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PubMed2001

Role of endothelium in shear stress-induced constrictions in rat middle cerebral artery.

BACKGROUND AND PURPOSE: Luminal shear stress has been reported to constrict cerebral arteries and arterioles of several species. Although the endothelium is not required for this response, it is not known whether the endothelium enhances or attenuates shear stress-induced constrictions. METHODS: Middle cerebral arteries (MCAs) were isolated from male Long-Evans rats, mounted in a tissue bath, and pressurized to 80 mm Hg in the absence of luminal flow. In some MCAs, the endothelium was selectively loaded with fura 2 for the measurement of endothelial Ca(2+) concentration. Luminal shear stress was increased by adjusting luminal flow while maintaining a constant intraluminal pressure. RESULTS: After the development of spontaneous tone in MCAs without luminal flow, inside diameters were approximately 190 microm. MCAs constricted approximately 15% when luminal flow was increased to produce a shear stress of 50 dyne/cm(2). The shear stress-induced constrictions were more pronounced in vessels without intact endothelium. Scavenging reactive oxygen species with 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron) or superoxide dismutase/catalase significantly inhibited the shear stress-induced constrictions in vessels with intact endothelium and in vessels in which the endothelium had been removed. In intact vessels, endothelial Ca(2+) increased 33 nmol/L (from 133+/-11 to 166+/-12 nmol/L) when shear stress was increased to 50 dyne/cm(2). The presence of N(G)-nitro-L-arginine methyl ester (L-NAME), L-NAME+indomethacin, or L-NAME+indomethacin+charybdotoxin had no significant effect on the shear stress-induced constrictions in MCAs with intact endothelium. CONCLUSIONS: We conclude that the endothelium plays a role in attenuating the shear stress-induced constrictions in rat MCAS: The attenuation does not appear to be by release of NO, prostacyclin, or endothelium-derived hyperpolarizing factor. The endothelium apparently attenuates the constriction by an unknown dilating factor, by a dilating process, or simply by attenuating the mechanical force of the shear stress as it is transmitted to the abluminal side of the vessel.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗

PubMed1992

Contractions to endothelin in normotensive and spontaneously hypertensive rats: role of endothelium and prostaglandins.

Contractions to endothelin-1 in aortas of the spontaneously hypertensive rats (SHR) were compared with those of normotensive controls (WKY); rings with and without endothelium were studied in organ chambers. Contractions to endothelin were smaller in aortas of SHR compared to WKY, whether the endothelium was present or not. The presence of a functional endothelium reduced contractions to the peptide in both strains. Endothelium-dependent relaxations to acetylcholine and endothelium-independent relaxations to nitric oxide were observed in rings from both strains during contraction with endothelin. Indomethacin reduced the contractions to endothelin in the aorta from SHR with endothelium, but not in those without endothelium; it did not significantly affect endothelin-induced contractions in rings of WKY with or without endothelium. These experiments demonstrate that contractions of the vascular smooth muscle to endothelin are reduced in the aorta of the SHR. The basal and stimulated release of endothelium-derived relaxing factor inhibits contractions to endothelin in the aorta from both strains. The inhibitor of cyclooxygenase indomethacin does not prevent the response of the vascular smooth muscle to endothelin; however, endothelin may stimulate the release of an indomethacin-sensitive endothelium-derived contracting factor in the SHR aorta.

Acetylcholine↗

PubMed1999

Pharmacologic characteristics of non-prostanoid, non-nitric oxide mediated and endothelium-dependent relaxation of guinea-pig aorta in response to substance P.

