Biomedical subjects

S T Davidge

Publications and source records attributed to S T Davidge.

At least 37 records · Page 2Linked to original sources

PubMed2000

Vascular wall function in insulin-resistant JCR:LA-cp rats: role of male and female sex.

Vascular wall function was assessed in obese insulin-resistant (cp/cp) and lean normal (+/?), male and female, JCR:LA-cp rats. Both male and female cp/cp rats showed enhanced maximum contractility in response to norepinephrine; impaired smooth muscle in response to sodium nitroprusside, a nitric oxide (NO) donor; and impaired relaxation in response to acetylcholine (ACh), compared with their lean counterparts. The abnormalities were similar in male and female cp/cp rats. The NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), inhibited ACh-mediated relaxation significantly in male rats, both cp/cp and +/?. The inhibition of ACh-mediated relaxation by L-NAME in +/? females was less, with no reduction in maximal relaxation, and was absent in cp/cp females. These effects suggest that the relative importance of NO in the endothelial modulation of smooth muscle contractility is greater in male rats. The results are consistent with a decreased role for endothelial NO in the cp/cp rats of both sexes and a reduction in NO-independent cholinergic relaxation in the male cp/cp rat. This NO-independent mechanism is not affected in the female cp/cp rats. The relatively small differences between males and females in smooth muscle cell and vascular function may contribute to sex-related differences in the atherogenesis, vasospasm, and ischemic damage associated with the obese insulin-resistant state.

Animals↗

PubMed2000

Role of matrix metalloproteinase-2 in thrombin-induced vasorelaxation of rat mesenteric arteries.

The vasodilator effects of thrombin depend on activation of proteinase-activated receptor (PAR)-1 and the subsequent release of endothelin (ET)-1, which stimulates the generation of nitric oxide and PGs. We recently showed that thrombin released matrix metalloproteinase-2 (MMP-2) from rat arteries. We have now studied the significance of this release for the vasodilator effects of thrombin. Thrombin (>/=100 pmol), but not a PAR-1-activating peptide (TFLLR-NH(2)), produced a long-lasting (>10 min) vasorelaxation of rat mesenteric arteries, as detected by a microperfusion bioassay. Thrombin induced a simultaneous release of vascular MMP-2 into arterial perfusates, as revealed by zymography. Interestingly, the vasodilator effects of thrombin were inhibited by a tissue inhibitor of MMP-2 (TIMP-2, 10 pmol). Moreover, infusion of exogenous MMP-2 (5 pmol) resulted in vasorelaxation. These vasodilatory effects of thrombin and MMP-2 were significantly (P < 0.05) inhibited by endothelium denudation and by PD-142893 (2 nmol), an antagonist of ET receptors. Furthermore, both thrombin and MMP-2 constricted endothelium-denuded arteries. These results show that the vasodilator effects of thrombin may depend, in part, on a release of vascular MMP-2 and downstream activation of ETs. Thus MMP-2-dependent signaling may complement the PAR-1-dependent pathway of vasodilator action of thrombin.

Animals↗

PubMed2000

Aging increases PGHS-2-dependent vasoconstriction in rat mesenteric arteries.

During aging, the vascular endothelium changes functionally and morphologically. Although previous studies have shown that endothelium-derived eicosanoids increase vessel tone in aging, the precise mechanism(s) has not been fully determined. We hypothesized that aging would increase prostaglandin H synthase (PGHS)-dependent vasoconstriction as well as decrease nitric oxide-dependent relaxation. Mesenteric arteries from 3-month-old (n=9) and 12-month-old (n=14) female Sprague-Dawley rats were studied in a myograph system. Aging significantly blunted the endothelium-dependent relaxation response to methacholine compared with young rats (EC(50)=7.77x10(-8) versus 2.68x10(-8) mol/L, P<0. 05). Nitric oxide synthase inhibition reduced methacholine-induced relaxation in the young (P<0.05) but had no effect in the aging group. Specific inhibition of the PGHS-1 isoform did not significantly affect methacholine-mediated relaxation in the young or aged groups. However, PGHS-2 inhibition greatly enhanced relaxation to methacholine (1.59x10(-8) versus 7.77x10(-8) mol/L, P<0.01) in the aged group only, restoring vessel function to that of the young. In the aged group, inhibition of the prostaglandin H(2)/thromboxane A(2) receptor enhanced methacholine-dependent relaxation similar to that of PGHS-2 inhibition. Moreover, arterial expression of PGHS-2 protein increased with age. In summary, nitric oxide-dependent modulation of vessel function decreased with age, PGHS-1 did not significantly affect vessel tone in either the young or aging group, and PGHS-2 greatly increased vasoconstriction in aging. Thus, we have identified enhanced PGHS-2-mediated vasoconstriction in aging and therefore suggest that inhibition of this isoform is potentially a new target for therapeutic intervention to improve vascular function.

