Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiovascular disease is an important cause of death among women. After the menopause there is a steep elevation of low-density lipoprotein (LDL) cholesterol and lipoprotein(a) concomitantly with other risk factors, followed by a striking increase in arteriosclerotic vascular disease, compatible with a lack of estrogens as a causative factor. The benefit of hormone replacement therapy has been documented in several large studies, although rigorous randomized trials are still under way. However, cardiovascular events have been reduced by approximately 50%. In order to optimize beneficial effects and minimize side-effects, the characteristics of selective estrogenic active compounds are a major target of research. The anti-estrogens are the prototype of partial and selective estrogen functions. The components of conjugated estrogens are under investigation for their specific effects. For example, both 17 alpha-dihydroequilin sulfate and 17 alpha-dihydroequilenin sulfate seem to exert antioxidant activity without significant proliferative effects on uterine or breast tissues. This suggests a selective estrogenic activity dependent on the predominant type of estrogen receptor in the particular tissue. Equilin sulfate exerts a significantly stronger antioxidant activity than 17 beta-estradiol in vitro, and delta 8-estrone sulfate increases the lag time for low-density lipoprotein oxidation in vivo. These actions on lipoproteins may add to the quantitative changes of lipoproteins, while other effects are independent of lipoproteins. The 17 alpha-dihydroequilin sulfate and equilin sulfate improved the action of insulin in vivo. Data from rhesus monkeys treated with 17 alpha-dihydroequilenin sulfate indicate that additional mechanisms are probably responsible for the observed cardiovascular protection. Further studies need to be conducted in order to identify selective estrogen receptor modulators and assess their potential, especially in lowering cardiovascular risk.
 ...
PMID:Modification of serum lipids and cardiovascular risk by estrogenic active compounds. 1086 65

Estrogen is important for the primary prevention of vascular disease in young women, but the mechanisms of protection at the vascular cell are still largely unknown. Although traditionally thought of as a nuclear transcription factor, the estrogen receptor has also been identified in the cell plasma membrane to signal but serve largely undefined roles. Here we show that estradiol (E2) rapidly activates p38beta mitogen-activated protein kinase in endothelial cells (EC), which activates the mitogen-activated protein kinase-activated protein kinase-2 and the phosphorylation of heat shock protein 27. The sex steroid preserves the EC stress fiber formation and actin and membrane integrity in the setting of metabolic insult. E2 also prevents hypoxia-induced apoptosis and induces both the migration of EC and the formation of primitive capillary tubes. These effects are reversed by the inhibition of p38beta, by the expression of a dominant-negative mitogen-activated protein kinase-activated protein kinase-2 protein, or by the expression of a phosphorylation site mutant heat shock protein 27. E2 signaling from the membrane helps preserve the EC structure and function, defining potentially important vascular-protective effects of this sex steroid.
 ...
PMID:Estrogen signals to the preservation of endothelial cell form and function. 1098 97

In summary, clinical and animal studies demonstrate that the effects of estrogen in the cardiovascular system protect against the development of histologic and clinical atherosclerosis. However, because estrogen affects so many cellular processes (Figure 4), there are many known adverse effects, including oncogenic and potential negative consequences on the vasculature, including procoagulant and plaque-destabilizing effects. Selective estrogen receptor modulators may allow us to target specific pathways that selectively and favorably effect beneficial responses. However, we must first gain a better understanding of the molecular mechanisms by which estrogen induces cellular signals, both genomic and nongenomic, before we can take full advantage of selective estrogen receptor modulators. As our ability to selectively modulate vascular responses to injury improves, it will be imperative that we have the ability to assess vascular structure, function and pathology with more practical, logistically accessible and biologically targeted approaches than those currently available. Such tools will allow us to test a broad spectrum of agents aimed at pharmacologic therapy for vascular disease.
 ...
PMID:Molecular mechanisms of estrogen actions on the vasculature. 1108

