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PubMed2002

Adenosine A(1) receptor mediates late preconditioning via activation of PKC-delta signaling pathway.

Protein kinase C (PKC) plays a central role in both early and late preconditioning (PC) but its association with inducible nitric oxide synthase (iNOS) is not clear in late PC. This study investigates the PKC signaling pathway in the late PC induced by activation of adenosine A(1) receptor (A(1)R) with adenosine agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) and the effect on iNOS upregulation. Adult male mice were pretreated with saline or CCPA (100 microg/kg iv) or CCPA (100 microg/kg iv) with PKC-delta inhibitor rottlerin (50 microg/kg ip). Twenty-four hours later, the hearts were isolated and perfused in the Langendorff mode. Hearts were subjected to 40 min of ischemia, followed by 30 min reperfusion. After ischemia, the left ventricular end-diastolic pressure (LVEDP) was significantly improved and the rate-pressure product (RPP) was significantly higher in the CCPA group compared with the ischemia-reperfusion (I/R) control group. Creatine kinase release and infarct size were significantly lower in the CCPA group compared with the I/R control group. These salutary effects of CCPA were abolished in hearts pretreated with rottlerin. Immunoblotting of PKC showed that PKC-delta was upregulated (150.0 +/- 11.4% of control group) whereas other PKC isoforms remained unchanged, and iNOS was also significantly increased (146.2 +/- 9.0%, P < 0.05 vs. control group) after 24 h of treatment with CCPA. The data show that PKC is an important component of PC with adenosine agonist. It is concluded that activation of A(1)R induces late PC via PKC-delta and iNOS signaling pathways.

Acetophenones↗
PubMed1998

Signaling pathway by which TGF-beta1 increases expression of latent TGF-beta binding protein-2 at the transcriptional level.

The cytokine transforming growth factor-beta has multiple effects on a wide variety of cell types. These effects include modulation of growth and regulation of gene transcription. In the present work, we demonstrate that TGF-beta1 increases transcription of the latent transforming growth factor-beta binding protein-2 ( LTBP-2) gene in cultured human fetal lung fibroblasts leading to a significant increase in LTBP-2 mRNA steady state level. The stability of LTBP-2 mRNA was not appreciably altered. A corresponding increase in production of LTBP-2 protein accompanied the increase in mRNA. Through the use of specific inhibitors, we demonstrate that a member of the Ras super family and a protein kinase C, probably of the atypical (non-diacylglycerol, non-Ca++ dependent) class are likely to be components in the signaling pathway. However, phospholipases, G proteins and extracellular-signal regulated kinases do not appear to be involved. These results combined with previous findings on elastin regulation by TGF-beta1 (Kucich et al. (1997). Am. J. Respir. Cell Mol. Biol., 17: 10-16) demonstrate that TGF-beta1 can coordinately increase the steady state levels of mRNAs encoding components of the elastic fiber, but through diverse mechanisms. In contrast to LTBP-2, increased elastin expression is achieved by message stabilization. Furthermore, the TGF-beta1 signaling pathways differ and while the pathway leading to increased LTBP-2 transcription shares components with those modulating transcription of other genes, it is unlikely to be precisely congruent with any other previously described one.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Key inflammatory signaling pathways are regulated by the proteasome.

Lipopolysaccharide (LPS) is a major structural component of all Gram-negative organisms and has been implicated in Gram-negative sepsis and septic shock. In the present study, Affymetrix microarray analysis of RNA derived from murine macrophages treated with LPS in the absence or presence of the proteasome inhibitor lactacystin revealed that the vast majority of genes regulated by LPS is under control of the proteasome. Analysis of the data has revealed that the products of these genes participate in 14 distinct signaling pathways. This represents a novel approach to the identification of signaling pathways that are both toll-like receptor 4- and proteasome-dependent and may lead to the development of new drug targets in Gram-negative sepsis and septic shock.

Acetylcysteine↗
PubMed1999

The hedgehog signalling pathway and its role in basal cell carcinoma.

