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PubMed1992

Modulation of venular microvessel permeability by calcium influx into endothelial cells.

It has been proposed that calcium ion influx into endothelial cells modulates the permeability of venular microvessels via a calcium-dependent contractile process. The results of recent investigations using permeabilized endothelial cell monolayers conform to this hypothesis by demonstrating a calcium-dependent interaction of endothelial actin and myosin during the retraction of adjacent endothelial cells exposed to inflammatory agents. Little is known about the pathway for calcium influx into endothelial cells after exposure to mediators of inflammation, but evidence suggests that the properties of the calcium entry pathways are similar to the calcium entry pathways that regulate the release of endothelium-derived relaxing factor (EDRF). Substances that stimulate EDRF release from arterial endothelium also increase venular microvessel permeability. Recently developed methods to measure cytoplasmic calcium concentration in the endothelial cells forming the walls of individually perfused microvessels enable a direct investigation of the modulation of the permeability of venular microvessels by calcium influx. These experiments demonstrate that the magnitude of the initial increase in the permeability of microvessels after exposure to an agent that increases permeability, such as a calcium ionophore, is determined by the magnitude of calcium ion influx into the endothelial cells. Furthermore, the magnitude of the calcium influx into endothelial cells is modulated by the membrane potential of the endothelial cells. Depolarization of the endothelial cell membrane reduces calcium influx and attenuates increases in permeability whereas hyperpolarization of the endothelial membrane increases calcium influx and potentiates increases in permeability. These data conform to the hypothesis that a passive conductance channel for calcium is a major pathway for calcium ion flux responsible to eliciting an increase in the permeability of the endothelial barrier in microvessels.

Animals↗

PubMed2002

Peripheral blood eosinophilia and eosinophil accumulation in coronary microvessels in acute Kawasaki disease.

BACKGROUND: Early stage Kawasaki disease (KD) histopathology includes perivasculitis and vasculitis of the microvessels. The lesions then extend to larger vessels. Therefore the analysis of microvessel lesions is important to better understand the initial pathogenesis of KD vasculitis. METHODS AND RESULTS: We studied epicardial microvessel lesions (<50 microm) and aneurysm lesions of paraffin-embedded cardiac tissues from 4 Japanese patients who died 7 to 22 days after KD onset. The cellular composition in the microvessel lesions was different from that in coronary aneurysm lesions; eosinophils were preferentially accumulated in the microvessel lesions. The average population of eosinophils was 16% of total infiltrated cells in the microvessel lesions, whereas it was 3% in the intima of aneurysm walls. We examined peripheral blood eosinophil cell counts in 95 KD patients and 95 febrile age-matched controls. Baseline eosinophil cell counts in KD patients were higher than those in febrile control patients (361 +/- 441 65 +/- 133; < 0.0001). Eosinophilia (>350 cells/microl) before therapy was documented in 36% of KD patients, but in only 4% of febrile controls ( < 0.0001). Sixty-six KD patients (69%) developed eosinophilia within 2 weeks of illness. CONCLUSIONS: Because the numbers of circulating eosinophils in the body are tightly regulated, eosinophil accumulation in blood or tissues may reflect the host's immune response against KD related antigen(s).

Child, Preschool↗

PubMed2005

In vivo quantification of the structural abnormalities in psoriatic microvessels before and after pulsed dye laser treatment.

BACKGROUND: Microvascular abnormalities (capillary elongation, widening and tortuosity) are a characteristic feature of psoriasis and form one of the pathological diagnostic criteria. These changes occur early in the progression of a psoriatic plaque, before there is clinical or histological evidence of epidermal hyperplasia. Treatment of psoriatic microvessels with a pulsed dye laser (PDL) has been associated with both clinical improvement and clearance of lesions. OBJECTIVES: To quantify the structural vascular abnormalities in plaque skin using noninvasive techniques in vivo. Investigations were carried out before and after PDL treatment to determine the nature of laser-induced microvascular changes and the relationship between these changes and clinical improvement. METHODS: Plaque microvessels were visualized using native capillaroscopy. Plaques were then treated three times with the PDL at 14-day intervals. Native capillaroscopy was repeated at 2 and 6 weeks after the final laser treatment. Images were analysed using a combination of nonstereological and stereological measurements. RESULTS: Whole body disease was stable. Treated plaques showed a 48% reduction in plaque severity score (P < 0.01). Native studies showed that the PDL significantly reduced plaque microvessel density (P < 0.05), image area fraction (P < 0.01), microvessel length density (P < 0.01) and vessel image width (P < 0.01). The reduction in plaque severity score (which denoted clinical improvement) was related quantitatively to the reduction in microvessel area per unit area of plaque skin, i.e. the image area fraction (correlation coefficient = 0.772, P < 0.01). The greatest response of plaque microvessels was within 2 weeks after the final laser treatment, while the greatest reduction in plaque severity score occurred between 2 and 6 weeks after the final laser treatment, i.e. clinical improvement was preceded by microvascular improvement. CONCLUSIONS: These findings indicate that there is a close correlation between the state of the superficial vasculature and the clinical status of psoriasis. The expanded superficial microvascular bed in plaque skin is a necessary component for maintaining clinical lesions and these blood vessels are thus a legitimate target for treatment.