Aging↗

PubMed2000

Estrogen replacement reduces age-associated remodeling in rat mesenteric arteries.

Estrogen replacement therapy significantly decreases the incidence of cardiovascular disease in postmenopausal women. In aging, there is an increase in vascular stiffness along with a decrease in matrix metalloproteinase (MMP) activity. Our hypothesis was that estrogen replacement would increase MMPs and therefore reduce the vascular stiffness that is associated with aging. Female Sprague-Dawley rats were implanted with a placebo or 17ss-estradiol-containing pellet (0.5 mg/pellet, 60-day release) at 10 months of age (n=6, each). Six young rats (3 months old) were also studied. After a 2-month exposure to the pellet, mesenteric arteries were studied on a pressurized arteriograph system. Distensibility and wall thickness were measured in response to stepwise increases in intraluminal pressure in Ca(2+)-free physiological saline solution buffer with papaverine (10(-4) mol/L). In response to increasing pressure, aged placebo rats exhibited a significant decrease in distensibility compared with young rats (P<0.05) that was accompanied by an increase in wall thickness (P<0.05). Conversely, estrogen replacement increased distensibility and decreased wall thickness in aged rats (old estrogen-replaced versus old placebo, P<0.05). Zymography data indicated that MMP-2 activity decreased in aging but was increased by estrogen replacement. In summary, estrogen replacement in aging female rats reduces age-associated vascular remodeling.

Aging↗

PubMed2000

Maternal smoking and preeclampsia.

OBJECTIVE: To study the relationship between maternal smoking and preeclampsia and whether this association differs between primiparous and multiparous women. STUDY DESIGN: We conducted a population-based, retrospective, cohort study of 58,216 singleton pregnancies from northern and central Alberta, Canada, between 1995 and 1997. Multivariate logistic regression was used to control for maternal alcohol consumption, drug dependence, maternal age, maternal weight, prior intrauterine growth restriction and other confounders. RESULTS: Maternal smoking was associated with a significantly reduced overall risk of preeclampsia (adjusted odds ratio [aOR]: .61; 95% confidence interval [CI]: .50-.75; P < .01). Stratified analyses showed that in primiparous pregnancies, maternal smoking was associated with a significantly decreased risk (aOR: .63; 95% CI: .50-.80; P < .01); in multiparous women, maternal smoking was not associated with a statistically significant decreased risk of preeclampsia (aOR: 0.72; 95% CI: .51-1.02; P > .05). CONCLUSION: Maternal smoking is protective against preeclampsia. Understanding the underlying biologic mechanisms of this protective effect may advance our knowledge of the pathogenesis of preeclampsia.

Adolescent↗

PubMed2000

Beneficial insulin-sensitizing and vascular effects of S15261 in the insulin-resistant JCR:LA-cp rat.

S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P <.05). Treatment with S15261 or S15511 decreased plasma insulin levels in fed rats and prevented the postprandial peak in insulin levels in a meal tolerance test. Y415 had no effect on insulin levels. Troglitazone halved the insulin response to the test meal, but metformin gave no improvement. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carboxylase and acyl-CoA synthase. S15261 also reduced the expression of carnitine palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesenteric resistance vessels to norepinephrine, and increased the maximal nitric oxide-mediated relaxation. S15261, through S15511, increased insulin sensitivity, decreased insulin levels, and reduced the vasculopathy of the JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.

Animals↗

PubMed1999

Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor.