The hedgehog signalling pathway plays a vital role in Drosophila embryonic patterning and development. Hedgehog is a secreted protein, unrelated to classical growth factors, which seems to form concentration gradients across those tissues involved in pattern formation. Cloning of vertebrate homologues of hedgehog and other genes has illustrated the remarkable conservation of function of this pathway throughout evolution. The human homologue of patched, a receptor for the hedgehog protein, was cloned as the gene responsible for naevoid basal cell carcinoma syndrome (NBCCS/'Gorlin Syndrome'), an autosomal dominant condition in which patients suffer from multiple basal cell carcinomas and a wide spectrum of developmental abnormalities. Its role as a tumour suppressor gene in both NBCCS and sporadic basal cell carcinoma led to the suggestion that mutation or inactivation of human patched may be an essential step in development of basal cell carcinomas and other skin tumours. This review describes our current understanding of hedgehog signalling in Drosophila and vertebrates and its relation to the development of human basal cell carcinoma and other skin tumours, together with a discussion of future avenues of research into this critical and intriguing pathway.

Animals↗
PubMed2002

Thrombin stimulation of vascular adhesion molecule-1 in endothelial cells is mediated by protein kinase C (PKC)-delta-NF-kappa B and PKC-zeta-GATA signaling pathways.

We recently demonstrated that thrombin induces the expression of vascular adhesion molecule-1 (VCAM-1) in endothelial cells by an NF-kappaB- and GATA-dependent mechanism. In the present study, we describe the signaling pathways that mediate this response. Thrombin stimulation of the VCAM-1 gene and promoter in human umbilical vein endothelial cells was inhibited by preincubation with the phosphatidylinositol 3-kinase inhibitor, LY294002, the protein kinase C (PKC)-delta inhibitor, rottlerin, a PKC-zeta peptide inhibitor, or by overexpression of dominant negative (DN)-PKC-zeta. In electrophoretic mobility shift assays, thrombin-mediated induction of NF-kappaB p65 binding to two NF-kappaB motifs in the upstream promoter region of VCAM-1 was blocked by LY294002 and rottlerin, whereas the inducible binding of GATA-2 to a tandem GATA motif was inhibited by LY294002 and the PKC-zeta peptide inhibitor. In co-transfection assays, thrombin stimulation of a minimal promoter containing multimerized VCAM-1 NF-kappaB sites was inhibited by DN-PKC-delta but not DN-PKC-zeta. In contrast, thrombin-mediated transactivation of a minimal promoter containing tandem VCAM-1 GATA motifs was inhibited by DN-PKC-zeta but not DN-PKC-delta. Finally, thrombin failed to induce VCAM-1 expression in vascular smooth muscle cells. Taken together, these data suggest that the endothelial cell-specific effect of thrombin on VCAM-1 expression involves the coordinate activity of PKC-delta-NF-kappaB and PKC-zeta-GATA signaling pathways.

Acetophenones↗
PubMed1998

An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans.

Mutations in daf-2 and age-1 cause a dramatic increase in longevity as well as developmental arrest at the dauer diapause stage in Caenorhabditis elegans. daf-2 and age-1 encode components of an insulin-like signaling pathway. Both daf-2 and age-1 act at a similar point in the genetic epistasis pathway for dauer arrest and longevity and regulate the activity of the daf-16 gene. Mutations in daf-16 cause a dauer-defective phenotype and are epistatic to the diapause arrest and life span extension phenotypes of daf-2 and age-1 mutants. Here we show that mutations in this pathway also affect fertility and embryonic development. Weak daf-2 alleles, and maternally rescued age-1 alleles that cause life span extension but do not arrest at the dauer stage, also reduce fertility and viability. We find that age-1(hx546) has reduced both maternal and zygotic age-1 activity. daf-16 mutations suppress all of the daf-2 and age-1 phenotypes, including dauer arrest, life span extension, reduced fertility, and viability defects. These data show that insulin signaling, mediated by DAF-2 through the AGE-1 phosphatidylinositol-3-OH kinase, regulates reproduction and embryonic development, as well as dauer diapause and life span, and that DAF-16 transduces these signals. The regulation of fertility, life span, and metabolism by an insulin-like signaling pathway is similar to the endocrine regulation of metabolism and fertility by mammalian insulin signaling.

Animals↗
PubMed1997

Requirement for JAK2 in erythropoietin-induced signalling pathways.