Adult↗

PubMed2004

Ageing and exposure to oxidative stress in vivo differentially affect cellular levels of PrP in mouse cerebral microvessels and brain parenchyma.

The biological function of cellular prion protein PrPc has not been established, despite in vitro studies suggesting antioxidant activity or link to signal transduction pathways. In this study, mice were exposed to hyperoxia to establish whether oxidative stress affected prion expression in vivo. C57Bl/6J mice aged 6, 18, and 24 months, maintained under normoxic conditions, exhibited age-related increases in PrPc in both cerebral microvessels and in microvessel-depleted brain homogenate. We demonstrate that PrPc is differentially affected by exposure to hyperoxia in vivo for 1 (24 h) or 2 (48 h) days, or for 1 day hyperoxia, followed by 1 day normoxia. Brain parenchymal cells from 6-month-old mice exposed to 1 day hyperoxia showed elevation of a glycosylated approximately 36 kDa form, whereas in 24-month-old mice cellular prion level was substantially reduced. Extending hyperoxia from 1 to 2 days resulted in significantly reduced PrPc level, regardless of age. Parenchymal PrPc is substantially elevated in 6-month-old mice, but declines in 18- and 24-month-old animals following 1 day hyperoxia. By contrast, PrPc content in cerebral microvessels from 6-month-old mice declined after a 2 day exposure to hyperoxia, while microvessels from 24-month-old brains showed elevated prion levels 24 h after hyperoxia. Moreover, unglycosylated 25-30 kDa PrPc, and a previously undescribed 50-64 kDa band containing at least some glycosylated protein, predominated in microvessels with lesser content of the glycosylated approximately 36 kDa form. Cellular content of these unglycosylated forms was correlated with age, while the response to hyperoxia was evident in both unglycosylated and glycosylated forms of the protein following 1 and 2 day exposures. The observed elevation of the 25-30 and 50-64 kDa bands of microvessel PrPc is not sustainable following 1 day hyperoxia, but returns to near normoxic levels within 24 h after hyperoxia. We also show in a knockout mouse for methionine sulfoxide reductase (MsrA), the enzyme responsible for reducing methionine sulfoxide back to methionine, and a regulator of cellular antioxidant defence, that following hyperoxia brain PrPc in the null mutant is elevated relative to PrPc content in the parent strain. Our results show up-regulated PrPc expression or reduced turnover in response to age-related, and hyperoxia-induced oxidative stress.

Aging↗

PubMed1985

Rapid sequestration and degradation of somatostatin analogues by isolated brain microvessels.

Somatostatin (SRIF) is a putative peptide neurotransmitter that may interact with brain capillaries following neurosecretion of the peptide. The present studies investigate the binding and metabolism of SRIF analogues in isolated bovine brain microvessels. 125I-[Tyr1]SRIF was rapidly degraded by capillary aminopeptidase with a half-time of approximately 3 min at 23 degrees C. The microvessel aminopeptidase had a low affinity and high capacity for the peptide, Km = 76 microM and Vmax = 74 nmol min-1 mgp-1. 125I-[Tyr11]SRIF was converted to free iodotyrosine at a much slower rate, presumably by a lower-activity endopeptidase. 125I-[Try11]SRIF was rapidly bound by microvessels, whereas another basic peptide, [Tyr8]bradykinin, or an acidic peptide, CCK8, or a neutral peptide, leucine enkephalin, were bound to a considerably less extent. The binding of 125I-[Tyr11]SRIF to the capillaries was nonsaturable up to a concentration of 1 microgram/ml of unlabeled peptide, and the binding reaction was extremely rapid, reaching equilibrium within 5 s at either 0 degrees C or 37 degrees C. Approximately 20% of the SRIF bound by the microvessels was resistant to acid wash and presumably represented internalized peptide. In addition, the 125I-[Tyr11]SRIF bound rapidly to the endothelial cytoskeleton remaining after a 1% Triton X-100 extraction of the microvessels. The peptide-cytoskeletal binding reaction was nonsaturable up to 1 microgram/ml of unlabeled [Tyr11]SRIF, but it was inhibited by 0.5% polylysine or 0.8 M KCl and was stimulated by 1 mM dithiothreiotol. These studies suggest that brain microvessels rapidly sequester and degrade SRIF analogues and that this may represent one mechanism for rapid inactivation of the neuropeptides subsequent to neurosecretion.