The pharmacologic characteristics of the non-prostanoid (prostacyclin, PGI2), non-nitric oxide (NO) mediated endothelium-dependent relaxation in response to substance P were examined in the guinea-pig aorta. Substance P, in a concentration-dependent manner, relaxed the ring preparations of guinea-pig thoracic aorta preconstricted with norepinephrine (NE) in an endothelium-dependent manner. Substance P-induced endothelium-dependent relaxation was not affected by indomethacin (3 x 10(-6) M) as in the case of acetylcholine (ACh)-induced endothelium-dependent relaxation. Although N(G)-nitro-L-arginine (L-NNA, 3 x 10(-5) M), an inhibitor of nitric oxide (NO) synthase, significantly inhibited substance P-induced endothelium-dependent relaxation in the presence of indomethacin, about 50% of the vasorelaxant response to substance P remained in the combined presence of L-NNA and indomethacin. By comparison, indomethacin-resistant component of endothelium-dependent relaxation to ACh was mostly suppressed by the treatment with L-NNA plus indomethacin. Substance P-induced non-PGI2, non-NO mediated vascular relaxation was attenuated markedly in high (40 mM) KCl solution or by tetraethylammonium (TEA, 5 x 10(-3) M). Furthermore, substance P-induced non- PGI2, non-NO mediated vascular relaxation was not appreciably affected by glibenclamide (10(-6) M), apamin (10(-7) M), iberiotoxin (1(-7) M), but was greatly attenuated by the combined treatment with charybdotoxin (10(-7) M) plus apamin (10(-7) M), which suggesting that endothelium-derived hyperpolarizing factor(s) (EDHF(s)) mediates the response. Interestingly, after applied repetitively, the substance P-induced vasorelaxant component remaining in the combined presence of indomethacin and L-NNA was decreased more profoundly than the response to substance P in the presence of indomethacin alone. Possible contribution of non-PGI2, non-NO vasorelaxant(s) (EDHF(s)) from the endothelium to the total relaxation response to substance P was greater in thoracic aorta isolated from adult guinea-pigs than that from neonatal ones. These findings suggest that 1) endothelium-dependent vascular relaxation of guinea-pig thoracic aorta in response to substance P is attributable to the release of both NO and EDHF(s); 2) possible release of EDHF(s) from the endothelium of guinea-pig thoracic aorta decreases after repetitive stimulation with substance P; and 3) contribution of EDHF(s) to substance P-induced functional relaxation of the thoracic aorta is greater in adult guinea-pigs than neonatal ones.

Aging↗

PubMed1999

[Mechanism of action of cicletanine on the relationship between endothelium and vascular smooth muscle in the rat thoracic aorta under normoxic and hypoxic conditions].

OBJECTIVE: The vascular mechanism of action of cicletanine, an antihypertensive agent, was studied on isolated Wistar rat aorta in presence and in absence of endothelium both in normoxic and hypoxic conditions. DESIGN AND METHODS: Isolated aorta, from 24 month-old rats, were precontracted with noradrenaline (10(-7) M), in presence and in absence of endothelium and exposed to cumulative cicletanine concentrations in presence and absence of either L-NNA (10(-4) M) or indomethacin (Indo) (10(-7) M). Thereafter, aorta were precontracted by noradrenaline 10(-7) M, and hypoxia was induced by switching gas mixture from 95%O2/5%CO2 to 95%N2/5%CO2 during 10 minutes. Results are expressed as mean +/- sem and statistical analysis were done using one-way analysis of variance. RESULTS: When aorta were precontracted with noradrenaline (10(-7) M), in presence of endothelium, cicletanine (10(-9)-10(-4) M), induced a biphasic concentration-dependent relaxation (EC50 approximately 10(-7) M and 3 x 10(-5) M). In absence of endothelium, the effect of cicletanine was abolished (10(-9) and 10(-5) M). Whereas, at higher concentration (10(-4) M), the magnitude of the relaxation reached 94 +/- 2% and 67 +/- 5% of the initial developed tension in presence and in absence of endothelium respectively. The endothelium-dependent relaxation induced by cicletanine was significantly reduced by Indo (10(-7) M) (p < 0.05) and L-NNA (10(-4) M) (p < 0.005). Addition of 10 mM of BaCl2 significantly reversed the relaxation induced by the higher concentration of cicletanine used (p < 0.005). Under hypoxic conditions, the aorta, in presence of endothelium, displayed an increased developed tension which was significantly attenuated by cicletanine. CONCLUSION: These results indicated that cicletanine relaxes vascular smooth muscle through both, an endothelium-dependent action which was mediated by cyclooxygenase and NOsynthase pathways and an endothelium-independent action that was mediated through K+ channels opening. Under hypoxic conditions, our findings indicate that the effects of cicletanine, appear related to an endothelium protective action associated to NO release.

