Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of chronic, collateral-dependent perfusion on beta-adrenergic coronary microvascular responses was examined. Ameroid constrictors were placed on the proximal left circumflex (LCx) coronary artery in 16 pigs. In 8 pigs, heparinized saline containing vascular endothelial growth factor (VEGF) was administered into the perivascular space of the proximal LCx artery using an implanted osmotic pump. After 5-7 weeks, coronary arterial microvessels (70-150 microns) were studied in a pressurized (40 mm Hg) no-flow state with video-microscopy. beta-Adrenoceptor-mediated relaxations of isolated microvessels from the collateral-dependent LCx region to isoproterenol (P < 0.01) were markedly reduced, as were those to the adenylate cyclase activator forskolin (P < 0.01), compared to the respective response of vessels from the normally perfused left anterior descending artery region. Responses to the Gs-protein activator NaF showed a similar trend, but the differences were not significant. Chronic treatment with VEGF normalized responses to isoproterenol, NaF, and forskolin in the collateral-dependent LCx region. Blood flow in the LCx region increased in both control (P < 0.01) and VEGF-treated (P < 0.05) groups during rapid atrial pacing. The absolute increase in LCx blood flow was greater in the VEGF group than in the control group at rest (P < 0.05), but not during rapid pacing. Thus, beta-adrenergic microvascular relaxation is impaired in the collateral-dependent coronary microcirculation. The periadventitial delivery of VEGF improves myocardial perfusion to the collateral-dependent area and preserves beta-adrenergic-mediated relaxation of microvessels in the collateral-dependent myocardium.
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PMID:Beta-adrenergic modulation of the collateral-dependent coronary microcirculation. 763 Jan 26

The expression of vascular endothelial growth factor (VEGF) in cultured bovine granulosa cells has been studied. As shown by northern blot analysis, granulosa cells express the VEGF gene. Analysis of the VEGF transcripts by the polymerase chain reaction technique shows that granulosa cells express predominantly the smallest VEGF coding forms (VEGF121 and VEGF164). Since in the promoter region of the VEGF gene there are four potential AP-1 sites and two potential AP-2 sites we have studied if TPA and forskolin could regulate VEGF gene expression. TPA induces VEGF transcription in a time- and dose-dependent fashion. Maximal VEGF mRNA levels are detected 6 h after TPA treatment. Induction apparently requires de novo protein synthesis since it does not occur when translation is inhibited by cycloheximide. Forskolin, a naturally occurring diterpene that activates adenylylcyclase, also increases VEGF mRNA content in a time-dependent manner. Induction does not require de novo protein synthesis and, in contrast to TPA, induction is strongly potentiated by cycloheximide. Luteotrophic hormone, a known activator of adenylylcyclase, also induces VEGF transcription. These results imply that granulosa cells may be a source of VEGF which could play a role in the angiogenic process associated with ovulation and corpus luteum formation.
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PMID:Transcriptional regulation of vascular endothelial growth factor gene expression in ovarian bovine granulosa cells. 846 53

We investigated the mechanism underlying vascular endothelial growth factor (VEGF) synthesis stimulated by prostaglandin E1 (PGE1) in osteoblast-like MC3T3-E1 cells. PGE1 induced the phosphorylation of both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. SB203580, a specific inhibitor of p38 MAP kinase, inhibited the PGE1-stimulated VEGF synthesis as well as PGE1-induced phosphorylation of p38 MAP kinase. PD98059, an inhibitor of the upstream kinase that activates p44/p42 MAP kinase, which reduced the PGE1-induced phosphorylation of p44/p42 MAP kinase, had little effect on the VEGF synthesis stimulated by PGE1. AH-6809, an antagonist of the subtypes of the PGE receptor, EP1 and EP2, or SC-19220, an antagonist of EP1 receptor, did not inhibit the PGE1-induced VEGF synthesis. H-89, an inhibitor of cAMP-dependent protein kinase, and SQ22536, an inhibitor of adenylate cyclase, reduced the VEGF synthesis induced by PGE1. Cholera toxin, an activator of G(s), and forskolin, an activator of adenylate cyclase, induced VEGF synthesis. SB203580 and PD169316, another specific inhibitor of p38 MAP kinase, reduced the cholera toxin-, forskolin- or 8bromo-cAMP-stimulated VEGF synthesis. However, PD98059 failed to affect the VEGF synthesis stimulated by cholera toxin, forskolin or 8-bromoadenosine-3',5'-cyclic monophosphate (8bromo-cAMP). SB203580 reduced the phosphorylation of p38 MAP kinase induced by forskolin or 8bromo-cAMP. These results strongly suggest that p44/p42 MAP kinase activation is not involved in the PGE1-stimulated VEGF synthesis in osteoblasts but that p38 MAP kinase activation is involved.
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PMID:p38 mitogen-activated protein (MAP) kinase but not p44/p42 MAP kinase is involved in prostaglandin E1-induced vascular endothelial growth factor synthesis in osteoblasts. 1152 43