Erythropoietin (EPO) exerts its activities by the induction of multiple signalling pathways through interaction with the erythropoietin receptor (EPOR). Previous studies have suggested that the Ras/MAP kinase as well as the JAK/STAT signalling cascades play significant roles in the induction of EPO-responsive genes. Here we show that, in HCD-57 erythroleukemic cells, both pathways are activated by EPO in a dose-dependent manner with similar sensitivities and kinetics. The activation of signalling molecules is closely related to the proliferative status of the cells. Using an antisense strategy, we were able to show that the downregulation of the JAK2 protein level in HCD-57 cells results in a distinct reduction of the ability to induce not only STAT5 DNA-binding, but also MAP kinase activity. Our results thus provide evidence for a significant contribution of the cytosolic tyrosine kinase JAK2 to the EPO-induced activation of the Ras/MAP kinase cascade.

Animals↗
PubMedDate not supplied

[Signaling pathways that control the growth and survival of prostate tumor cells in the absence of androgens].

Androgen-dependent human prostate adenocarcinoma cell line LNCaP was used to study the effect of androgen deprivation on the cell response to TNF-related cytokines. Several signaling pathways were implicated in cell survival in the absence of androgens. In androgen-deprived LNCaP cells, TNF-alpha and TRAIL stimulated the cell growth and activated the mitogenic and antiapoptotic signaling pathways involving NF-kappa B, STAT3, PI3K, and beta-catenin. The results suggested a role of cytokines in the survival of prostate adenocarcinoma cells deprived of androgens in vitro.

Acetylcysteine↗
PubMed2004

The CD40-induced signaling pathway in endothelial cells resulting in the overexpression of vascular endothelial growth factor involves Ras and phosphatidylinositol 3-kinase.

Ligation of endothelial cell (EC) CD40 induces the expression of several proinflammatory cytokines as well as angiogenesis factors, including vascular endothelial growth factor (VEGF). Moreover, despite the reported importance of CD40 in cell-mediated immunity, little is known of the CD40-induced signaling pathways in EC. In this study, we have investigated the function of the Ras signaling pathway(s) for CD40-induced overexpression of VEGF. EC were transiently transfected with a full-length VEGF promoter-luciferase construct and a dominant-inhibitory mutant of Ras (Ras17N). Following transfection, ligation of CD40 with soluble CD40 ligand resulted in a significant increase in VEGF transcriptional activation, and the inhibitory mutant of Ras blocked this CD40-induced VEGF overexpression. Using EMSA and Western blot analysis, we demonstrated that CD40-dependent binding of nuclear protein(s) to the VEGF promoter and CD40-induced VEGF protein expression in EC were also inhibited by the Ras mutant. Immunoprecipitation studies revealed that ligation of CD40 on EC promoted an increased association of Ras with its effector molecules Raf, Rho, and phosphatidylinositol 3-kinase (PI3K). But, cotransfection of effector-loop mutants of Ras determined that only PI3K was functional for Ras-induced VEGF transcription. Also, wortmanin and a dominant-inhibitory mutant of PI3K inhibited CD40-induced overexpression of VEGF. Together these findings demonstrate that both Ras and PI3K are intermediaries in CD40-induced regulation of VEGF in EC. We believe our findings are of importance in several chronic inflammatory diseases, including atherosclerosis and allograft rejection associated with both CD40-CD40 ligand signaling as well as VEGF expression and function.

CD40 Antigens↗
PubMed2001

Drosophila MyD88 is an adapter in the Toll signaling pathway.

Toll-like receptors comprise a family of cell surface receptors that play a crucial role in the innate immune recognition of both Drosophila and mammals. Previous studies have shown that Drosophila Toll-1 mediates the induction of antifungal peptides during fungal infection of adult flies. Through genetic studies, Tube, Pelle, Cactus, and Dif have been identified as downstream components of the Toll-1 signaling pathway. Here we report characterization of a Drosophila homologue of human MyD88, dMyD88. We show that dMyD88 is an adapter in the Toll signaling pathway that associates with both the Toll receptor and the downstream kinase Pelle. Expression of dMyD88 in S2 cells strongly induced activity of a Drosomycin reporter gene, whereas a dominant-negative version of dMyD88 potently inhibited Toll-mediated signaling. We also show that dMyD88 associates with the death domain-containing adapter Drosophila Fas-associated death domain-containing protein (dFADD), which in turn interacts with the apical caspase Dredd. This pathway links a cell surface receptor to an apical caspase in invertebrate cells and therefore suggests that the Toll-mediated pathway of caspase activation may be the evolutionary ancestor of the death receptor-mediated pathway for apoptosis induction in mammals.