Phytoestrogens derived from soybeans reverse endothelial dysfunction in a number of animal models of systemic vascular disease. Based on these studies, we hypothesized that phytoestrogens would reverse chronic hypoxia-induced endothelial dysfunction in rat pulmonary arteries. To test this hypothesis we examined the effect of genistein, the major phytoestrogen found in soybeans, on carbachol-induced relaxation in phenylephrine-constricted pulmonary artery rings isolated from normoxic rats and rats exposed to 14 days of hypobaric hypoxia. Compared with that in normoxic rats, the response to carbachol was impaired in pulmonary arteries isolated from rats exposed to chronic hypoxia. In normoxic rat pulmonary arteries, genistein (30 microM) did not change the maximum relaxation to carbachol. In contrast, genistein significantly enhanced the relaxation response to carbachol in pulmonary arteries from hypoxic rats, restoring it to the levels seen in normoxic rats. 17beta-estradiol (10 microM) and daidzein (30 microM), a structural analog of genistein lacking inhibitory effects on tyrosine kinases, also restored the relaxation response to carbachol in hypoxic rat pulmonary arteries. The nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine (100 microM) completely blocked the genistein, daidzein, and 17beta-estradiol-induced restoration of the relaxation response to carbachol, whereas the estrogen receptor antagonist ICI 182,780 (10 microM) had no effect on the relaxation responses. We conclude that the phytoestrogens genistein and daidzein act like estrogen in restoring nitric oxide-mediated relaxation in chronically hypoxic rat pulmonary arteries and that this effect does not appear to be mediated by inhibition of tyrosine kinases or by known estrogen receptors.
 ...
PMID:Phytoestrogens restore nitric oxide-mediated relaxation in isolated pulmonary arteries from chronically hypoxic rats. 1135 18

Estrogen is believed to protect postmenopausal women from coronary vascular disease, in part by increasing production of nitric oxide (NO). In this study, we investigated the possibility that transcriptional activation of inducible NO synthase (iNOS) is responsible for a component of the estrogen-induced increase in coronary blood flow. Twenty-two ewes were instrumented with Doppler flow probes on their left circumflex coronary and pulmonary arteries. Nine ewes received 17beta-estradiol (1 microg/kg), and the coronary vascular response was followed for 16 h. Estradiol significantly increased coronary blood flow by 22 +/- 4% over baseline and the peak response occurred at 2 h (P < 0.01). To examine the effect of estrogen on NOS expression in the ovine coronary artery, 17 noninstrumented animals were killed 2 h after administration of estradiol or vehicle. Coronary arteries were analyzed for ovine iNOS and endothelial NOS (eNOS) expression by semiquantitative RT-PCR. PCR primers were based on partial cDNA clones for ovine eNOS and iNOS isolated as part of this study. The expression of iNOS was significantly increased (27-fold) by the administration of estradiol, whereas the expression of eNOS was much weaker (2-fold). To confirm these effects in vivo, additional instrumented animals received either the estrogen receptor (ER) antagonist ICI-182,780 (n = 5), the iNOS antagonist dexamethasone (n = 5), or pyrrolidine dithiocarbamic acid, an inhibitor of nuclear factor-kappaB (n = 5). All three antagonists inhibited estrogen-induced increases in coronary blood flow and increases in cardiac output by over 85%. These results strongly support the hypothesis that 17beta-estradiol increases coronary blood flow in the unanesthetized nonpregnant ewe via an ER-dependent mechanism that results in an increase in both eNOS and iNOS expression.
 ...
PMID:Estrogen increases iNOS expression in the ovine coronary artery. 1218 Nov 48