Aminopeptidases↗

PubMed1986

Nucleoside transporter of cerebral microvessels and choroid plexus.

The nucleoside transporter of cerebral microvessels and choroid plexus was identified and characterized using [3H]nitrobenzylthioinosine (NBMPR) as a specific probe. [3H]NBMPR bound reversibly and with high affinity to a single specific site in particulate fractions of cerebral microvessels, choroid plexus, and cerebral cortex of the rat and the pig. The dissociation constants (KD 0.1-0.7 nM) were similar in the various tissue preparations from each species, but the maximal binding capacities (Bmax) were about fivefold higher in cerebral microvessels and choroid plexus than in the cerebral cortex. Nitrobenzylthioguanosine and dipyridamole were the most potent competitors for [3H]NBMPR binding. Several naturally occurring nucleosides displaced specific [3H]NBMPR binding to cerebral microvessels in vitro, in a rank order that correlated well with their ability to cross the blood-brain barrier in vivo. Adenosine analogues and theophylline were less effective in displacing [3H]NBMPR binding than in displacing adenosine receptor ligands. Photoactivation of cerebral microvessels and choroid plexus bound with [3H]NBMPR followed by solubilization and polyacrylamide gel electrophoresis labeled a protein(s) with a molecular weight of approximately 60,000. These results indicate that cerebral microvessels and choroid plexus have a much higher density of the nucleoside transporter moiety than the cerebral cortex and that this nucleoside transporter has pharmacological properties and a molecular weight similar to those of erythrocytes and other mammalian tissues.

Adenosine↗

PubMed1989

Brain microvessels produce 12-hydroxyeicosatetraenoic acid.

Cerebral microvessels isolated from perfused, adult murine brain produce a compound with the chromatographic properties of a monohydroxyeicosatetraenoic acid when incubated with arachidonic acid or stimulated with calcium ionophore A23187. The formation of this arachidonic acid metabolite is not reduced in the presence of the cyclooxygenase inhibitor ibuprofen, but it is abolished by the lipoxygenase inhibitor nordihydroguaiaretic acid. Analysis by gas chromatography combined with chemical ionization and electron impact mass spectrometry of reduced and nonreduced derivatives of the metabolite, indicate that the compound is 12-hydroxyeicosatetraenoic acid. Fractions of isolated microvessels enriched with capillaries produce 2.1 times more 12-hydroxyeicosatetraenoic acid per microgram of protein than do fractions of microvessels enriched with arterioles. These studies confirm that brain microvessels can produce 12-hydroxyeicosatetraenoic acid and strongly suggest that cerebral endothelia are the primary source of microvessel-derived 12-hydroxyeicosatetraenoic acid. They further suggest that in brain injury, the liberation and accumulation of arachidonic acid in cerebral tissues may lead to the production of 12-hydroxyeicosatetraenoic acid within microvessels. The 12-hydroxyeicosatetraenoic acid formed in this way may mediate some of the blood-brain barrier and cerebrovascular dysfunction that occurs following stroke, brain trauma, or seizures.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1994

Ontogenic increase in PGE2 and PGF2 alpha receptor density in brain microvessels of pigs.