Adaptor Proteins, Signal Transducing↗
PubMed1994

Extracellular ATP triggers two functionally distinct calcium signalling pathways in PC12 cells.

We have investigated the effects of extracellular ATP on Ca2+ signalling, and its relationship to secretion in rat pheochromocytoma (PC12) cells. In single cells, extracellular ATP evoked two very distinct subcellular distributions of intracellular calcium concentration ([Ca2+]i), only one of which could be mimicked by the pyrimidine nucleotide UTP, suggesting the involvement of more than one cell surface receptor in mediating the ATP-induced responses. ATP and UTP were equipotent in activating a receptor leading to inositol phosphate production and the mobilisation of intracellular Ca2+. In some cells (19%) this rise in [Ca2+]i initiated at a discrete site and then propagated across the cell in the form of a Ca2+ wave. In addition to mobilising intracellular Ca2+ through a 'nucleotide' receptor sensitive to ATP and UTP, the results indicate that ATP also activates divalent cation entry through an independent receptor-operated channel. Firstly, ATP-induced entry of Ca2+ or Mn2+ was independent of Ca2+ mobilisation, as prior treatment of cell populations with UTP abolished the ATP-evoked release of intracellular Ca2+ stores, but left the Ca(2+)- and Mn(2+)-entry components uneffected. Secondly, although UTP and ATP were equally effective in generating inositol phosphates, only ATP stimulated divalent cation entry, indicating that ATP-activated influx was independent of phosphoinositide turnover. Thirdly, single cell experiments revealed a subpopulation of cells that responded to ATP with divalent cation entry without mobilising Ca2+ from intracellular stores. Lastly, the dihydropyridine antagonist, nifedipine, reduced the ATP-induced rise in [Ca2+]i by only 24%, suggesting that Ca2+ entry was largely independent of L-type voltage-operated Ca2+ channels. The Ca2+ signals could also be distinguished at a functional level. Activation of ATP-induced divalent cation influx was absolutely required to evoke transmitter release, because ATP triggered secretion of [3H]dopamine only in the presence of external Ca2+, and UTP was unable to promote secretion, irrespective of the extracellular [Ca2+]. The results suggest that the same extracellular stimulus can deliver different Ca2+ signals into the same cell by activating different Ca2+ signalling pathways, and that these Ca2+ signals can be functionally distinct.

Adenosine Triphosphate↗
PubMed1996

TC21 causes transformation by Raf-independent signaling pathways.

Although the Ras-related protein TC21/R-Ras2 has only 55% amino acid identity with Ras proteins, mutated forms of TC21 exhibit the same potent transforming activity as constitutively activated forms of Ras. Therefore, like Ras, TC21 may activate signaling pathways that control normal cell growth and differentiation. To address this possibility, we determined if regulators and effectors of Ras are also important for controlling TC21 activity. First, we determined that Ras guanine nucleotide exchange factors (SOS1 and RasGRF/CDC25) synergistically enhanced wild-type TC21 activity in vivo and that Ras GTPase-activating proteins (GAPs; p120-GAP and NF1-GAP) stimulated wild-type TC21 GTP hydrolysis in vitro. Thus, extracellular signals that activate Ras via SOS1 activation may cause coordinate activation of Ras and TC21. Second, we determined if Raf kinases were effectors for TC21 transformation. Unexpectedly, yeast two-hybrid binding analyses showed that although both Ras and TC21 could interact with the isolated Ras-binding domain of Raf-1, only Ras interacted with full-length Raf-1, A-Raf, or B-Raf. Consistent with this observation, we found that Ras- but not TC21-transformed NIH 3T3 cells possessed constitutively elevated Raf-1 and B-Raf kinase activity. Thus, Raf kinases are effectors for Ras, but not TC21, signaling and transformation. We conclude that common upstream signals cause activation of Ras and TC21, but activated TC21 controls cell growth via distinct Raf-independent downstream signaling pathways.