Matrix metalloproteinase-2 (MMP-2, gelatinase A) and its tissue inhibitor (TIMP-2) are mainly known for their roles in the (patho)physiological remodeling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rupture. A mechanism of action of MMP-2 is the proteolytic breakdown of specific extracellular matrix proteins. The amino acid sequences in interstitial collagen (Gly-Leu/Ile) and laminin-5 (Ala-Leu) that are cleaved by MMP-2 are homologous to a region (Gly(32)-Leu(33)) within human big endothelin-1[1 to 38] (big ET-1). Big ET-1 requires cleavage to an active form to produce vasoconstriction. We tested the hypothesis that vascular MMP-2 can cleave big ET-1, thus generating a vasoconstrictor peptide. In perfused rat mesenteric arteries with an intact endothelium, inhibition of vascular MMP-2 with TIMP-2 reduced (by 16.2+/-4.2%) the vasoconstrictor effects of big ET-1 (50 pmol). However, when the endothelium was mechanically removed, TIMP-2 abolished (>90%) the vasoconstriction of big ET-1, and this effect was mimicked by an anti-MMP-2 antibody. Incubation of big ET-1 with recombinant human MMP-2 resulted in the specific cleavage of the Gly(32)-Leu(33) bond of big ET-1. Moreover, the resultant peptide ET-1[1 to 32] exerted greater vasoconstrictor effects than big ET-1. We conclude that vascular MMP-2 contributes to the vasoconstrictor effects of big ET-1 by cleaving big ET-1 to yield a novel and potent vasoconstrictor, ET-1[1 to 32]. These data implicate, for the first time, the endogenous MMP-2/TIMP-2 system in the regulation of vascular reactivity.

Animals↗

PubMed1999

Enhancement of post-ischemic myocardial function by chronic 17 beta -estradiol treatment: role of alterations in glucose metabolism.

This study was designed to assess the effects of chronic estrogen replacement therapy on mechanical function and glucose utilization in aerobic and post-ischemic hearts. Ovariectomized female rats were either untreated or were treated subcutaneously with 17 beta -estradiol (0.25 mg 21-day slow release pellets). After 14 days, when serum concentrations of 17 beta -estradiol were 3.8+/-0.8 and 148+/-15 pg/ml, respectively, hearts were isolated and perfused in working mode with Krebs-Henseleit solution containing 1.2 m m palmitate and 11 m m[5-(3)H/U-(14)C]glucose. Hearts were perfused aerobically (60 min) and then subjected to low-flow ischemia (0.5 ml/min, 60 min) followed by reperfusion (30 min). During reperfusion, hearts from rats treated chronically with 17 beta -estradiol had an improved (two-fold) recovery of mechanical function. 17 beta -estradiol (400 p m, 109 pg/ml), when present acutely in heart perfusate during ischemia and reperfusion, did not improve recovery. Chronic 17 beta -estradiol increased glucose oxidation during reperfusion as well as during aerobic perfusion but had no effect on glycolysis. Chronic 17 beta -estradiol also altered post-ischemic glycogen metabolism and increased glycogen content and glycogen synthase activity at the end of reperfusion. As stimulation of glucose oxidation has been shown previously to be cardioprotective, and as the enhanced rate of glucose oxidation was not simply a consequence of enhanced recovery of mechanical function, alterations in glycogen and glucose utilization may contribute to the direct cardioprotective effects of chronic estrogen treatment.

Animals↗

PubMed1999

Impact of pregnancy-induced hypertension on fetal growth.

OBJECTIVE: The purpose of this study was to evaluate the effect of different types of pregnancy-induced hypertension on fetal growth. STUDY DESIGN: A retrospective cohort study was conducted on the basis of 16,936 births from January 1, 1989, through December 31, 1990, by means of data from a population-based perinatal database in Suzhou, China. Pregnancy-induced hypertension was classified as gestational hypertension, preeclampsia, or severe preeclampsia-eclampsia. Univariate and multivariate regression analyses were performed to examine the effect of the various types of pregnancy-induced hypertension on gestational age, preterm birth, birth weight, low birth weight, and intrauterine growth restriction. RESULTS: Gestation was 0.6 week shorter in women with severe preeclampsia than in normotensive women (P <.01). However, the risk of preterm birth was not increased with any classification of pregnancy-induced hypertension (for severe preeclampsia: adjusted odds ratio 1.75; 95% confidence interval, 0.88-3.47). After adjustment for duration of gestation and other confounders, preeclampsia and severe preeclampsia increased the risk of intrauterine growth restriction and low birth weight. The adjusted odds ratios of low birth weight were 2.65 (1.73-4.39) for preeclampsia and 2.53 (1.19-4.93) for severe preeclampsia. However, the risk of low birth weight was not increased significantly for gestational hypertension (adjusted odds ratio 1.56 [1.00-2.41]). CONCLUSION: Preeclampsia increases the risk of intrauterine growth restriction and low birth weight.