White adipose tissue from rats was examined for insulin- responsive vascular endothelial growth factor 165 (VEGF) secretion and mRNA expression. When separated into it constituent fat vs. stromal-vascular cells using collagenase digestion methods, only the adipocytes (or whole fat tissue) responded to physiological insulin concentrations by doubling VEGF release over 4 and 24 h in culture. Adipocyte VEGF mRNA expression increased similarly. Several adipose depots were tested. Although omental fat cells had the highest rates of VEGF release, the differences were not significant. Insulin-stimulated VEGF release was mediated in part via PI3K, but not PKC. Additional hormones/agents were tested, including steroids, leptin, an adenosine analog, and norepinephrine. Only the latter compound increased VEGF production, and this effect was mediated by adenylate cyclase. Adjusting the incubation glucose concentration between 0-20 mM did not alter adipocyte VEGF release. An experimental mimic of hypoxia, CoCl(2), also increased adipocyte VEGF, and this effect was additive with 100 nM insulin. These studies demonstrate that physiological insulin concentrations stimulate VEGF formation and expression in cultured rodent white adipocytes. Although the biological significance of this observation remains to be determined, if white adipocyte-derived VEGF has paracrine or systemic endocrine actions, these might hypothetically impact on adipose expansion or the vascular comorbidities of obesity.
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PMID:White adipocyte vascular endothelial growth factor: regulation by insulin. 1186 17

We studied the in vitro effects of sex hormones on vascular endothelial growth factor (VEGF) production in differentiated THP-1 monocytic cells. Phorbol-12-myristate-13-acetate differentiated THP-1 into macrophage-like cells. 17beta-estradiol (10 (-9) M) increased VEGF secretion of controls 3.1-fold in differentiated THP-1 and this effect of 17beta-estradiol was antagonized by dihydrotestosterone, although dihydrotestosterone alone did not alter VEGF secretion. 17beta-estradiol increased steady-state mRNA level of VEGF and the increase was counteracted by dihydrotestosterone in differentiated THP-1, although dihydrotestosterone alone did not alter the VEGF mRNA level. Progesterone did not affect the constitutive and 17beta-estradiol-induced VEGF secretion and mRNA level. Transient transfection revealed that 17beta-estradiol enhanced chloramphenicol acetyl transferase expression driven by VEGF promoter and the enhancement was antagonized by dihydrotestosterone. Adenylate cyclase inhibitor suppressed 17beta-estradiol-induced enhancement of VEGF secretion, mRNA level, and promoter activity, whereas dihydrotestosterone-induced suppression on the effects of 17beta-estradiol was counteracted by 3',5'-adenosine cyclic monophosphate (cAMP) analog. 17beta-estradiol increased intracellular cAMP level by activating adenylate cyclase, while dihydrotestosterone reduced the basal and 17beta-estradiol-increased cAMP level by inhibiting adenylate cyclase. Transfection with 5'-deleted VEGF promoters demonstrated that the region between -88 and -66 bp may be involved in the transcriptional regulation by each hormone. The mutation within activator protein-2 element in this region abrogated the transcriptional stimulation and repression by the respective hormones. 17beta-estradiol activated transcription from activator protein-2-responsive reporter plasmid while dihydrotestosterone antagonized the effect of 17beta-estradiol. These results suggest that 17beta-estradiol enhances VEGF production while dihydrotestosterone antagonizes the effect of 17beta-estradiol via up- or downregulation of adenylate cyclase in differentiated THP-1.
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PMID:17beta-estradiol enhances vascular endothelial growth factor production and dihydrotestosterone antagonizes the enhancement via the regulation of adenylate cyclase in differentiated THP-1 cells. 1187 93