Animals↗

PubMed2002

Prediction of LDL concentration at the luminal surface of a vascular endothelium.

To find out whether concentration polarization of low-density lipoprotein (LDL) occurs at the surface of a vascular endothelium or not, transport of LDL in flowing blood to an water-permeable endothelium was studied theoretically by means of CFD. Calculations were carried out for an endothelium exposed to a Couette flow by assuming that the surface geometry of the endothelium could be expressed by a cosine function. Two typical cases were considered for the permeability of endothelium to water; one was uniform permeability everywhere in the endothelium, and the other was uneven permeability which was augmented at the intercellular junction. It was found that, in both cases, the surface concentration of LDL increased in going distally from the entrance, taking locally high and low values at the valleys and hills of the endothelium, respectively, and the variation was larger in the case of endothelium with uneven permeability. These results clearly showed that concentration polarization of LDL which might affect the uptake of LDL by the arterial wall certainly occurs at the surface of the endothelium even if the flow is disturbed microscopically by the uneven surface of the endothelium.

Biological Transport↗

PubMed2004

[Human heart and endothelium functional activity depending on age and sex].

The complex study ofcardio-hemodynamics and functional activity of the endothelium in healthy persons of different age allowed us to establish that aging accompanied with a gradual worsening in the endothelium functioning with resulting increase in peripheral vascular resistance and blood pressure as well as decrease in the myocardial contractile activity. Such age shifts might be involved in pathogenesis of cardiovascular diseases, which prevalence is highly rises with increased age. Analysis of sex difference in the endothelium functioning showed a progressing lowering of the endothelium-dependent vasodilatory reaction to begin in the men as early as after 40 years of age. This leads to the decrease in the vasodilatory reserve with increase in peripheral vascular resistance and blood pressure. Worsening in the myocardial contractility in 40-year men can be also stipulated by changing in the endothelium synthetic activity that was evidenced by decrease in plasma levels of NO stable metabolites. In the women, such a lowering of the endothelium functional activity begins 10 years later and progresses more slowly compared to the men. The rate of worsening in the endothelium functioning in the men is twice of that in the women. Therefore, the elderly women have the endothelium to be 20 years "younger" than that in the elderly men, and perhaps namely this explains the better functioning of the cardiovascular system in the elderly women. So, a functional activity of the endothelium can be a main age and sex determinant, which stipulates well-known age and sex differences in prevalence of cardiovascular diseases and life expectancy. Prevention of the endothelium function disturbances might lead to the alignment of the differences between men and women in prevalence of cardiovascular diseases and life expectancy, decrease in general morbidity with improvement of life quality in elderly.

Adult↗

PubMed1989

Hypercholesterolemia impairs endothelium-dependent relaxations to aggregating platelets in porcine iliac arteries.

