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Results for “Muscle, Smooth, Vascular”

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PubMed1991

The role of ion antiporters in the maintenance of intracellular pH in rat vascular smooth muscle cells.

Vascular smooth muscle intracellular pH is maintained by the Na+/H+ and Cl-/HCO3- antiporters. The Na+/H+ exchanger is a major route of H+ extrusion in most eukaryotic cells and is present in vascular smooth muscle cells in a similar capacity. It extrudes H+ into the extracellular space in exchange for Na+. The Cl-/HCO3- exchanger plays an analogous role to lower the pH of vascular smooth muscle cells when increases in intracellular pH occur. Its activity has also been demonstrated in A7r5 and A10 vascular smooth muscle cells. The Na+/H+ exchanger is regulated by a number of agents which act through inositol trisphosphate/diacylglycerol, to stimulate the antiporter. Calcium-calmodulin dependent protein kinase may also activate the antiporter in vivo. Phosphorylation of the Cl-/HCO3- exchanger has also been observed but its physiological role is not known. Both these antiporters exist in the plasma membrane as integral proteins with free acidic cytoplasmic termini. These regions may be important in 'sensing' changes in intracellular pH, to which these antiporters respond.

Animals↗

PubMed1996

Signal transduction in vascular smooth muscle.

INTRODUCTION: Vascular smooth muscle participates in the normal control of vascular tone and in the pathological adaptation of arteries in hypertension and atherosclerosis. Growth factors and vasoconstrictors activate overlapping signalling pathways that include activation of phospholipase C isoforms, phospholipase D, protein kinase C, tyrosine kinases and mitogen-activated protein kinases. ANGIOTENSIN II AS A PARADIGM OF A MULTIFUNCTIONAL HORMONE: Angiotensin II initiates a biphasic sequence of second messenger generation in vascular smooth muscle cells that appears to result from signalling that occurs in two distinct domains involving aggregated and sequestered receptors. It also activates membrane-associated reduced nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide phosphate oxidases that contribute to the control of the redox state of the cell. CONCLUSION: Vasoactive agents generate a complex signalling pattern that controls both the normal and pathophysiological responses of vascular smooth muscle.

Angiotensin II↗

PubMed2005

Cyclooxygenase-2 induction by bradykinin in aortic vascular smooth muscle cells.

Vascular smooth muscle cell proliferation and migration play an important role in the pathophysiology of several vascular diseases, including atherosclerosis. Prostaglandins that have been implicated in this process are synthesized by two isoforms of cyclooxygenase (COX), with the expression of the regulated COX-2 isoform increased in atherosclerotic plaques. Bradykinin (BK), a vasoactive peptide increased in inflammation, induces the formation of prostaglandins through specific receptor activation. We hypothesized that BK plays an important role in the regulation of COX-2, contributing to the increase in production of prostaglandins in vascular smooth muscle cells. Herein we examined the signaling pathways that participate in the BK regulation of COX-2 protein levels in primary cultured aortic vascular smooth muscle cells. We observed an increase in COX-2 protein levels induced by BK that was maximal at 24 h. This increase was blocked by a B2 kinin receptor antagonist but not a B1 receptor antagonist, suggesting that the B2 receptor is involved in this pathway. In addition, we conclude that the activation of mitogen-activated protein kinases p42/p44, protein kinase C, and nitric oxide synthase is necessary for the increase in COX-2 levels induced by BK because either of the specific inhibitors for these enzymes blocked the effect of BK. Using a similar approach, we further demonstrated that reactive oxygen species and cAMP were not mediators on this pathway. These results suggest that BK activates several intracellular pathways that act in combination to increase COX-2 protein levels. This study suggests a role for BK on the evolution of the atheromatous plaque by virtue of controlling the levels of COX-2.

Adenylyl Cyclase Inhibitors↗

PubMed1992

Platelet-derived growth factor BB-dimer suppresses the expression of macrophage colony-stimulating factor in human vascular smooth muscle cells.