1. The hypothesis that the relative vasoconstrictor ineffectiveness of prostaglandin E2 (PGE2) and PGF2 alpha on cerebral vessels of newborn pigs might be due to fewer receptors for these prostanoids was tested by comparing receptors for PGE2 (EP) and PGF2 alpha (FP) in cerebral microvessels from newborn and adult pigs. 2. Specific binding of [3H]-PGE2 and [3H]-PGF2 alpha to membranes prepared from brain microvessels showed that EP and FP receptor density (Bmax) in tissues from newborn animals was less than 50% of that determined in tissues from adults. By contrast, estimates of affinity (KD) were unchanged. 3. Specifically bound [3H]-PGE2 to brain microvessels from both the newborn and adult was displaced by AH 6809 (EP1-selective antagonist) by 80-90%, and only by approximately 30-35% by both 11-deoxy PGE1 (EP2/EP3 agonist) and M&B 28,767 (EP3 agonist); butaprost (EP2 agonist) was completely ineffective. 4. PGE2, 17-phenyl trinor PGE2 (EP1 agonist), PGF2 alpha and fenprostalene (PGF2 alpha analogue) caused significantly less increase in inositol 1,4,5-triphosphate (IP3) in brain microvessels from the newborn than in those from adult pigs. The stimulation of IP3 by PGE2 and 17-phenyl trinor PGE2 was almost completely inhibited by the EP1 antagonist, AH 6809. 5. PGE2, 11-deoxy PGE1 and M&B 28,767 produced small reduction of adenosine 3':5'-cyclic monophosphate (cyclic AMP) production in adult vessels but no effect in newborn tissues. 6. The lower density of EP and FP receptors in microvessels of newborn pigs compared to adults may explain the reduced ability of PGE2 and PGF2 alpha to stimulate production of IP3 in tissues from newborn animals. This in turn, may provide an explanation for previous observations demonstrating that these prostanoids elicit contraction of adult cerebral microvessels, but exert minimal effects on these vessels in newborn animals.

Animals↗

PubMed2005

Clostridium perfringens epsilon-toxin increases permeability of single perfused microvessels of rat mesentery.

Epsilon-toxin, the primary virulence factor of Clostridium perfringens type D, causes mortality in livestock, particularly sheep and goats, in which it induces an often-fatal enterotoxemia. It is believed to compromise the intestinal barrier and then enter the gut vasculature, from which it is carried systemically, causing widespread vascular endothelial damage and edema. Here we used single perfused venular microvessels in rat mesentery, which enabled direct observation of permeability properties of the in situ vascular wall during exposure to toxin. We determined the hydraulic conductivity (L(p)) of microvessels as a measure of the response to epsilon-toxin. We found that microvessels were highly sensitive to toxin. At 10 microg ml(-1) the L(p) increased irreversibly to more than 15 times the control value by 10 min. At 0.3 microg ml(-1) no increase in L(p) was observed for up to 90 min. The toxin-induced increase in L(p) was consistent with changes in ultrastructure of microvessels exposed to the toxin. Those microvessels exhibited gaps either between or through endothelial cells where perfusate had direct access to the basement membrane. Many endothelial cells appeared necrotic, highly attenuated, and with dense cytoplasm. We showed that epsilon-toxin, in a time- and dose-dependent manner, rapidly and irreversibly compromised the barrier function of venular microvessel endothelium. The results conformed to the hypothesis that epsilon-toxin interacts with vascular endothelial cells and increases the vessel wall permeability by direct damage of the endothelium.

Animals↗

PubMed2004

fMLP-stimulated neutrophils increase endothelial [Ca2+]i and microvessel permeability in the absence of adhesion: role of reactive oxygen species.

Our previous study demonstrated that firm attachment of leukocytes to microvessel walls does not necessarily increase microvessel permeability (Am J Physiol Heart Circ Physiol 283: H2420-H2430, 2002). To further understand the mechanisms of the permeability increase associated with leukocyte accumulation during acute inflammation, we investigated the direct relation of reactive oxygen species (ROS) release during neutrophil respiratory burst to changes in microvessel permeability and endothelial intracellular Ca(2+) concentration ([Ca(2+)](i)) in intact microvessels. ROS release from activated neutrophils was quantified by measuring changes in chemiluminescence. When isolated rat neutrophils (2 x 10(6)/ml) were exposed to formyl-Met-Leu-Phe-OH (fMLP, 10 microM), chemiluminescence transiently increased from 1.2 +/- 0.2 x 10(4) to a peak value of 6.7 +/- 1.0 x 10(4) cpm/min (n = 12). Correlatively, perfusing individual microvessels with fMLP-stimulated neutrophils in suspension (2 x 10(7)/ml) increased hydraulic conductivity (L(p)) to 3.7 +/- 0.4 times the control value (n = 5) and increased endothelial [Ca(2+)](i) from 84 +/- 7 nM to a mean peak value of 170 +/- 7 nM. In contrast, perfusing vessels with fMLP alone did not affect basal L(p). Application of antioxidant agents, superoxide dismutase, vitamin C, or an iron chelator, deferoxamine mesylate, attenuated ROS release in fMLP-stimulated neutrophils and abolished increases in L(p). These results indicate that release of ROS from fMLP-stimulated neutrophils increases microvessel permeability and endothelial [Ca(2+)](i) independently from leukocyte adhesion and the migration process.