Adult↗

PubMed1999

Biphasic stimulation of prostacyclin by endogenous nitric oxide (NO) in endothelial cells transfected with inducible NO synthase.

Nitric oxide (NO) regulates prostaglandin H synthase (PGHS) activity in various cell types, but reports conflict in regard to its stimulatory versus inhibitory role. Murine lung endothelial cells infected with a retroviral vector expressing the human inducible NO synthase gene were used to prevent ambiguous effects of NO from either exogenous chemical donors or cytokine-stimulated cells. Low concentrations of endogenous NO led to a dose-dependent increase in 6-keto PGF1alpha production (p < 0.05), whereas the highest production of NO resulted in lower 6-keto PGF1alpha production. These data demonstrate a complex regulation of PGHS activity by NO that needs to be considered when proposing a physiological or pathophysiological role for NO.

6-Ketoprostaglandin F1 alpha↗

PubMed1999

The role of reactive nitrogen/oxygen intermediates in cytokine-induced trophoblast apoptosis.

Reactive oxygen and nitrogen intermediates (ROI, RNI), such as superoxide anion, nitric oxide (NO) and peroxynitrite, are present in villous trophoblasts and mediate TNF-alpha-induced apoptosis in other cell types. We therefore proposed that ROI/RNI mediate cytokine-induced apoptosis of cultured villous cytotrophoblasts. Treatment of cultures of highly purified term cytotrophoblasts with TNF-alpha and IFN-gamma had no effect on NO synthase (NOS) protein expression measured by immunoblot analysis: iNOS was not expressed and eNOS expression was unaffected. NO production assessed by nitrite levels was below detection limits of the Griess reaction and the NOS inhibitors L-NAME and L-NMMA did not decrease cytokine-stimulated apoptosis. Trophoblasts produced ROI and expressed Cu/Zn superoxide dismutase (SOD) protein but neither was affected by cytokine treatment. ROI scavengers (exogenous SOD, ascorbic acid and butylated hydroxyanisole) also had no effect on cytokine-stimulated apoptosis. Nitrotyrosine immunoblot analysis indicated peroxynitrite production but again cytokines did not reproducibly alter expression patterns or band intensities. Exogenous peroxynitrite stimulated cytotrophoblast apoptosis but only at high levels (1000 microM). We conclude that, although present in cultured villous cytotrophoblasts, ROI/RNI are not induced by TNF-alpha and IFN-gamma and do not mediate cytokine-induced apoptosis.

Apoptosis↗

PubMed1999

Death receptor Fas/Apo-1/CD95 expressed by human placental cytotrophoblasts does not mediate apoptosis.

Trophoblasts, the fetal cells that line the villous placenta and separate maternal blood from fetal tissue, express both Fas antigen and the tumor necrosis factor (TNF) receptor p55 (TNFRp55), two members of the TNF receptor family that contain a cytoplasmic "death domain" that mediates apoptotic signals. We show that Fas mRNA expressed by cultured villous cytotrophoblasts isolated from term placentas encodes transmembrane sequences and that the protein is full-length (approximately 45 kDa), suggesting that the product is an active plasma membrane-anchored receptor. Its location on the cell surface was confirmed by cellular ELISA analysis of live cells. Although cytotrophoblast apoptosis was induced by TNFalpha, and both anti-Fas antibody (CH11) and FasL-expressing T lymphocyte hybridoma (activated A1.1) cells induced HeLa cell apoptosis, neither CH11 antibody nor activated A1.1 cells stimulated apoptosis in term or first-trimester cytotrophoblasts or in term syncytiotrophoblasts. We conclude that Fas- but not TNFRp55-mediated apoptosis is blocked in primary villous trophoblasts. These data suggest that the Fas response is specifically inactivated by unknown mechanisms to avoid autocrine or paracrine killing by Fas ligand constitutively expressed on neighboring cyto- or syncytiotrophoblasts.

Apoptosis↗

PubMed1999

Modulation of vasomotion in resistance arteries of JCR:LA-cp rats: a model of insulin resistance.