Vascular smooth muscle cell is a major cell component involved in the process of atherosclerosis. In the present study, we investigated the effects of platelet-derived growth factor (PDGF)-BB dimer on the expression of macrophage-colony stimulating factor (M-CSF) in vascular smooth muscle cells isolated from human umbilical artery. On Northern blot analysis of total RNAs isolated from smooth muscle cells, with human cDNA for M-CSF, a marked dose-dependent reduction of mRNA level was found in PDGF-BB-treated smooth muscle cells. Cellular production of M-CSF was estimated by immunoblot analysis of cell lysate with specific polyclonal antibody against recombinant human M-CSF. A concentration of 10 ng/ml PDGF-BB significantly reduced M-CSF mass in smooth muscle cells compared with that in the absence of PDGF-BB. These results suggest that PDGF-BB plays an important role in the cellular metabolism of vascular wall by regulating the rate of M-CSF production in vascular smooth muscle cells.

Antibodies↗

PubMed1986

Effect of methylated bepridil on slow action potentials in cardiac muscle and vascular smooth muscle.

The anti-anginal agent bepridil blocks slow Ca2+ channels in a variety of tissues. Since bepridil accumulates inside cells, the possibility exists that bepridil acts, at least partially, from inside the cell. To test this possibility, we examined the effects of a quaternary ammonium analog of bepridil, methylated bepridil, which presumably would enter the cells less readily, on the Ca2+-dependent slow action potentials of guinea pig papillary muscles (in 25 mM [K+]0) and rabbit pulmonary arteries (in tetraethylammonium chloride). In cardiac muscle, methylated bepridil had little effect on the slow action potentials at low stimulation frequencies (0.5 Hz), but at higher frequencies (1.0 and 2.0 Hz) the slow action potentials were depressed and/or the muscle was unable to follow each stimulation. These effects are similar to those obtained with bepridil, but bepridil was more potent than methylated bepridil. In vascular smooth muscle cells, methylated bepridil inhibited the slow action potentials at a somewhat lower dose than bepridil. We conclude that, in cardiac muscle, bepridil probably has two sites of action, one outside the cell (presumably on or associated with the slow Ca2+ channel) and a second site inside the cell. On the other hand, in vascular smooth muscle cells, bepridil may act only on an external site.

Action Potentials↗

PubMed2006

Cyclic GMP-dependent protein kinase Ialpha inhibits thrombin receptor-mediated calcium mobilization in vascular smooth muscle cells.

Vascular smooth muscle contractile state is regulated by intracellular calcium levels. Nitric oxide causes vascular relaxation by stimulating production of cyclic GMP, which activates type I cGMP-dependent protein kinase (PKGI) in vascular smooth muscle cells (VSMC), inhibiting agonist-induced intracellular Ca2+ mobilization ([Ca2+]i). The relative roles of the two PKGI isozymes, PKGIalpha and PKGIbeta, in cyclic GMP-mediated inhibition of [Ca2+]i in VSMCs are unclear. Here we have investigated the ability of PKGI isoforms to inhibit [Ca2+]i in response to VSMC activation. Stable Chinese hamster ovary cell lines expressing PKGIalpha or PKGIbeta were created, and the ability of PKGI isoforms to inhibit [Ca2+]i in response to thrombin receptor stimulation was examined. In Chinese hamster ovary cells stably expressing PKGIalpha or PKGIbeta, 8-Br-cGMP activation suppressed [Ca2+]i by thrombin receptor activation peptide (TRAP) by 98 +/- 1 versus 42 +/- 5%, respectively (p <0.002). Immunoblotting studies of cultured human VSMC cells from multiple sites using PKGIalpha- and PKGIbeta-specific antibodies showed PKGIalpha is the predominant VSMC PKGI isoform. [Ca2+]i following thrombin receptor stimulation was examined in the absence or presence of cyclic GMP in human coronary VSMC cells (Co403). 8-Br-cGMP significantly inhibited TRAP-induced [Ca2+]i in Co403, causing a 4-fold increase in the EC50 for [Ca2+]i. In the absence of 8-Br-cGMP, suppression of PKGIalpha levels by RNA interference (RNAi) led to a significantly greater TRAP-stimulated rise in [Ca2+]i as compared with control RNAi-treated Co403 cells. In the presence of 8-Br-cGMP, the suppression of PKGIalpha expression by RNAi led to the complete loss of cGMP-mediated inhibition of [Ca2+]i. Adenoviral overexpression of PKGIbeta in Co403 cells was unable to alter TRAP-stimulated Ca2+ mobilization either before or after suppression of PKGIalpha expression by RNAi. These results support that PKGIalpha is the principal cGMP-dependent protein kinase isoform mediating inhibition of VSMC activation by the nitric oxide/cyclic GMP pathway.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1991

Serum, phorbol ester, and polypeptide mitogens increase class 1 and 2 heparin-binding (acidic and basic fibroblast) growth factor gene expression in human vascular smooth muscle cells.