We previously reported that endogenous prostaglandins (PGs) may increase cAMP facilitated angiogenesis through the induction of vascular endothelial growth factor (VEGF) in rat sponge implantation models. In the present experiment, we tested whether or not adenylate cyclase / protein kinase A (AC/PKA)-dependent VEGF induction enhanced angiogenesis in this model. Topical daily injections of 8-bromo-cAMP enhanced angiogenesis in a dose-dependent manner. Forskolin, an activator of AC, also facilitated angiogenesis as did amrinone, an inhibitor of phosphodiesterase. VEGF induction was confirmed by the increased levels in the fluids in the sponge matrix after topical injection of 8-bromo-cAMP. Immunohistochemical investigation further revealed the VEGF-expressed cells in the sponge granulation tissues to be fibroblasts, and the intensity of positive reactions was enhanced by 8-bromo-cAMP, forskolin and amrinone. Angiogenesis without topical injections of the above compounds was suppressed by SQ22,536, an inhibitor for AC, or H-89, an inhibitor for PKA, with concomitant reductions in VEGF levels. Daily topical injections of neutralizing antibody or anti-sense oligonucleotide against VEGF significantly suppressed angiogenesis. PGE2-induced angiogenesis was suppressed with SQ22,536 or H-89. These results suggested that AC/PKA-dependent induction of VEGF certainly enhanced angiogenesis and that pharmacological tools for controlling this signaling pathway may be able to facilitate the management of conditions involving angiogenesis.
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PMID:Adenylate cyclase/protein kinase A signaling pathway enhances angiogenesis through induction of vascular endothelial growth factor in vivo. 1188 66

Adenosine has been reported to stimulate or inhibit the release of angiogenic factors depending on the cell type examined. To test the hypothesis that differential expression of adenosine receptor subtypes contributes to endothelial cell heterogeneity, we studied microvascular (HMEC-1) and umbilical vein (HUVEC) human endothelial cells. Based on mRNA level and stimulation of adenylate cyclase, we found that HUVECs preferentially express A2A adenosine receptors and HMEC-1 preferentially express A2B receptors. Neither cells expressed A1 or A3 receptors. The nonselective adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) increased expression of interleukin-8 (IL-8), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in HMEC-1, but had no effect in HUVECs. In contrast, the selective A2A agonist 2-p-(2-carboxyethyl)phenylethylamino-NECA (CGS 21680) had no effect on expression of these angiogenic factors. Cotransfection of each type of adenosine receptors with a luciferase reporter in HMEC-1 showed that A2B receptors, but not A1, A2A, or A3, activated IL-8 and VEGF promoters. These effects were mimicked by constitutively active alphaG(q), alphaG12, and alphaG13, but not alphaG(s) or alphaG(i1-3). Furthermore, stimulation of phospholipase C indicated coupling of A2B receptors to G(q) proteins in HMEC-1. Thus, differential expression of adenosine receptor subtypes contributes to functional heterogeneity of human endothelial cells. A2B receptors, predominantly expressed in human microvascular cells, modulate expression of angiogenic factors via coupling to G(q), and possibly via G12/13.
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PMID:Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation. 1190 16

Stimulation of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) increases the expression of CXCR4 on endothelial cells, rendering these cells more responsive to stromal-derived factor 1 (SDF-1), an angiogenic CXC chemokine and unique ligand for CXCR4. Here, we show that prostaglandin E2 (PGE2) mediates the effects of bFGF and VEGF in up-regulating CXCR4 expression on human microvascular endothelial cells (HMECs). Forskolin or 3-isobutyl-1-methyl xanthine (IBMX), 2 inducers of adenylate cyclase, markedly enhanced, whereas cyclooxygenase (COX) inhibitors including aspirin, piroxicam, and NS398 markedly inhibited CXCR4 expression on HMECs. Furthermore, the ability of PGE2 to augment in vitro tubular formation in SDF-1alpha containing matrigel was inhibited completely by blocking CXCR4. Treatment of bFGF- or VEGF-stimulated HMECs with COX inhibitors blocked tubular formation by about 50% to 70%. Prostaglandin-induced human endothelial cell organization and subsequent vascularization can be inhibited to a greater extent by a neutralizing antibody to human CXCR4 in severe combined immunodeficient mice. Additionally, VEGF- and bFGF-induced angiogenesis in vivo was also inhibited by about 50% by NS-398 or piroxicam, and this inhibitory effect was accompanied by decreased expression of CXCR4 on murine endothelial cells. Consequently, by inducing CXCR4 expression, prostaglandin accounts for about 50% of the tubular formation in vitro and in vivo angiogenic effects of VEGF and bFGF. Moreover, augmentation of CXCR4 expression by VEGF, bFGF, and PGE2 involves stimulation of transcription factors binding to the Sp1-binding sites within the promoter region of the CXCR4 gene. These findings indicate that PGE2 is a mediator of VEGF- and bFGF-induced CXCR4-dependent neovessel assembly in vivo and show that angiogenic effects of PGE2 require CXCR4 expression.
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PMID:Angiogenic effects of prostaglandin E2 are mediated by up-regulation of CXCR4 on human microvascular endothelial cells. 1279 66