3T3 Cells↗
PubMed2006

Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion.

Protein expression in the heart is altered following periods of myocardial ischemia. The changes in protein expression are associated with increased cell size that can be maladaptive. There is little information regarding the regulation of protein expression through the process of mRNA translation during ischemia and reperfusion in the heart. Therefore, the purpose of this study was to identify changes in signaling pathways and downstream regulatory mechanisms of mRNA translation in an in vivo model of myocardial ischemia and reperfusion. Hearts were collected from rats whose left main coronary arteries had either been occluded for 25 min or reversibly occluded for 25 min and subsequently reperfused for 15 min. Following reperfusion, both the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways were activated, as evidenced by increased phosphorylation of Akt (PKB), extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase. Activation of Akt stimulated signaling through the protein kinase mammalian target of rapamycin, as evidenced by increased phosphorylation of two of its effectors, the ribosomal protein S6 kinase and the eukaryotic initiation factor eIF4E binding protein 1. Ischemia and reperfusion also resulted in increased phosphorylation of eIF2 and eIF2B. These changes in protein phosphorylation suggest that control of mRNA translation following ischemia and reperfusion is modulated through a number of signaling pathways and regulatory mechanisms.

Animals↗
PubMed2004

New insight into the signalling pathways of heat stress-induced myocardial preconditioning: protein kinase Cepsilon translocation and heat shock protein 27 phosphorylation.

1. Heat stress (HS) is known to induce delayed preconditioning against myocardial infarction 24 h later, but the exact signalling pathway of this response remains to be elucidated. In previous studies, we have shown evidence for the implication of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK) in the HS-induced reduction in infarct size. Furthermore, in their phosphorylated state, small heat shock proteins (Hsp27) seem to confer cytoskeletal protection. In the present study, we sought to determine the effect of HS on the subcellular distribution of PKC isoforms and on Hsp27 phosphorylation. 2. Rats were subjected to either HS (42 degrees C for 15 min; HS group) or sham anaesthesia (sham group) before their hearts were excised. Myocardial tissue extracts obtained 20 min or 24 h after HS were processed for western blot analysis. 3. In the HS group, PKCepsilon translocated from the cytosolic to the particulate fraction (4426 +/- 128 vs 6258 +/- 316 arbitrary units; P = 0.002). Chelerythrine (5 mg/kg, i.p.), a PKC inhibitor, abolished this translocation. Western blot analysis of Hsp27 24 h after HS showed a marked increase in protein expression and phosphorylation in the particulate fraction. 4. In the present study, we have shown that HS induces the translocation of PKCepsilon from the cytosolic to the particulate fraction. Along with our previous observation that PKC is a trigger of HS-induced myocardial preconditioning, the results of the present study suggest an important role of the epsilon isoform of PKC in this cardioprotective mechanism. Furthermore, we have also demonstrated that the cytoprotective protein Hsp27 is phosphorylated following HS. Therefore, we can conclude that PKC and MAPK/Hsp27 are involved in the signalling pathway of HS-induced cardioprotection.

Animals↗
PubMed2004

Signaling pathway of magnolol-stimulated lipolysis in sterol ester-loaded 3T3-L1 preadipocyes.

The aims of the present study were to examine the effect of magnolol on lipolysis in sterol ester (SE)-loaded 3T3-L1 preadipocytes and to determine the signaling mechanism involved. We demonstrate that magnolol treatment resulted in a decreased number and surface area of lipid droplets, accompanied by release of glycerol. The lipolytic effect of magnolol was not mediated by PKA based on the facts that magnolol did not induce an elevation of intracellular cAMP levels, and protein kinase A (PKA) inhibitor KT5720 did not block magnolol-induced lipolysis. Calcium/calmodulin-dependent protein kinase (CaMK) was involved in this signaling pathway, since magnolol-induced a transient rise of intracellular [Ca(2+)] and Ca(2+) influx across the plasma membrane, and CaMK inhibitor significantly abolished magnolol-induced lipolysis. Moreover, magnolol increased the relative levels of phosphorylated extracellular signal-related kinases (ERK1 and ERK2). In support of the involvement ERK, we demonstrated that magnolol-induced lipolysis was inhibited by PD98059, an inhibitor of mitogen-activated protein kinase kinase (MEK), and PD98059 reversed magnolol-induced ERK phosphorylation. Further, the relationship between CaMK and ERK was connected by the finding that CaMK inhibitor also blocked magnolol-induced ERK phosphorylation. Taken together, these findings suggest that magnolol-induced lipolysis is both CaMK- and ERK-dependent, and this lipolysis signaling pathway is distinct from the traditional PKA pathway. ERK phosphorylation is reported to enhance lipolysis by direct activation of hormone sensitive lipase (HSL), thus magnolol may likely activate HSL through ERK and increase lipolysis of adipocytes.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2005

Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway.