Obesity and insulin resistance are strongly associated with an increased risk of vascular disease. Vasomotion is the cyclic variation in the diameter of arteries and is a general feature of the vasculature that may have important physiological consequences. We tested the hypothesis that obesity - insulin resistance is associated with abnormal vasomotion by comparing obese, insulin-resistant JCR:LA-cp rats, known to develop vasculopathy, atherosclerosis, and ischemic lesions of the heart, with lean insulin-sensitive animals from the same strain. Vasomotion was assessed using isolated mesenteric arteries on a myograph system after preconstriction to 50% of maximal constriction with norepinephrine. The amplitude of vasomotion was enhanced by the presence of meclofenamate, a prostaglandin H synthase inhibitor, and was diminished by N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Removal of the endothelium essentially abolished vasomotion, and meclofenamate had no effect on de-endothelialized arteries. Frequency was not altered by either L-NAME or meclofenamate. Although pharmacological inhibition of nitric oxide and eicosanoid production clearly altered vasomotion, there was no difference in the amplitude or frequency of vasomotion in arteries from obese rats compared with lean rats. These results indicate that the endothelium plays a central role in modulating vasomotion, involving both enhancing and inhibiting effects, and that vasomotion is similar between obese, insulin-resistant and lean, insulin-sensitive rats.

Animals↗

PubMed1999

Estrogen replacement increases coronary artery distensibility in ovariectomized rats.

The effect of estrogen on the passive characteristics of arteries is not known. We hypothesized that estrogen would increase arterial distensibility as part of its protective effect on the vasculature. Female Sprague-Dawley rats were ovariectomized at 11 weeks of age. One group received a placebo (n = 6), while two other groups (n = 5 each) of rats received a 17beta-estradiol pellet (0.15 mg or 0.5 mg with 60-day release). After 4 weeks of estrogen replacement, coronary and mesenteric arteries (<200 microm diameter) were dissected and mounted on a dual-chamber arteriograph. Lumen diameter and wall thickness were measured in pressurized arteries. The relative changes in diameter (distensibility) as well as wall thickness per unit change in pressure were significantly increased (p < 0.05) in the coronary arteries of the 0.5 mg estradiol replaced rats compared with the ovariectomized control animals and the 0.15 mg estradiol replaced rats. Surprisingly, in the mesenteric arteries from the same animals, there was no difference in distensibility or pressure - wall thickness among the groups. This study provides experimental data of a novel hypothesis that estrogen may afford part of its protection through vascular remodeling of the coronary circulation.

Animals↗

PubMed1999

Vascular wall dysfunction in JCR:LA-cp rats: effects of age and insulin resistance.

We tested the hypothesis that aging and insulin resistance interact to increase vascular dysfunction by comparing the function of isolated mesenteric resistance arteries in obese, insulin-resistant JCR:LA-cp rats and lean, insulin-sensitive rats of the same strain at 3, 6, 9, and 12 mo of age. The peak constrictor responses to norepinephrine, phenylephrine, and high potassium were elevated in arteries from obese rats. Responses to these agents increased with age in both obese and lean rats. An eicosanoid constrictor contributed substantially to vasoconstriction in the arteries from both lean and obese animals. Inhibition of nitric oxide synthase increased the vasoconstrictor response to norepinephrine in both obese and lean rats. This effect increased with age in lean rats only. Vascular relaxation in response to acetylcholine and sodium nitroprusside was impaired in the obese rats and did not alter with age. The results suggest that obese JCR:LA-cp rats have enhanced maximal constriction, which originates in the arterial smooth muscle and increases with age. There is evidence that the ability of the arteries to compensate for the enhanced contractility is impaired in obese rats, particularly with advanced age.

Acetylcholine↗

PubMed1999

Evidence for peroxynitrite formation in the vasculature of women with preeclampsia.

-Preeclampsia is a multisystemic disorder of pregnancy in which the normal vascular adaptations to pregnancy are compromised. Oxidative stress as well as endothelial cell dysfunction have been implicated as pathophysiological features of preeclampsia. Endothelial cells produce the vasorelaxant nitric oxide (NO). However, NO is also known to react with superoxide anions (produced under conditions of oxidative stress), yielding peroxynitrite that may impair vascular function. Our objective was to use immunohistochemical techniques to determine whether there is evidence of peroxynitrite formation in the maternal systemic vasculature of women with preeclampsia. Vessels were obtained from a biopsy of subcutaneous fat at the time of cesarean section from normal pregnant (n=7) and preeclamptic (n=7) women or at the time of hysterectomy from nonpregnant women (n=5). There were significantly more vessels staining with greater intensity for nitrotyrosine and endothelial NO synthase in the endothelium of vessels from women with preeclampsia compared with that of normal pregnant women or nonpregnant women. Both endothelial and smooth muscle cells from all vessels showed evidence for the presence of superoxide dismutase (SOD), an enzyme that scavenges superoxide anions. However, the intensity of staining for SOD in the endothelium was significantly lower in the preeclamptic and nonpregnant women than in normal pregnant women. These data of increased endothelial NO synthase, decreased SOD, and increased nitrotyrosine immunostaining in the maternal vasculature of women with preeclampsia suggest increased peroxynitrite formation. We speculate that peroxynitrite is involved in endothelial cell dysfunction in preeclamptic women and contributes to the pathophysiology of this pregnancy disorder.