Vascular smooth muscle cell proliferation is regarded as a key early event in the pathogenesis of atherosclerosis. Heparin-binding growth factor (HBGF)-1 and HBGF-2, also referred to as acidic and basic fibroblast growth factor, are potent mitogens for human vascular smooth muscle cells. These cells coexpress HBGF-1 and HBGF-2 and thus represent a vessel wall source for both polypeptides. In this report, we demonstrate that HBGF-1 and HBGF-2 expression is increased when quiescent human smooth muscle cells are treated with fetal bovine serum. The kinetics of HBGF-1 and HBGF-2 mRNA accumulation following serum treatment are distinct. In addition, HBGF-1 transcripts remain elevated for a longer time period; this may reflect the different decay rates of the HBGF-1 and HBGF-2 mRNAs. Serum-inducible HBGF-1 and HBGF-2 mRNA expression does not occur when RNA synthesis is repressed by actinomycin D but can occur in the presence of cycloheximide, an inhibitor of protein synthesis. Immunoprecipitation experiments indicate that serum treatment also increases HBGF-1 and HBGF-2 production. Smooth muscle cells treated with phorbol 12-myristate 13-acetate or certain combinations of polypeptide growth factors also express increased levels of HBGF-1 and HBGF-2 transcripts. Potential sources for these growth factors in vivo include platelets, macrophages, and T lymphocytes; thus, smooth muscle cells located at sites of vascular injury or inflammation may express elevated levels of HBGF-1 and HBGF-2.

Animals↗

PubMed1997

Effects of licorice derivatives on vascular smooth muscle function.

Vascular smooth muscle contains a bidirectional form of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) which can inactivate (dehydrogenase) endogenous circulating glucocorticoids (GCs) or activate (oxo-reductase) 11-dehydro-metabolites by their conversion back to the parent steroid. Enzyme direction in vascular smooth muscle (VSM) has potential physiological consequences since GCs may enhance the response to known vasoconstrictors. We determined that carbenoxolone is a competitive inhibitor of 11beta-HSD contained in VSM cells with a lower Ki for forward dehydrogenase reaction (0.02 microM) compared to the oxo-reductase reaction (0.41 microM). To test whether changes in enzyme directional activity can affect the contractile response, aortae from adrenally intact Sprague Dawley rats were removed and sectioned into 2.5 mm rings. Rings were incubated with corticosterone 10 nM plus carbenoxolone (CBX) 10 microM (a concentration well above the Ki for both the dehydrogenase and oxo-reductase reaction) for 24 hrs. These rings showed an enhanced dose dependent contractile response to phenylephrine (PE) 0.01 microM(-1) microM and to angiotensin II 1 microM compared to rings incubated with corticosterone alone, CBX alone, or controls: [e.g. response to PE 1 microM in mg of contractile force, mean +/- SE: corticosterone plus CBX 1495 +/- 162 (n=10) vs corticosterone 1039 +/- 64 (n=9), p<0.05]. Aortic rings preincubated with 11-dehydrocorticosterone 10(-7)M and CBX 10 microM displayed a decreased contractile response compared to 11-dehydrocorticosterone alone. Thus in situ glucocorticoid metabolism is important in mediating the constrictor responses of vascular tissue.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed2005

Effect of serum withdrawal on the contribution of L-type calcium channels (CaV1.2) to intracellular Ca2+ responses and chemotaxis in cultured human vascular smooth muscle cells.