We have previously demonstrated that endothelin (ET)-1 and its subtype A receptor (ET-AR) expression are increased in lung under hypoxic conditions and that activation of ET-AR by ET-1 is a major mediator of hypoxia-induced pulmonary hypertension in the rat. The present study tested the hypothesis that the hypoxia-responsive tyrosine kinase receptor-activating growth factors fibroblast growth factor (FGF)-1, FGF-2, and platelet-derived growth factor (PDGF)-BB stimulate expression of the ET-AR in pulmonary arterial smooth muscle cells (PASMCs). Quiescent rat PASMCs were incubated under hypoxia (1% O2), or with FGF-1, FGF-2, PDGF-BB, vascular endothelial growth factor, ET-1, angiotensin II, or atrial natriuretic peptide under normoxic conditions for 24 h. FGF-1 and -2 and PDGF-BB, but not hypoxia, vascular endothelial growth factor, ET-1, angiotensin II, or atrial natriuretic peptide, significantly increased ET-AR mRNA levels. FGF-1-induced ET-AR expression was inhibited by FGF-receptor inhibitor PD-166866, MEK inhibitor U-0126, transcription inhibitor actinomycin D, and translation inhibitor cycloheximide. In contrast, the stimulatory effect of FGF-1 on ET-AR mRNA expression was not altered by PI3 kinase, PKA, PKC, or adenylate cyclase inhibitors. PASMC ET-AR gene transcription, assessed by nuclear-runoff analysis, was increased by FGF-1. These results provide novel finding that ET-AR in PASMCs in vitro is unresponsive to hypoxia per se but is robustly simulated by tyrosine kinase receptor-associated growth factors (FGF-1, FGF-2, PDGF-BB) that themselves are stimulated by hypoxia in lung. This observation suggests a novel signaling mechanism that may be responsible for overexpression of ET-AR in lung, and may contribute to the hypoxia-induced pulmonary vasoconstriction, hypertension, and vascular remodeling in hypoxia-adapted animal.
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PMID:Fibroblast growth factor mediates hypoxia-induced endothelin-- a receptor expression in lung artery smooth muscle cells. 1285 19

Changes in human endometrium are essential to allow the establishment of pregnancy. These changes are induced in vivo by progesterone, and include appearance within the tissue of a specific uterine natural killer cell, characterized by an abundant expression of CD56. Changes also occur in the stromal cells, which undergo a characteristic decidualization reaction. Decidualized stromal cells are derived from the fibroblast-like cells within the endometrium, which maintain their progesterone receptors in the presence of progesterone. Prolonged exposure to progesterone induces a rounded cell characterized by release of prolactin and insulin-like growth factor binding protein-1 (IGFBP-1), and expression of tissue factor. Additional changes include the secretion of interleukin (IL)-15, vascular endothelial growth factor, and surface expression of zinc dependent metalloproteinases such as CD10 and CD13. In vitro, elevated intracellular cAMP as well as progesterone is necessary for decidualization. In vivo, these conditions may be provided by progesterone from the corpus luteum, by prostaglandin E, a stimulator of adenyl cyclase, and relaxin, which has recently been shown to be a phosphodiesterase inhibitor. Given the co-distribution of uterine natural killer cells and decidualized stromal cells, a mutual interaction might provide the correct regulatory environment for successful implantation, and penetration of the maternal blood vessels by trophoblastic cells.
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PMID:Decidualization of the human endometrial stromal cell: an enigmatic transformation. 1456 82


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