In the broadest sense, cellular stress describes conditions wherein cells encounter and react to a 'non-normal' state. Perturbations may originate through both extracellular and intracellular means. Whereas transient levels of stress are expected to occur on a regular basis, a series of checks and balances ensures that cells are well equipped to maintain a homeostatic state. In the case of supra-physiological stress signaling, cellular challenges are more severe, and programmed cell death may be the best option for the organism. The ability of a cell, and by extension, an organism, to adequately manage cellular stress is fundamental--a question of life or death. The endoplasmic reticulum (ER) is exquisitely poised to sense and respond to cellular stresses including those that result from metabolic and/or protein folding imbalances. In response to stress originating from within the ER, the PERK and Ire1 protein kinases, along with other proximal signaling molecules, initiate a program of transcriptional and translational regulation termed the unfolded protein response. A consequence of ER stress is the accumulation of reactive oxygen species that promotes a state of oxidative stress. PERK signaling, via activation of the Nrf2 and ATF4 transcription factors, coordinates the convergence of ER stress with oxidative stress signaling. Here we discuss progress regarding the signaling pathways involved in these cellular stresses and the implications of the intersection between the two signaling pathways.

Activating Transcription Factor 6↗
PubMed2003

From calcium to NF-kappa B signaling pathways in neurons.

NF-kappa B plays crucial roles in the nervous system, including potential roles in long-term responses to synaptic plasticity, pro- or antiapoptotic effects during developmental cell death, and neurodegenerative disorders. We report here the characterization of signaling pathways leading to the constitutive activation of NF-kappa B in primary cultures of neonatal cerebellar granule neurons, consecutive to calcium entry into the cytosol. We found that opening of calcium channels at the plasma membrane and at intracellular stores is indispensable for the basal NF-kappa B activity. We demonstrated further that three cellular sensors of the cytosolic Ca(2+) levels, calmodulin, protein kinases C (PKCs), and the p21(ras)/phosphatidylinositol 3-kinase (PI3K)/Akt pathway are simultaneously involved in the steps linking the Ca(2+) second messenger to NF-kappa B activity. Calmodulin triggers the activity of calcineurin, a phosphatase which plays a role in the basal NF-kappa B activity, while stimulation of both the calmodulin kinase II and Akt kinase pathways results in the up-regulation of the transcriptional potential of the p65 subunit of NF-kappa B. Finally, using pharmacological and molecular approaches, we analyze interactions between these three pathways at different levels and demonstrate a connection between PKCs and PI3K. All three components converge towards NF-kappa B, at the level of both nuclear translocation and transcriptional activity. These results stand in contrast to the situation in nonneuronal cells, which either do not respond to Ca(2+) or do not simultaneously activate all three cascades. By using a global approach in studying signaling pathways in neurons, these results provide further evidence to validate the concept of networks of transducing cascades, specific to cells and to physiological situations.

Active Transport, Cell Nucleus↗
PubMed2004

Novel angiogenic signaling pathways and vascular targets.

Intense investigation into the molecular basis of angiogenesis is rapidly revealing novel signaling pathways involved in the generation of new vasculature. These range from elucidation of the mechanism by which hypoxia initiates expression of a proangiogenic gene repertoire via the hypoxia-inducible transcription factors (HIFs) to molecular pathways involved in extra- and intracellular signaling during new vessel formation. Extracellular pathways include those of the Notch/delta, ephrin/Eph receptor and roundabout/slit families, and intracellular pathway members of the hedgehog and sprouty families. The involvement of these pathways in angiogenesis is discussed, together with some comments on recently identified targets in the vasculature that present new therapeutic opportunities.

Animals↗