Vascular smooth muscle cell (VSMC) chemotaxis is fundamental to atherosclerosis and intimal hyperplasia. An increase in intracellular Ca2+ [Ca2+]i is an important signal in chemotaxis, but the role of L-type calcium channels (CaV1.2) in this response in human vascular smooth muscle cells (hVSMC) has not been examined. hVSMC were grown from explant cultures of saphenous vein. Confluent hVSMC at passage 3 were studied after culture in medium containing 15% foetal calf serum (FCS) (randomly cycling) or following serum deprivation for up to 7 days. Smooth muscle alpha-actin was measured by immunoblotting and immunofluorescence microscopy. [Ca2+]i was measured using fura 2 fluorimetry. Chemotaxis was measured using a modified Boyden chamber technique and cell attachment to gelatin-coated plates was also quantified. The number and affinity of dihydropyridine-binding sites was assessed using [5-methyl-3H]PN 200-110 binding. In randomly cycling cells, the calcium channel agonist, Bay K 8644a and 100 mM KCl did not affect [Ca2+]i. In addition, the rise in [Ca2+]i induced by platelet-derived growth factor-BB (PDGF) was unaffected by the CaV1.2 antagonists, amlodipine and verapamil. In randomly cycling cells amlodipine did not affect PDGF-induced migration. In serum-deprived cells, smooth muscle alpha-actin was increased and Bay K 8644a and 100 mM KCl increased [Ca2+]i. PDGF-induced rises in [Ca2+]i were also inhibited by amlodipine and verapamil. The ability of Bay K 8644a to increase [Ca2+]i and verapamil to inhibit PDGF-induced rises in [Ca2+]i was evident within 3 days after serum withdrawal. In serum-deprived hVSMC Bay K 8644a induced chemotaxis and amlodipine inhibited PDGF-induced migration. Cell attachment in the presence of PDGF was unaffected by amlodipine in either randomly cycling or serum-deprived hVSMC. Serum withdrawal was associated with a decrease in the maximum number of dihydropyridine-binding sites (B(max)) and a decrease in affinity (K(D)). Serum deprivation of hVSMC results in increased expression of smooth muscle alpha-actin, a marker of more differentiated status, and increased [Ca2+]i responses and chemotaxis mediated by CaV1.2. These observations may have important implications for understanding the therapeutic benefits of calcium channel antagonists in cardiovascular disease.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1992

Na+, K(+)-adenosine triphosphatase regulation in hypertrophied vascular smooth muscle cells.

Vascular smooth muscle cell hypertrophy is a normal compensatory state that may play a pathogenic role in hypertension. Angiotensin II stimulates a hypertrophic response in cultured vascular smooth muscle cells. As part of the growth response, angiotensin II rapidly activates the Na(+)-H+ exchanger, increasing Na+ influx. Because Na+, K(+)-ATPase is the major cellular mechanism for regulating intracellular Na+, we studied the effects of angiotensin II-induced hypertrophy on Na+, K(+)-ATPase expression and activity. Angiotensin II caused rapid increases in both steady-state Na+, K(+)-ATPase activity (ouabain-sensitive 86Rb uptake) and intracellular [Na+]. Angiotensin II also caused a sustained increase in Na+, K(+)-ATPase at 24 hours with a 73% increase in maximal 86Rb uptake per milligram protein and a fourfold increase in Na+, K(+)-ATPase alpha-1 messenger RNA levels. Thus, angiotensin II hypertrophy was associated with rapid increases in Na+, K(+)-ATPase activity due to increased Na+ entry and sustained increases due to a specific increase in Na+, K(+)-ATPase expression. These data demonstrate dynamic regulation of Na+, K(+)-ATPase at the functional and molecular level and suggest that similar compensatory mechanisms should be present in vivo. Alterations in such compensatory pathways may be fundamental to the pathogenesis of hypertension.

Angiotensin II↗

PubMed1992

Stretch-induced increases in intracellular calcium of isolated vascular smooth muscle cells.

Vascular smooth muscle responds to stretch with an increase in active force development. To investigate the role of Ca2+ in this response, we used the fluorescent dye fura-2 to quantitate changes in cytosolic Ca2+ in single, vascular smooth muscle cells during rapid stretch. Cells were enzymatically dispersed from pig coronary arteries, loaded with fura-2/AM, and studied using a digital-imaging microscope. Stretch of individual cells was accomplished by attachment with suction to two patch-type micropipettes to apply force to the ends of the cell. Stretch induced the release of Ca2+ from intracellular stores as well Ca2+ influx across the plasma membrane. In physiological saline solution containing 1.5 mM Ca2+, intracellular calcium increased with cell stretch in a sigmoidal fashion. This relationship was shifted upward in 10 mM Ca2+ bath solution and abolished after several minutes in Ca(2+)-free solution. The dihydropyridine Ca2+ channel blocker nifedipine, in doses sufficient to completely block inward Ca2+ current, produced only a partial block of the sustained stretch-induced intracellular Ca2+ response. It is concluded that in isolated pig coronary arterial smooth muscle cells, stretch-induced Ca2+ influx occurs in part via a nifedipine-resistant pathway, which may be a stretch-activated cation channel.