The purpose of the present study was to examine in peripheral arteries whether the endothelium plays a protective role against aggregating platelets and whether the responses to platelets are altered by hypercholesterolemia. Male Yorkshire pigs were fed either a normal diet or a 2% high-cholesterol diet for 10 weeks. Endothelium-dependent responses were examined in vitro. In isolated iliac arteries from control animals, aggregating platelets caused contractions that were significantly inhibited by the endothelium. In rings with endothelium from pigs fed a cholesterol diet, the contractions were augmented and no difference was noted between rings with and rings without endothelium. In rings taken from control pigs contracted with prostaglandin F2 alpha, aggregating platelets caused endothelium-dependent relaxations, which were attenuated by blockade of adenosine diphosphate or serotonin. Adenosine diphosphate and serotonin also caused endothelium-dependent relaxations. In arteries from cholesterol-fed animals, the inhibitory effects of the endothelium to aggregating platelets, adenosine diphosphate, and serotonin were impaired. These experiments indicate that in porcine iliac arteries the endothelium exerts inhibitory effects on the responses to aggregating platelets, which are mediated by adenosine diphosphate and serotonin released from platelets. Hypercholesterolemia impairs the endothelium-dependent relaxations to aggregating platelets caused by reduced relaxations to adenosine diphosphate and serotonin and unmasks the contractions evoked by aggregating platelets. This may increase the level of vascular tone, decrease blood flow and increase platelet aggregation, and eventually facilitate the occurrence of peripheral arterial occlusive disease.

Animals↗

PubMed1988

Endothelium-dependent effects of carteolol.

Experiments were designed to study the effect of the beta adrenergic antagonist, carteolol, on the endothelium-dependent responsiveness of isolated arteries. Rings of canine coronary arteries were suspended in organ chambers for isometric tension recording; carteolol inhibited the relaxation to isoproterenol and abolished the difference in responsiveness to the beta adrenergic agonist between rings with and without endothelium. Carteolol did not cause endothelium-dependent relaxations of femoral or coronary arteries. In bioassay experiments, carteolol augmented the basal release of relaxing factors from the endothelium of the femoral artery; this effect was prevented by indomethacin. In rings of femoral arteries, carteolol increased the endothelium-dependent relaxations induced by the alpha-2 adrenergic agonist UK 14,304; this was not affected by indomethacin but prevented by propranolol. Carteolol did not modify the endothelium-dependent relaxations to acetylcholine, adenosine diphosphate, bradykinin, thrombin and the Ca+-ionophore A23187. Carteolol inhibited the endothelium-dependent hypoxic contraction of the canine coronary artery. It did not affect endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. These experiments suggest that carteolol facilitates the abluminal release of endothelium-dependent relaxing factor caused by alpha-2 adrenergic activation, and causes the intraluminal release of vasodilator prostaglandins. The compound prevents the endothelium-dependent contractions which are not mediated by products of cyclooxygenase. These actions may contribute to the vasodilatator properties of carteolol in the intact organism.

Acetylcholine↗

PubMed1986

Vascular endothelium contributes to decreased aortic contractility in experimental sepsis.

In this study, we compared responses to norepinephrine (NE) by thoracic aortic rings isolated from rats made septic by cecal ligation with puncture, and aortic tissue from sham-operated control rats. We also examined the responses of septic and sham-operated rat aortas after removal of the vascular endothelium. Acetylcholine caused relaxation of NE-induced contractions in septic and sham tissue with an intact endothelium but had no effect on tissue with the endothelium removed experimentally. In preparations with intact endothelium, septic tissue manifests a significantly diminished maximal contractile response to NE (424 +/- 62 (SE) mg tension/mg tissue) in comparison to sham tissue (747 + 30). Tissues with the endothelium removed show no significant maximal contractile difference between septic (688 +/- 23) and sham (669 +/- 32) preparations, or the equivalent sham tissue with an intact endothelium. No difference in the log ED50 for sham tissue (-7.33 +/- 0.12 M) and septic tissue (-7.53 +/- 0.15) with intact endothelium existed. Removal of the endothelium from both septic and sham tissue shifted the dose response curves to the left, disclosing a significant difference in the ED50 between sham (-8.88 +/- 0.14) and septic (-8.18 +/- 0.20) tissue. In conclusion, a significant impairment of vascular contractility in response to NE, with no change in ED50, persists in septic vascular tissue in vitro, and the sepsis-induced defect in contractility is mediated, at least in part, by vascular endothelium, since removal of the endothelium partially restores the NE-stimulated contraction to normal.

Acetylcholine↗

PubMed1985

Ouabain inhibits endothelium-dependent relaxations to arachidonic acid in canine coronary arteries.