Animals↗

PubMed2005

fMLP-stimulated release of reactive oxygen species from adherent leukocytes increases microvessel permeability.

Our previous study (Am J Physiol Heart Circ Physiol 288: H1331-H1338, 2005) demonstrated that TNF-alpha induced significant leukocyte adhesion without causing increases in microvessel permeability, and that formyl-Met-Leu-Phe-OH (fMLP)-stimulated neutrophils in the absence of adhesion increased microvessel permeability via released reactive oxygen species (ROS). The objective of our present study is to investigate the mechanisms that regulate neutrophil respiratory burst and the roles of fMLP-stimulated ROS release from adherent leukocytes in microvessel permeability. A technique that combines single-microvessel perfusion with autologous blood perfusion was employed in venular microvessels of rat mesenteries. Leukocyte adhesion was induced by systemic application of TNF-alpha. Microvessel permeability was assessed by measuring hydraulic conductivity (L(p)). The 2-h autologous blood perfusion after TNF-alpha application increased leukocyte adhesion from 1.2 +/- 0.2 to 13.3 +/- 1.6 per 100 microm of vessel length without causing increases in L(p). When fMLP (10 microM) was applied to either perfusate (n = 5) or superfusate (n = 8) in the presence of adherent leukocytes, L(p) transiently increased to 4.9 +/- 0.9 and 4.4 +/- 0.3 times the control value, respectively. Application of superoxide dismutase or an iron chelator, deferoxamine mesylate, after fMLP application prevented or attenuated the L(p) increase. Chemiluminescence measurements in isolated neutrophils demonstrated that TNF-alpha alone did not induce ROS release but that preexposure of neutrophils to TNF-alpha in vivo or in vitro potentiated fMLP-stimulated ROS release. These results suggest a priming role of TNF-alpha in fMLP-stimulated neutrophil respiratory burst and indicate that the released ROS play a key role in leukocyte-mediated permeability increases during acute inflammation.

Animals↗

PubMed2005

Platelet-activating factor increases endothelial [Ca2+]i and NO production in individually perfused intact microvessels.

We have demonstrated that inhibition of NO synthase (NOS) in endothelial cells by either the NOS inhibitor N(omega)-monomethyl-l-arginine (l-NMMA) or the internalization of caveolin-1 scaffolding domain attenuated platelet-activating factor (PAF)-induced increases in microvessel permeability (Am J Physiol Heart Circ Physiol 286: H195-H201, 2004) indicating the involvement of an NO-dependent signaling pathway. To investigate whether an increase in endothelial cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) is the initiating event and Ca(2+)-dependent NO production is crucial for permeability increases, PAF (10 nM)-induced changes in endothelial [Ca(2+)](i) and NO production were measured in individually perfused rat mesenteric venular microvessels via fluorescence microscopy. When venular microvessels were exposed to PAF, endothelial [Ca(2+)](i) increased from 69 +/- 8 nM to a peak value of 374 +/- 26 nM within 3 min and then declined to a sustained level at 190 +/- 12 nM after 15 min. Inhibition of NOS did not modify PAF-induced increases in endothelial [Ca(2+)](i). PAF-induced NO production was visualized and quantified at cellular levels in individually perfused microvessels using 4,5-diaminofluorescein diacetate and fluorescence imaging. Increased fluorescence intensity (FI), which is an indication of increased NO production, occurred in 75 +/- 7% of endothelial cells in each vessel. The mean maximum FI increase was 140 +/- 7% of baseline value. This increased FI was abolished by pretreatment of the vessel with l-NMMA and attenuated in the absence of extracellular Ca(2+). These results provide direct evidence from intact microvessels that increased endothelial [Ca(2+)](i) is the initial signal that activates endothelial NOS, and the subsequent increased NO production contributes to PAF-induced increases in microvessel permeability.