Animals↗

PubMed1992

Platelet-derived growth factor induces c-fms and scavenger receptor genes in vascular smooth muscle cells.

Vascular smooth muscle cells proliferate and transform to foam cells in the process of atherosclerosis. In the present study, we demonstrated that platelet-derived growth factor (PDGF)-BB induced expression of proto-oncogene c-fms in vascular smooth muscle cells, which normally do not express c-fms, isolated from either human umbilical artery or rabbit aorta. No effect of the protein kinase C activator, phorbol ester, was demonstrated on mRNA expression of c-fms. In contrast, the scavenger receptor activity was induced by both PDGF-BB and phorbol ester. These results indicate that two characteristic genes of monocyte-macrophages were induced by PDGF-BB via the different pathways, and suggest that PDGF-BB plays an important role in initiating phenotypic conversion of smooth muscle cells to macrophage-like cells.

Animals↗

PubMed1994

Regulation of vascular smooth muscle tone.

Vascular smooth muscle tone is regulated primarily by the sarcoplasmic free Ca2+ concentration, which determines the level of myosin phosphorylation. Stimulation of the muscle results in an increase in free [Ca2+], whereupon Ca2+ binds to calmodulin, inducing a conformational change enabling calmodulin to interact with and activate myosin light chain kinase. The active Ca2+.calmodulin.myosin light chain kinase complex catalyses the phosphorylation of serine-19 of the two 20-kDa light chains of myosin; this triggers cross-bridge cycling and the development of force. Relaxation follows restoration of free [Ca2+] to the resting level, whereupon calmodulin dissociates from myosin light chain kinase, which is thereby inactivated, and myosin is dephosphorylated by myosin light chain phosphatase and remains detached from actin. Overwhelming evidence now exists in favour of the central role of myosin phosphorylation-dephosphorylation in smooth muscle contraction-relaxation. However, considerable evidence supports the existence of additional, secondary mechanisms that can modulate the contractile state of smooth muscle either by altering the Ca2+ sensitivity of the contractile response or otherwise modulating one of the molecular events occurring downstream of the Ca2+ signal, e.g., the interaction of phosphorylated myosin heads with actin. The interplay of several regulatory elements confers on the contractile response of vascular smooth muscle the high degree of flexibility and adaptability required for the effective regulation of blood pressure.

Amino Acid Sequence↗

PubMed1983

Membrane abnormalities occur in vascular smooth muscle but not in non-vascular smooth muscle from rats with deoxycorticosterone-salt induced hypertension.

Microsomal fractions were isolated from the smooth muscle of gastric fundus, vasa deferentia and mesenteric arteries of rats made hypertensive by deoxycorticosterone-salt treatment. Several enzymatic activities, Ca2+ binding and ATP-dependent Ca2+ accumulation of the microsomal fractions from these hypertensive rats were compared with those from the control of rats which remained normotensive under similar treatment. Altered membrane properties were observed in microsomal fractions isolated from vascular smooth muscle but not in those isolated from non-vascular smooth muscles in this form of experimental hypertension. These alterations included decreased Mg2+ ATPase activity, enhanced alkaline phosphatase activity, decreased Ca2+ binding in the absence of ATP and decreased ATP-dependent Ca2+ accumulation. This result is in contrast to our previous findings that decreased ATP-dependent Ca2+ accumulation was observed in microsomal fraction isolated from non-vascular smooth muscles of rats with genetic hypertension. The present study, together with our previous findings, support the contention that altered Ca2+ handling by vascular smooth muscle is associated with the pathogenesis of hypertension, whereas altered Ca2+ handling by non-vascular smooth muscles previously observed in spontaneous hypertension may be associated with genetic factors not related to hypertension.

Animals↗

PubMed1988

Sodium/calcium exchange and the control of contractility in cardiac muscle and vascular smooth muscle.

A sodium/calcium exchange mechanism that mediates both Ca2+ exit and Ca2+ entry is present in the sarcolemma of most types of muscle including mammalian cardiac muscle and vascular smooth muscle (VSM). The rate and direction of Ca2+ transport mediated by the exchanger are normally regulated primarily by: (a) the intracellular free Ca2+ concentration (since both Ca2+ entry and exit are activated by intracellular Ca2+), (b) the intracellular Na+, and (c) the absolute difference between the membrane potential and the exchanger reversal potential. In both cardiac muscle and VSM, the exchanger biases the level of [Ca2+]i and thereby controls the amount of Ca2+ stored in the sarcoplasmic reticulum and, thus, the amount available for release when the cells are activated. In both tissues, the exchanger also plays an important role in the extrusion of Ca2+ following contractile activation.