Experiments were designed to analyze the effects of ouabain on the actions of exogenous arachidonic acid on endothelial and vascular smooth muscle cells. Rings or strips were prepared from left circumflex canine coronary arteries and suspended for isometric tension recording in organ chambers filled with oxygenated modified Krebs-Ringer-bicarbonate solution. During contractions evoked by prostaglandin F2 alpha, arachidonic acid caused relaxations both in the presence and the absence of endothelium. However, removal of the endothelium reduced its inhibitory action. Indomethacin prevented the relaxations in rings without endothelium, but did not affect the response to high doses (10(-6) to 10(-5) M) of arachidonic acid in preparations with endothelium. The inhibitor of lipoxygenase, nordihydroguaiaretic acid, had no effect on the inhibitory responses to arachidonic acid in rings with or without endothelium. Ouabain abolished both the endothelium-dependent and the direct relaxations to arachidonic acid. Endothelium-dependent relaxations in response to oleic acid, elaidic acid, adenosine diphosphate and thrombin were not affected by ouabain. In the presence of indomethacin, coronary artery strips without endothelium were relaxed by arachidonic acid only when layered (intimal surface against intimal surface) with a longitudinal strip with endothelium. In layered preparations, treatment of the intact longitudinal strip with ouabain before layering prevented the relaxation, whereas pretreatment of the strip without endothelium had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1984

Cell biology of pulmonary endothelium.

Since the late 1960s, understanding of the cell biology of endothelium has been transformed. Endothelium is not merely a metabolically inert, semipermeable barrier separating blood from parenchyma; rather, it is a layer of metabolically active cells. In lungs, even gas exchange may be assisted by reactions occurring on the endothelial surface. Endothelial cells synthesize specific proteins (some for export); these cells have receptors and enzymes capable of reacting with certain hormones and other excitatory substances as they pass in circulating blood. Endothelium is antithrombogenic unless injured; when injured, endothelium becomes thrombogenic and then thrombolytic. Endothelium may sometimes retard the development of inflammation and at other times may facilitate it. In addition to providing sites for exchange of nutrients and metabolites, endothelium interacts with prohormones and hormones to determine the composition of blood moving downstream. The latter is a key function of pulmonary endothelium: its venous effluent is systemic arterial blood. Efforts to understand how endothelium accomplishes its wide range of metabolic activities have motivated parallel efforts to define the fine structure of the endothelial cell. Thus it has become feasible to visualize habitats of two surface enzymes, angiotensin-converting enzyme and carboxypeptidase N. Efforts to visualize surface enzymes required development of means of replicating cell surfaces, a methodology that in turn provided the first en face view of the glycocalyx. Given the ubiquity of vascular endothelium and its activities, it is difficult to imagine an area of medical practice that can safely ignore requirements for appropriately functioning endothelium.

Cardiology↗

PubMed1994

Enhancement of endothelium-dependent contraction of the canine coronary artery by UW solution.

University of Wisconsin (UW) solution has been used almost routinely in the preservation of the hepatic, pancreatic, renal, and cardiac allografts. However, its effect on vascular endothelium is unknown. Experiments were designed to evaluate its effect on canine coronary endothelium. Canine coronary arteries (n = 8 in each group) were preserved in cold (4 degrees C) UW solution (group 1) and physiological solution (group 2) for 6 hr immediately after harvesting. Segments of preserved and control (group 3) coronary arteries with or without endothelium were then suspended in organ chambers to measure isometric force. Perfusate hypoxia (pO2 30 +/- 5 mmHg) caused endothelium-dependent contraction in the arteries of all 3 groups. However, vascular segments with endothelium of group 1 exhibited hypoxic contractions (107 +/- 26% of the initial tension contracted by prostaglandin F2 alpha 2 x 10(-6) mol/L, P < 0.05) that were significantly greater than those of the group 2 and group 3 segments with endothelium (25 +/- 5% and 20 +/- 4%). The hypoxic contraction in arteries of group 1 could be attenuated by NG-monomethyl-L-arginine (L-NMMA), the blocker of endothelial cell synthesis of the nitric oxide from L-arginine. The action of L-NMMA could be reversed by L-arginine but not D-arginine. Endothelium-dependent relaxation of coronary endothelium to acetylcholine and adenosine diphosphate and endothelium-independent relaxation and contraction of coronary smooth muscle were not altered by the UW solution. After preservation with the UW solution, endothelium-dependent contraction of the canine coronary arteries, occurs by L-arginine-dependent pathway, is enhanced. This augmentation by the UW solution would favor vasospasm after transplantation.