Estrogen is known to induce rapid vasodilatory response in isolated arteries. Because estrogen is a nonselective receptor agonist, the involvement of estrogen receptor (ER) subtypes in acute estrogenic responses has remained elusive. Acute administration of the selective ERalpha agonist 4,4',4''-(4-propyl-[(1)H]pyrazole-1,3,5-triyl) tris-phenol (PPT) to precontracted aortic rings from intact female rats dose-dependently induced an ER-dependent vascular relaxation fully overlapping to that induced by 17beta-estradiol. By contrast, the selective ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) had no acute effect on vasomotion. This short-term vasorelaxant action of PPT was abolished by the NO synthase inhibitor N(omega)-nitro-l-arginine methyl ester and by endothelium removal. In aortic tissues from ovariectomized (OVX) rats, however, neither 17beta-estradiol nor PPT induced acute vascular relaxation. The effect of PPT was restored in preparations from estrogen-replaced OVX rats, whereas DPN remained ineffective even after estrogen replacement. PPT acted through an ER-dependent mechanism, as shown by impaired response in the presence of the anti-estrogen ICI 182,780 (7alpha,17beta-[9[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol). Accordingly, isolated rat aortic endothelial cells expressed both ERalpha and ERbeta. These data show that selective ERalpha but not ERbeta agonists reproduced the acute vasodilation of estrogen via a receptor-mediated pathway in the aorta from intact as well as 17beta-estradiol-replaced OVX rats. This beneficial effect was undetectable in tissues from OVX rats. Selective pharmacological targeting of ER subtypes may thus represent a novel and promising approach in the treatment of vascular disease.
 ...
PMID:The acute estrogenic dilation of rat aorta is mediated solely by selective estrogen receptor-alpha agonists and is abolished by estrogen deprivation. 1572 4

Aromatase inhibitors (AIs) are becoming the endocrine treatment of first choice for postmenopausal women with hormone receptor-positive breast cancer and are under investigation for use in breast cancer prevention. AIs reduce circulating estrogen to barely detectable concentrations. It is possible that such a low concentration will be deleterious to the vascular system since estrogen receptors are known to be in the cell walls of blood vessels and estrogen is thought to be important in maintaining blood vessel integrity. Because most women who present with primary breast cancer are cured by surgery and systemic therapy and the major cause of female death is vascular disease, it is particularly important to investigate the vascular side effects of AIs in current breast cancer adjuvant and prevention trials. In order to set the vascular toxicities of AIs reported in the current adjuvant trials into context, here we compare them with the toxicities seen during treatment with hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs). Clinical trial evidence indicates that HRT increases risk of coronary heart disease (CHD) whereas SERMs and AIs (to date) appear to be neutral. Cerebrovascular disease and venous thromboembotic events are increased by HRT and SERMs but appear to be unaffected by treatment with AIs. Cognitive function is also considered here since it may also have a vascular component and is potentially a serious potential side effect/benefit of AIs. Recent studies indicate that HRT has a small detrimental effect on cognitive function and is associated with a doubling of the incidence of dementia. A comprehensive study of the SERM, raloxifene, on cognitive function showed no significant effect. There are no definitive reported studies investigating tamoxifen and none for AIs on cognitive function, although there is one in progress in the context of the IBIS II prevention trial which compares anastrozole to placebo in women at high risk. At present concerns about deleterious vascular side effects are confined to HRT and SERMs. However, we have few long-term data using AIs for the treatment and prevention of breast cancer.
 ...
PMID:Vascular effects of aromatase inhibitors: data from clinical trials. 1593 88