Animals↗

PubMed2001

A novel transgenic marker for migrating limb muscle precursors and for vascular smooth muscle cells.

A unique pattern of LacZ expression was found in a transgenic mouse line, likely due to regulatory elements at the site of integration. Two new genes flanking the transgene were identified. At early stages of development, the transgene is transiently expressed in ventro-lateral demomyotomal cells migrating from the somites into the limb buds. At late developmental stages and in the adult, lacZ staining marks vascular smooth muscle cells throughout the vascular bed, with the exception of the major elastic arteries, and in pericytes. No expression was detected in skeletal and smooth muscles. Different patterns of expression in vascular smooth muscles was observed at distinct levels of the vascular tree, in arteries as well as in veins. Vessel injury, resulting in stimulation of smooth muscle cells proliferation and migration, is associated with transgene down-regulation. After the formation of neointima thickening, it is reactivated. This transgenic insertion may therefore be used as a useful marker to identify novel physiological cues or genetic elements involved in the regulation of the vascular smooth muscle phenotype(s). It may also provide an experimental tool for studying vasculature and the involvement of pericytes in regulating microvascular homeostasis.

Animals↗

PubMed1982

Fluorescence demonstration of a cathepsin H-like protease in cardiac, skeletal and vascular smooth muscles.

A cathepsin H-like enzyme was localized by histochemical techniques in cardiac muscle, extensor digitorum longus and soleus skeletal muscles, and vascular smooth muscle. Using the specific exopeptidase activity of this enzyme against the substrate arg-4-methoxy-beta-naphthylamide, valid histochemical assay conditions were developed. More fluorescent granules were observed in cardiac muscle than in the soleus and about equal amounts in vascular smooth muscle and the extensor digitorum longus. The reaction rate was enhanced by chloride ions and inhibited by 1 mM p-chloromercuribenzoate. The maximal activity was observed between pH 5.5 and 6.0 Chemical fixation with periodate-lysine-paraformaldehyde preserved a small amount of enzymatic activity.

Animals↗

PubMed1999

Matrix Gla protein synthesis and gamma-carboxylation in the aortic vessel wall and proliferating vascular smooth muscle cells--a cell system which resembles the system in bone cells.

Matrix GLA protein (MGP) is an inhibitor of calcification in the arterial wall and its activity is dependent upon vitamin K-dependent gamma-carboxylation. This modification is carried out by a warfarin sensitive enzyme system that converts specific Glu residues to gamma-carboxyglutamic acid (GLA) residues. Recent studies have demonstrated that the gamma-carboxylation system in the arterial wall, in contrast to that in the liver, is unable to use vitamin K as an antidote to warfarin. By use of immunohistochemistry we demonstrate that MGP is expressed in the arterial wall and immunocytochemistry localized the MGP precursors to the endoplasmic reticulum in vascular smooth muscle cells. Resting smooth vascular muscle cells in the aortic wall and proliferating cells from explants of the aorta have all the enzymes needed for gamma-carboxylation of MGP. However, when compared to the liver system, expression of the enzymes of the gamma-carboxylation system in vascular smooth muscle cells is different. Of particular interest is the finding that the specific activity of the warfarin sensitive enzyme vitamin K epoxide reductase is 3-fold higher in vascular smooth muscle cells than in liver. DT-diaphorase, which catalyses the antidotal pathway for vitamin K reduction in liver, is 100-fold less active in resting vascular smooth muscle cells than in liver. Data obtained from an in vitro gamma-carboxylation system suggest that the antidotal pathway catalyzed by DT-diaphorase in the vessel wall is unable to provide the carboxylase with enough reduced vitamin K to trigger gamma-carboxylation of MGP. This finding provides an explanation to the inability of vitamin K to work as an antidote to warfarin intoxication of the arterial wall. Therefore the vitamin K dependent gamma-carboxylation system in the arterial wall share a common feature with the system in bone cells by being unable to utilize vitamin K as an antidote.

Animals↗