Acetylcholine↗

PubMed1996

Expression of cell cycle-associated proteins in human and rabbit corneal endothelium in situ.

PURPOSE: It is unknown why human corneal endothelium exhibits limited capacity to divide while the endothelia of other species, such as rabbit, divide in vivo at wounding and in culture. A potentially valuable source of information concerning why human endothelium has such a limited proliferative capacity lies in elucidating any differences in the molecular events governing the cell cycle of these two species. A recent study of the relative expression of cell cycle-associated proteins in donor corneas suggests that human corneal endothelial cells in vivo have not exited the cell cycle but are arrested in G1-phase. The purpose of the current study was to identify differences in cell cycle protein expression in human and rabbit endothelium that would explain the difference in their relative proliferative capacities. Specifically, the authors first ascertained the relative proliferative status of rabbit corneal endothelial cells in vivo. The expression and intracellular distribution of G1-phase regulatory proteins was then determined in both species, and the results were compared. METHODS: Corneas from New Zealand white rabbits (weight range, 2 to 3 kg) and from human donors (age range, 6 months to 67 years) were fresh frozen, cryostat sectioned, and prepared for indirect immunofluorescence microscopy using an established protocol. The following monoclonal antibodies were localized in rabbit corneal endothelium only: cyclins D, E, A, and B1; protein kinase p34cdc2; and Ki67, a marker of actively cycling cells. Localization patterns for the following G1-phase regulatory proteins were compared in both human and rabbit corneal endothelia: the tumor suppressors, pRb, p53, and p16INK4, and the transcription factor, E2F. Reverse transcription-polymerase chain reaction studies were conducted to detect mRNA for Ki67 in human and rabbit corneal cells. RESULTS: Cyclins D, E, and A were localized in the cytoplasm of rabbit corneal endothelium, whereas cyclins B1 and p34cdc2 were detected in the nucleus. No Ki67 protein or mRNA expression was detected in the endothelium of either species. In human and rabbit endothelia, p53 and p16INK4 were localized to the cytoplasm, whereas pRb was detected in the nucleus. E2F exhibited a nuclear and a cytoplasmic localization in each species. CONCLUSIONS: The corneal endothelium of rabbits stained positively for cyclins D, E, and A and did not stain for Ki67, suggesting that, as in humans, rabbit corneal endothelium in vivo is arrested in G1-phase upstream from Ki67 synthesis. Cyclin E was located in the cytoplasm of rabbit cells, whereas it was found in the nucleus in human endothelium. The apparent difference in cellular distribution of cyclin E in these two species may be significant because this cyclin is active during the G1-/S-phase transition. It is possible that in situ human and rabbit corneal endothelial cells are arrested at different points within G1-phase and/or that the difference in relative proliferative capacity exhibited by the corneal endothelium in these two species may be caused by differences in their relative ability to overcome G1-phase arrest.

Adolescent↗

PubMed1993

Endothelium-derived contracting and relaxing factors contribute to hypoxic responses of pulmonary arteries.