Adult↗

PubMed1999

Effect of estrogen replacement on vasoconstrictor responses in rat mesenteric arteries.

Recent studies have shown that estrogen can increase endothelial nitric oxide synthase expression and/or activity and that nitric oxide may play a role in attenuating vasoconstrictor responses. Yet there are still controversies in this field. Our hypothesis was that the role of nitric oxide in modulating vasoconstrictor responses in estrogen-replaced animals depends on the agonist. The aim of the study was to determine the effect of long-term estrogen replacement on vascular reactivity of resistance-sized mesenteric arteries in ovariectomized rats with the use of a variety of vasoconstrictors. Female Sprague-Dawley rats were ovariectomized at 11 weeks of age. 17beta-estradiol pellets (0.5 mg/pellet) were implanted in the estrogen-replaced group (n=9) for 4 weeks; placebo pellets were used in the ovariectomized group (n=10). Resistance-sized mesenteric arteries were dissected and mounted onto a dual-chamber arteriograph system. Estradiol replacement did not alter the response of mesenteric arteries to either arginine vasopressin or the thromboxane mimetic U46619. Inhibition of nitric oxide synthase with N(G)-monomethyl-L-arginine (100 micromol/L) did not modulate these vasoconstrictor responses in either group of rats. In contrast, the dose-response curve of the adrenergic agonist phenylephrine was significantly attenuated for the estradiol-replaced rats compared with the ovariectomized group (EC(50)=0.90+/-0.17 vs 0.44+/-0.08 micromol/L, P<0.05). After incubation with N(G)-monomethyl-L-arginine, the EC(50) of phenylephrine significantly decreased in both groups, but a significant difference remained between the 2 groups (EC(50)=0.41+/-0.08 vs 0.28+/-0.02 micromol/L, P<0.05). Importantly, Western immunoblotting demonstrated that the expression of alpha(1)-adrenergic receptors was significantly suppressed by estradiol replacement. We conclude that estrogen may have a specific effect on adrenergic vasoconstriction by modulating its receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1999

Rapid release of matrix metalloproteinase (MMP)-2 by thrombin in the rat aorta: modulation by protein tyrosine kinase/phosphatase.

Matrix metalloproteinase-2 (MMP-2, gelatinase A) and thrombin contribute to many long-term (patho)physiological processes requiring the proteolytic breakdown of the vascular extracellular matrix (e.g., normal tissue repair, remodeling, tumor invasion, atherosclerosis plaque rupture). Thrombin (10 to 1000 nM, 0.5 to 50 U/ml) induced a rapid secretion of MMP-2 from freshly isolated rat aortic tissue (detectable after 1 min of thrombin exposure). This secretion was mediated by an unidentified thrombin receptor, distinct from the proteinase activated receptors (PAR)-1 and -2. Protein tyrosine kinase/phosphatase activity differentially modulated the basal and the thrombin-induced release of MMP-2. The inhibitors of protein tyrosine kinase, herbymicin A, genistein, and tyrphostin 1288 (1 to 100 microM), enhanced the basal release of MMP-2 but did not affect the thrombin-induced secretion of MMP-2. The inhibitor of phosphotyrosine phosphatases, vanadate (100 microM), selectively inhibited the thrombin-induced, but not the basal, release of MMP-2. Rapid release of vascular MMP-2 by thrombin could contribute to short-term processes where thrombin is involved such as the regulation of platelet aggregation and vascular reactivity. Vascular tyrosine kinase/phosphatase likely modulates this action of thrombin to prevent exaggerated platelet aggregation, thrombosis, and vasospasm.

Animals↗