. Although managing to slow the progression of the disease, these molecules still do not cure PH. More effective treatments need to be developed, and novel therapeutic strategies, targeting in particular vascular remodelling, are currently under investigation. Reactive oxygen species (ROS) are important physiological messengers in vascular cells. In addition to atherosclerosis and other systemic vascular diseases, emerging evidence also support a role of ROS in PH pathogenesis. ROS production is increased in animal models of PH, associated with NADPH oxidases increased expression, in particular of several Nox enzymes thought to be the major source of ROS in the pulmonary vasculature. These increases have also been observed in vitro and in vivo in humans. Moreover, several studies have shown either the deleterious effect of agents promoting ROS generation on pulmonary vasculature or, conversely, the beneficial effect of antioxidant agents in animal models of PH. In these studies, ROS production has been directly linked to pulmonary vascular remodelling, endothelial dysfunction, altered vasoconstrictive responses, inflammation and modifications of the extracellular matrix, all important features of PH pathophysiology. Altogether, these findings indicate that ROS are interesting therapeutic targets in PH. Blockade of ROS-dependent signalling pathways, or disruption of sources of ROS in the pulmonary vasculature, targeting in particular Nox enzymes, represent promising new therapeutic strategies in this disease.
AJP: Heart and Circulatory Physiology, 2007
Congenital cardiac defects associated with increased pulmonary blood flow (Q p ) produce pulmonary hypertension. We have previously reported attenuated endothelium-dependent relaxations in pulmonary arteries (PA) isolated from lambs with increased Q p and pulmonary hypertension. To better characterize the vascular alterations in the nitric oxide-superoxide system, twelve fetal lambs underwent in-utero placement of an aorto-pulmonary vascular graft (shunt). Twin lambs served as controls. PA were isolated from these lambs at 4-6 weeks of age. Electron paramagnetic resonance spectroscopy on fourth generation PA showed significantly increased superoxide anion generation in shunt PA that were decreased to control levels following inhibition of nitric oxide synthase (NOS) with 2-Ethyl-2-thiopseudourea. Preconstricted fifth generation PA rings were relaxed with a NOS agonist (A23187), a NO donor (SNAP), polyethylene glycol conjugated superoxide dismutase (PEG-SOD), or H 2 O 2 . A23187, PEG-SOD and H 2 O 2 mediated relaxations were impaired in shunt PA compared to controls. Pretreatment with PEG-SOD significantly enhanced the relaxation response to A23187 and SNAP in shunt but not control PA. Inhibition of NOS with L-nitroarginine or scavenging superoxide anions with tiron enhanced relaxation to SNAP and inhibited relaxation to PEG-SOD in shunt PA. Pretreatment with catalase inhibited relaxation of shunt PA to A23187, SOD and H 2 O 2 . We conclude that NOS catalyzes the production of superoxide anions in shunt PA. PEG-SOD relaxes shunt PA by converting these anions to H 2 O 2 , a Page 3 of 39 Copyright Information 4 pulmonary vasodilator. The redox environment, influenced by the balance between production and scavenging of ROS, may have important consequences on pulmonary vascular reactivity in the setting of increased Q p .
Superoxide and endothelium-dependent constriction to flow in porcine small pulmonary arteries
British Journal of Pharmacology, 1998
The aim of this study was to determine the response of porcine small pulmonary arteries to intralumenal ow and to identify the cellular mechanisms and potential mediators involved in the response. 2 Porcine small pulmonary arteries were isolated from a branch of the main intrapulmonary artery of the lower lung lobe and studied in a perfusion myograph system that allowed independent control of transmural pressure and intralumenal¯ow. At a transmural pressure of 20 mmHg, the baseline internal diameter (BID) of the arteries was 251.2+16.1 mm (n=16). 3 Under quiescent conditions or during constriction with U46619 to *60% of BID, intralumenal¯ow caused reversible constriction in arteries with endothelium (in the presence of U46619,¯ow decreased diameter from 60.0+2.5% to 49.5+3.0% BID at 10 ml min 71 , n=16, P50.05) but no change in diameter of arteries without endothelium. 4 In the presence of superoxide dismutase (SOD, 150 u ml 71), the response to¯ow was converted from constriction to vasodilatation (in presence of U46619 and SOD,¯ow increased diameter from 54.2+3.4% to 76.7+4.5% BID at 10 ml min 71 , n=10, P50.05). Inhibition of NO synthase with L-NAME (3610 75 M) abolished the¯ow-induced vasodilatation occurring in the presence of SOD and thē ow-induced constriction occurring in the absence of SOD. In arteries with endothelium, L-NAME (3610 75 M) caused signi®cant vasoconstriction, whereas SOD did not alter vasomotor tone. 5 Acetylcholine (10 78 to 10 76 M) caused endothelium-dependent relaxation of small pulmonary arteries that was not signi®cantly aected by SOD (150 u ml 71) but was inhibited by L-NAME (3610 75 M). 6 These results suggest that in small, porcine, isolated pulmonary arteries, intralumenal¯ow increases the production of NO but this is obscured by the generation of superoxide which causes vasoconstriction.
AJP: Heart and Circulatory Physiology, 2007
Growth-related oncogene-α (GRO-α) is a member of the CXC chemokine family, which is involved in the inflammatory process including atherosclerosis. We hypothesized that GRO-α may affect endothelial functions in both porcine coronary arteries and human coronary artery endothelial cells (HCAECs). Vasomotor function was analyzed in response to thromboxane A2 analog U-46619 for contraction, bradykinin for endothelium-dependent vasorelaxation, and sodium nitroprusside (SNP) for endothelium-independent vasorelaxation. In response to 10−6 M bradykinin, GRO-α (50 and 100 ng/ml) significantly reduced endothelium-dependent vasorelaxation by 34.73 and 48.8%, respectively, compared with controls ( P < 0.05). There were no changes in response to U-46619 or SNP between treated and control groups. With the lucigenin-enhanced chemiluminescence assay, superoxide anion production in GRO-α-treated vessels (50 and 100 ng/ml) was significantly increased by 50 and 86%, respectively, compared with cont...
Suppression of Oxidative Stress in the Endothelium and Vascular Wall
Endothelium, 2004
There is growing evidence that oxidative stress, meaning an excessive production of reactive oxygen and nitrogen species, underlies many forms of cardiovascular disease. The major source of oxidative stress in the artery wall is an NADPH oxidase. This enzyme complex in vascular cells, including endothelium, differs from that in phagocytic leucocytes in both biochemical structure and functions. The crucial flavin-containing catalytic subunits Nox1 and Nox4 are not present in leucocytes, but are highly expressed in vascular cells and upregulated in vascular remodeling, such as that found in hypertension and atherosclerosis. This offers the opportunity to develop "vascular specific" NADPH oxidase inhibitors that do not compromise the essential physiological signaling and phagocytic function carried out by reactive oxygen and nitrogen molecules. Although many conventional antioxidants fail to significantly affect outcomes in cardiovascular disease, targeted inhibitors of NADPH oxidase that block the source of oxidative stress in the vasculature are more likely to prevent the deterioration of vascular function that leads to stroke and heart attack.