The response of porcine pulmonary arteries to hypoxia depended on their location in the vasculature and the degree and duration of the hypoxic challenge. In rings of pulmonary artery suspended for isometric tension recording (37 degrees C, 16% O2 and 5% CO2), moderate hypoxia (10% and 4% O2) caused endothelium-dependent relaxation in distal arteries but transient endothelium-dependent contraction in proximal arteries. In both proximal and distal arteries, the initial response to anoxia (0% O2) was a transient endothelium-dependent contraction. This was followed by a slowly developing, sustained endothelium-dependent contraction in proximal arteries, or by an endothelium-independent relaxation in distal arteries. The endothelium-dependent relaxation to moderate hypoxia in distal arteries was inhibited only by combined inhibition of endothelium-derived relaxing factor (EDRF)-nitric oxide (NO) synthase [N omega-nitro-L-arginine methyl ester (L-NAME)] and cyclooxygenase (indomethacin), suggesting mediation by EDRF-NO and prostacyclin. Transient endothelium-dependent contractions to moderate hypoxia (proximal arteries) or anoxia (all arteries) were abolished by L-NAME, but the late endothelium-dependent anoxic contraction observed in proximal arteries was not reduced by L-NAME and/or indomethacin. Therefore, hypoxia/anoxia may initiate contraction of pulmonary arteries by decreasing the activity of EDRF-NO, but the contractions appear to be maintained by an increased activity of an endothelium-derived contracting factor.

Acetylcholine↗

PubMed1992

Endothelium-derived contracting factors.

The endothelium not only mediates relaxation but is a source of contracting factors. Endothelium-dependent contractions are elicited by physical and chemical stimuli (i.e., hypoxia, pressure, and stretch) and autacoids, local and circulating hormones. The mechanism of endothelium-dependent contractions to hypoxia involves withdrawal of nitric oxide. The endothelial cyclooxygenase pathway can produce thromboxane A2, prostaglandin H2, and superoxide anions. The peptide endothelin is a potent contracting factor; its production is stimulated by vasopressor hormones, platelet-derived factors, coagulation products, and cytokines, whereas endothelium-derived nitric oxide, prostacyclin, and a smooth muscle cell-derived inhibitory factor reduce endothelin production. In hypertension, the release of cyclooxygenase-dependent endothelium-derived contracting factors to stretch, acetylcholine, and platelet-derived products is augmented. Vascular endothelin production in hypertension remains controversial but appears mostly normal; it is augmented in the presence of vascular disease or renal insufficiency. The endothelium-dependent inhibition of endothelin-induced contractions is reduced in hypertension while the reactivity of vascular smooth muscle may be normal, increased, or reduced. The potentiating effects of low concentrations of endothelin on contractions to norepinephrine are augmented with aging and hypertension. In atherosclerosis, the production of the cyclooxygenase-dependent endothelium-derived contracting factors and endothelin is enhanced. Thus, endothelium-derived contracting factors can profoundly affect vascular tone and counteract relaxing factors produced within the endothelium. In hypertension and atherosclerosis, the role of contracting factors appears to become more dominant, leading to an imbalance of endothelium-dependent vascular regulation.

Endothelins↗

PubMedDate not supplied

Guanidino succinic acid is not the endogenous source of endothelium-derived relaxing factor in the porcine isolated splenic artery.

The possibility that guanidino succinic acid is the major endogenous source of endothelium-derived relaxing factor has been examined using the porcine isolated splenic artery. Administration of 100 microM NG-nitro-L-arginine methyl ester (L-NAME) caused a substantial, endothelium-dependent contraction of the splenic artery that was inhibited by L-arginine (1 mM) but was unaffected by D-arginine (1 mM). L-NAME enhanced the responsiveness of the splenic artery to 5-hydroxytryptamine in endothelium-intact segments only, and the potentiating action of L-NAME was inhibited by L-arginine but not by D-arginine. Administration of 100 microM guanidino succinic acid did not relax the splenic artery and it did not inhibit or reverse contractions of the splenic artery induced by L-NAME. Administration of guanidino succinic acid, either before or after L-NAME, did not affect the potentiating action of L-NAME on the 5-hydroxytryptamine-induced contraction of the splenic artery in endothelium-intact segments. Although substance P caused an endothelium-dependent relaxation of preconstricted segments of the splenic artery, guanidino succinic acid did not relax preconstricted, endothelium-intact or endothelium-denuded segments of the artery. L-NAME inhibited the relaxation induced by substance P in endothelium-intact preparations. The findings for the effects of arginine are consistent with L-arginine being a source of endothelium-derived relaxing factor in the porcine splenic artery, while observations with guanidino succinic acid indicate that it is not a substrate for the synthesis of endothelium-derived relaxing factor in this blood vessel.