Animals↗

PubMed1993

Hypercapnia slightly raises blood volume and sizably elevates flow velocity in brain microvessels.

The increase in local cerebral blood flow (LCBF) caused by hypercapnia may be mainly accomplished by raising the velocity of plasma and/or red blood cell (RBC) flow through the microvessels and not by perfusing more capillaries. This suggestion was tested in awake rats exposed to 8% CO2 and in control rats. LCBF was measured by the 14C-labeled iodoantipyrine method. The volume of blood in small parenchymal microvessels was estimated from the distribution spaces of 125I-labeled serum albumin (RISA) and 55Fe-labeled RBCs. Hypercapnia elevated LCBF 2.0- to 3.5-fold in the 40 brain areas studied, marginally raised the RBC spaces, and significantly increased the RISA and whole blood distribution spaces (approximately 25 and 19%, respectively). These changes in microvessel distribution volumes could be the result of perfusing a slightly larger fraction of capillaries (recruitment), increasing microvessel diameter somewhat, or both. With hypercapnia, the mean transit times fell to approximately 45% of control, which indicated that LCBF was mainly increased by raising the velocity of RBC and plasma flow through already perfused microvessels. Overall, few, if any, capillaries or other microvessels were recruited by hypercapnia.

Animals↗

PubMed2005

Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome.

This study tested the hypothesis that chronically elevated oxidant stress contributes to impaired active hyperemia in skeletal muscle of obese Zucker rats (OZR) vs. lean Zucker rats (LZR) through progressive deteriorations in microvascular structure. Twelve-week-old LZR and OZR were given 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol) in the drinking water for approximately 4 wk. Subsequently, perfusion of in situ gastrocnemius muscle was determined during incremental elevations in metabolic demand, while a contralateral skeletal muscle arteriole and the gastrocnemius muscle was removed to determine dilator reactivity, vessel wall mechanics, and microvessel density. Under control conditions, active hyperemia was impaired at all levels of metabolic demand in OZR, and this was correlated with a reduced microvessel density, increased arteriolar stiffness, and impaired dilator reactivity. Chronic tempol ingestion improved perfusion during moderate to high metabolic demand only and was associated with improved arteriolar reactivity and microvessel density; passive vessel mechanics were unaltered. Combined antioxidant therapy and nitric oxide synthase inhibition in OZR prevented much of the restored perfusion and microvessel density. In LZR, treatment with N(omega)-nitro-L-arginine methyl ester (L-NAME) hydrochloride and hydralazine (to prevent hypertension) impaired active hyperemia, dilator reactivity, and microvessel density, although arteriolar distensibility was not altered. These results suggest that with the development of the metabolic syndrome, chronic reductions in nitric oxide bioavailability, in part via the scavenging actions of oxidative free radicals, contribute to a loss of skeletal muscle microvessels, leading to impaired muscle perfusion with elevated metabolic demand.

Animals↗

PubMed1991

Cholesterol esterase in preglomerular microvessels from normal and cholesterol-fed rabbits.

Feeding cholesterol to rabbits produces an atherosclerotic model sharing common metabolic features with the disease in humans, including the vascular lipid accumulation. In coronary vascular cells, this lipid accumulation has been associated with decreased prostacyclin (PGI2) biosynthesis and acid cholesterol esterase activity. Unlike the coronary vascular bed, renal microvasculature appears relatively resistant to atherosclerotic injury. This study examined whether renal microvessels from cholesterol-fed rabbits demonstrated similar metabolic changes in coronary vascular cells. Rabbits were fed either a 0% or 2% cholesterol diet for 1 mo. Similar to coronary vascular cells, in renal microvessels from cholesterol-fed rabbits PGI2 biosynthesis decreased and tissue concentrations of cholesterol and cholesteryl esters increased. However, unlike coronary vascular cells, renal microvascular cholesterol esterase activity increased. Light and electron microscopy revealed sporadic lipid deposits in renal microvessels from cholesterol-fed rabbits and no foam cells or occlusive lesions. In vitro addition of prostanoids to normal renal microvessels had no effect on cholesterol esterase activity. It is inviting to speculate that the increased acid cholesterol esterase activity in renal microvessels from cholesterol-fed rabbits protected them from developing extensive microvascular lesions. These biochemical events may explain the relative resistance of human renal microvessels to the development of occlusive atherosclerotic microvascular lesions.