We report here that estrogen (E(2)) modulates mitochondrial function in the vasculature. Mitochondrial dysfunction is implicated in the etiology of vascular disease; thus, vasoprotection by estrogen may involve hormonal effects on the mitochondria. To test this hypothesis, mitochondria were isolated from cerebral blood vessels obtained from ovariectomized female rats, with or without E(2) replacement. Estrogen receptor-alpha (ER-alpha) was detected in mitochondria by immunoblot and confocal imaging of intact vessels. E(2) treatment in vivo increased the levels of specific proteins in cerebrovascular mitochondria, such as ER-alpha, cytochrome c, subunit IV of complex IV, and manganese superoxide dismutase, all encoded in the nuclear genome, and subunit I of complex IV, encoded in the mitochondrial genome. Levels of glutathione peroxidase-1 and catalase, however, were not affected. Functional assays of mitochondrial citrate synthase and complex IV, key rate-limiting steps in energy production, showed that E(2) treatment increased enzyme activity. In contrast, mitochondrial production of hydrogen peroxide was decreased in vessels from E(2)-treated animals. In vitro incubation of cerebral vessels with 10 nM 17beta-estradiol for 18 h also elevated levels of mitochondrial cytochrome c. This effect was blocked by the estrogen receptor antagonist fulvestrant (ICI-182,780, Faslodex) but was unaffected by inhibitors of nitric-oxide synthase or phosphoinositide-3-kinase. Nuclear respiratory factor-1 protein, a primary regulator of nuclear gene-encoded mitochondrial genes, was significantly increased by long-term estrogen treatment in vivo. In summary, these novel findings suggest that vascular protection by E(2) is mediated, in part, by modulation of mitochondrial function, resulting in greater energy-producing capacity and decreased reactive oxygen species production.
 ...
PMID:Estrogen increases mitochondrial efficiency and reduces oxidative stress in cerebral blood vessels. 1599 67

Activation of the estrogen receptor-alpha (ERalpha) mediates the vasculoprotective effects of estrogen, in part, through modulating nitric oxide (NO) production and vasodilation. Whereas inflammation is accompanied by altered vascular reactivity and underlies the pathogenesis of vascular disease, the role of the ERalpha in the vascular responses associated with acute systemic inflammation remains poorly characterized. Contractile and relaxation responses of isolated aortic segments were investigated 12 h after ip injection of saline or lipopolysaccharide (LPS, 10 mg/kg) in male wild-type (ERalpha(+/+)) and ERalpha-deficient (ERalpha(-/-)) mice. As previously observed, LPS-injected ERalpha(+/+) mice displayed reduced contractile responses to phenylephrine and enhanced vasodilation in response to acetylcholine. In contrast, aortic tissues from LPS-injected ERalpha(-/-) mice displayed enhanced contractile responses and reduced sensitivity to acetylcholine- and sodium nitroprusside-induced vasodilation. LPS treatment in ERalpha(+/+) and ERalpha(-/-) mice resulted in similar increased levels of systemic NO production and inducible NO synthase expression in the vascular wall. However, expression of mRNA and protein for endothelial NOS and soluble guanylate cyclase (alpha- and beta-subunits) were significantly reduced in aortic tissues from LPS-treated ERalpha(-/-) animals, possibly accounting for reduced endothelial NO production and reduced smooth muscle responses to NO. These findings represent new evidence of the functional role of ERalpha in the male vasculature and suggest that during acute LPS-induced inflammatory responses, the ERalpha mediates the sustained expression of the molecular machinery essential for endothelial NO synthesis (i.e. endothelial NOS) and the vascular responses to NO (i.e. soluble guanylate cyclase).
 ...
PMID:Compromised aortic vasoreactivity in male estrogen receptor-alpha-deficient mice during acute lipopolysaccharide-induced inflammation. 1715 9

Estrogens are correlated with a lower incidence of atherosclerotic vascular disease, but also provide a protective effect on neovascular disorders, such as Kaposi's sarcoma (KS). Estrogens mediate indirect antiatherosclerotic vascular effects by reducing low-density lipoprotein (LDL) levels and by influencing fibrinolysis, and they exert direct actions on vascular cells including vascular relaxation and vasodilatation, thus reducing progression of the lesion. It is increasingly appreciated that the estrogenic effects are mediated not only by the classic genomic action via the specific nuclear hormone receptors ERalpha and ERbeta, but also by distinct rapid, nongenomic actions. Vascular cells have the capacity to express different types of estrogen receptors, and we provide evidence for selective expression of estrogen receptor subtypes on different human vascular cell types. Moreover, we give an overview on the vascular effects of estrogens, selective estrogen receptor modulators (SERMs), and androgens on normal and malignant vascular cells, with particular focus on the protective estrogenic potential on the vasculature.
 ...
PMID:Estrogens in human vascular diseases. 1726 86


1 2 3 Next >>