Animals↗

PubMed1996

Vascular adhesion protein 1 mediates binding of T cells to human hepatic endothelium.

BACKGROUND & AIMS: Molecules that regulate T-cell adhesion to hepatic endothelium and thereby recirculation of T cells to the liver are poorly understood. Because the adhesion molecule vascular adhesion protein-1 (VAP-1), which mediates lymphocyte binding to lymph node endothelium, is expressed on hepatic endothelium, it could play a role in regulating T-cell recruitment to the liver. The aim of this study was to investigate the distribution of VAP-1 expression in human liver and the ability of VAP-1 to support T-cell binding to hepatic endothelium in vitro. METHODS: Hepatic VAP-1 expression was investigated using immunohistochemistry and specific monoclonal antibodies, and VAP-1-mediated adhesion to hepatic endothelium was investigated with a tissue-binding adhesion assay using human liver sections. RESULTS: VAP-1 was expressed on sinusoidal and vascular endothelium in non-inflamed liver and in inflamed liver from patients with either allograft rejection or primary biliary cirrhosis. T cells from healthy donors bound to hepatic endothelium when added to noninflamed liver sections; this binding was inhibited by a specific anti-VAP-1 antibody but not by antibodies to intercellular adhesion molecule 1, lymphocyte function--associated antigen 1, or very late after activation (antigen) 4. VAP-1--mediated adhesion was unaffected by T-cell activation with phorbol ester. CONCLUSIONS: VAP-1 is constitutively expressed on hepatic endothelium and mediates T-cell adhesion to hepatic endothelium in vitro. VAP-1 could play a critical role in regulating T-cell recirculation to the liver in vivo.

Cell Adhesion↗

PubMed1996

The unique role of interferon-gamma in the regulation of MHC expression on arterial endothelium.

We examined the expression of MHC class I and II in the arterial endothelium of interferon-gamma (IFN-gamma, GKO) and IFN-gamma-R (IFN-gamma-R, GRKO) gene knockout mice in comparison with mice with intact IFN-gamma and IFN-gamma-R genes, BALB/c and 129Sv/J wild-type, respectively. The GKO and GRKO were produced by gene targeting. MHC class I and II expression was assessed by mAb binding to frozen tissue (kidney, spleen, heart, liver) sections by immunoperoxidase staining in the basal state and after various stimuli: allogeneic cells, oxazolone skin sensitization, LPS, and rIFN-gamma. As controls, we also examined the expression of two other IFN-gamma inducible genes present in the endothelium, Ly-6 and ICAM-1. We found that basal class I expression was present in the small arteries and arterioles of BALB/c and 129Sv/J wild-type mice but absent from arterial endothelium of GKO and GRKO mice. Class I was induced in the endothelium of BALB/c and 129Sv/J wild-type mice by three in vivo stimuli: allogeneic, LPS, and oxazolone, whereas class II was only induced after allogeneic stimulus. Administration of rIFN-gamma induced class I in the endothelium of GKO and BALB/c wild-type mice. The basal expression of Ly-6 and ICAM-1 was similar in the arteries of GKO and BALB/c wild-type mice, indicating that, the basal expression of these proteins in endothelium is IFN-gamma independent, unlike class I. In summary, basal class I expression in arterial endothelium is not constitutive as previously believed, but is dependent on basal IFN-gamma production. IFN-gamma has an essential role in the induction of class I and II expression in arterial endothelium. The fact that MHC class I is induced in endothelium may be useful therapeutically for reduction of immune recognition in transplantation.

Animals↗