Animals↗

PubMed1992

Technique-dependent variations in cerebral microvessel blood volumes and hematocrits in the rat.

To quantitate small parenchymal microvessel blood volumes in the brain, the distribution spaces of radiolabeled red blood cells (RBC) and serum albumin (RISA) were assessed in rats by different methods of tissue sampling and radioassay. Three minutes after intravenous administration of 55Fe-RBCs and/or 125I-RISA, the rats were decapitated. The brain was either immediately frozen within the skull and later removed (head-frozen group) or rapidly removed from the skull and then frozen (brain-frozen group). Radioactivity was measured either by liquid scintillation counting of tissue pieces, which contained pial plus large and small parenchymal microvessels, or by quantitative autoradiography (QAR) of tissue sections, which indicated small parenchymal microvessel blood only. In 12 of 15 areas, the RISA, RBC, and blood volumes determined by liquid scintillation counting of head-frozen tissue pieces were equal to or greater than those of brain-frozen tissue; this indicated less than or equal to 25% greater blood retention in pial and parenchymal microvessels with head freezing. At the parenchymal microvessel level (QAR assay), the distribution volumes of RBCs, RISA, and blood were similar with the two freezing techniques; hence with QAR either freezing procedure can be used to assess small parenchymal microvessel blood volumes.

Animals↗

PubMedDate not supplied

Properties of angiotensin-converting enzyme in intact cerebral microvessels.

Angiotensin-converting enzyme (ACE) was studied in preparations of microvessels isolated from rabbit cerebral cortex. Activity was determined by measuring the degradation of hippuryl-histidyl-leucine (Hip-His-Leu) by the intact microvessels in a physiological salt solution at pH 7.4. ACE activity was dependent on both substrate and chloride ion concentration and was inhibited by captopril in a manner similar to that observed previously with tissue homogenates. Angiotensin I was rapidly degraded by the intact microvessels, even in the presence of 10(-6)M captopril. An advantage of the methodology employed was the ability to pretreat the microvessels and then assess the effect of pretreatment by transfer to a postincubation assay system. Pretreatment with a hyperosmolar urea solution did not change ACE activity or cause release of ACE from the microvessels, although lactic dehydrogenase and lysosomal enzymes were released. Pretreatment with captopril caused a lag in the subsequent degradation of Hip-His-Leu, presumably reflecting dissociation of inhibitor from the cell-associated enzyme. ACE activity was unaffected by hypoxic or anoxic incubation conditions. The ability to measure ACE activity of the microvessels in vitro provides a unique opportunity to study the properties of the enzyme in intact cerebrovascular endothelial cells.

Animals↗

PubMed1985

alpha-Adrenergic receptors in cerebral microvessels of normotensive and spontaneously hypertensive rats.

In rat cerebral microvessels, we characterized alpha 1- and alpha 2-adrenergic receptors, using [3H]prazosin and [3H]-p-amino-clonidine as radioligands. [3H]Prazosin binding to the cerebral microvessels was saturable and of high affinity (dissociation constant of 78 pM), with a maximum binding of 48 fmol/mg protein. [3H]Prazosin binding reached equilibrium within 15 minutes and was dissociated by the addition of 10 microM phentolamine. The inhibitory effects of isomers of norepinephrine and epinephrine on the binding showed that l-isomers were over 10 times more potent than d-isomers. [3H]-p-Amino-clonidine binding to the cerebral microvessels was saturable and of high affinity (KD = 0.61 nM) with a Bmax of 73 fmol/mg protein. The binding reached equilibrium within 30 minutes, and was dissociated by the addition of 100 microM l-norepinephrine. l-Isomers of norepinephrine and epinephrine were over 10 times more potent than d-isomers in displacing the binding. Thus, both [3H]prazosin and [3H]-p-amino-clonidine bindings to the cerebral microvessels were characterized by saturability, high affinity, reversibility, and stereo-specificity. Furthermore, the specificity of both binding sites was pharmacologically evaluated by the inhibitory effects of various adrenergic agonists and antagonists on the bindings. These data indicate the existence of alpha-adrenergic receptors in the cerebral microvessels and are consistent with the hypothesis that the cerebral microcirculation is regulated by adrenergic innervation. Furthermore, the receptors were measured in cerebral microvessels of spontaneously hypertensive rats and Wistar-Kyoto controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