C P Wheeler-Jones

University of Concepción, Ciudad de Concepcion, Biobío, Chile

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Publications (111)378.02 Total impact

  • D Vara, C Wheeler-Jones, K Mace, H Mellor, G Pula
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    ABSTRACT: Redox regulation of angiogenesis is an important and emerging topic in vascular sciences; reactive oxygen species (ROS) modulate vascular endothelial cell (EC) proliferation and migration, but the molecular mechanism underlying this phenomenon remains largely unclear. We have shown micromolar concentrations of the pro-angiogenic metabolite deoxyribose-1-phosphate (dRP) detected by mass spectrometry (MS) and nuclear magnetic resonance (NMR) in the supernatants of collagen- and thrombin-stimulated platelets. The genetic silencing of dRP-generating enzymes uridine phosphorylase (UP) and thymidine phosphorylase (TP) in mouse platelets significantly reduced the levels of dRP in platelet supernatants and impaired the ability of protein-free platelet supernatants to enhance human umbilical vein endothelial cell (HUVEC) motility. Chick chorioallantoic membrane (CAM) vascularisation assays performed with protein-free supernatants suggested that the release of dRP by platelets stimulates angiogenesis in vivo. To understand the pro-angiogenic effect of dRP, we investigated further the molecular mechanism of action of dRP and whether this effect was observed in other nucleoside derivatives deoxyribose-5-phospate (dR5P), ribose-1-phosphate (R1P) and deoxyribose (dR). Using live cell real-time confocal imaging and fluorescence assays, HUVEC treatment with dRP significantly increased ROS generation. Similarly, dR5P and R1P also induced ROS accumulation in HUVECs, whereas dR did not. The protein expression of the redox stress marker heme oxygenase-1 (HO-1) and Integrin β3 were shown to be upregulated by dRP and its phosphorylated derivatives (except dR) by immunoblot experiments. Vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), interleukin 8 (IL-8), and stromal cell-derived factor 1α (SDF-1α) showed a similar effect. In parallel, only dRP and its phosphorylated derivatives increased HUVEC cell motility in scratch-healing assays and capillary tube formation using Matrigel(™) assays. The causative link between integrin β3 upregulation and increased HUVEC motility/capillary tube formation was proved using integrin-specific inhibitory antibodies'. Furthermore the angiogenic potential of dRP was confirmed in vivo. In summary, dRP and its phosphorylated derivatives were shown to play a relevant role in the paracrine regulation of EC motility and pro-angiogenic activity by up-regulating integrin β3 in a ROS-dependent manner possibly signaling via VEGFR2. dRP is likely to play a role in the stimulation of postnatal angiogenesis and tissue regeneration.
    Cardiovascular research. 07/2014; 103(suppl 1):S97.
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    Nicola A Talbot, Caroline P Wheeler-Jones, Mark E Cleasby
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    ABSTRACT: Obesity and saturated fatty acid (SFA) treatment are both associated with skeletal muscle insulin resistance (IR) and increased macrophage infiltration. However, the relative effects of SFA and unsaturated fatty acid (UFA)-activated macrophages on muscle are unknown. Here, macrophages were treated with palmitic acid, palmitoleic acid or both and the effects of the conditioned medium (CM) on C2C12 myotubes investigated. CM from palmitic acid-treated J774s (palm-mac-CM) impaired insulin signalling and insulin-stimulated glycogen synthesis, reduced Inhibitor κBα and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in myotubes. p38 MAPK inhibition or siRNA partially ameliorated these defects, as did addition of tumour necrosis factor-α blocking antibody to the CM. Macrophages incubated with both FAs generated CM that did not induce IR, while palmitoleic acid-mac-CM alone was insulin sensitising. Thus UFAs may improve muscle insulin sensitivity and counteract SFA-mediated IR through an effect on macrophage activation.
    Molecular and Cellular Endocrinology 06/2014; · 4.04 Impact Factor
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    ABSTRACT: Dogs with congenital portosystemic shunts (CPSS) have liver hypoplasia and hepatic insufficiency. Surgical CPSS attenuation results in liver growth associated with clinical improvement. The mechanism of this hepatic response is unknown, although liver regeneration is suspected. This study investigated whether markers of liver regeneration were associated with CPSS attenuation. Dogs treated with CPSS attenuation were prospectively recruited. Residual liver tissue was collected for gene expression analysis (seven genes) from 24 CPSS dogs that tolerated complete attenuation, 25 dogs that tolerated partial attenuation and seven control dogs. Relative gene expression was measured using quantitative polymerase chain reaction (qPCR). Blood samples were collected before, 24 h and 48 h post-surgery from 36 CPSS dogs and from 10 control dogs. Serum hepatocyte growth factor (HGF) concentration was measured using a canine specific enzyme-linked immunosorbent assay (ELISA). HGF mRNA expression was significantly decreased in CPSS compared to control dogs (P = 0.046). There were significant increases in HGF (P = 0.050) and methionine adenosyltransferase 2 A (MAT2A; P = 0.002) mRNA expression following partial CPSS attenuation. Dogs with complete attenuation had significantly greater MAT2A (P = 0.024) mRNA expression compared to dogs with partial attenuation. Serum HGF concentration significantly increased 24 h following CPSS attenuation (P < 0.001). Hepatic mRNA expression of two markers of hepatocyte proliferation (HGF and MAT2A) was associated with the response to surgery in dogs with CPSS, and serum HGF significantly increased following surgery, suggesting hepatocyte proliferation. These findings support the concept that hepatic regeneration is important in the hepatic response to CPSS surgery.
    The Veterinary Journal 01/2014; · 2.42 Impact Factor
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    ABSTRACT: The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders.
    Cell and Tissue Research 12/2013; · 3.68 Impact Factor
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    Rosemary J Keogh, Rebecca A Houliston, Caroline P D Wheeler-Jones
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    ABSTRACT: Adenosine is released from the myocar- dium, endothelial cells, and skeletal muscle in ischemia and is an important regulator of coronary blood flow. We have already shown that acute (2 min) activation of A2a purinoceptors stimulates NO production in human fetal umbilical vein endothelial cells (1) and now report a key role for p42/p44 mitogen-activated protein ki- nases (p42/p44MAPK) in the regulation of the L-argi- nine-nitric oxide (NO) signaling pathway. Expression of mRNA for the A2a-, A2b-, and A3-adenosine receptor subtypes was abundant whereas A1-adenosine receptor mRNA levels were negligible. Activation of A2a purino- ceptors by adenosine (10 M) or the A2a receptor agonist CGS21680 (100 nM) resulted in an increase in L-arginine transport and NO release that was not medi- ated by changes in intracellular Ca2, pH, or cAMP. Stimulation of endothelial cells with adenosine was associated with a membrane hyperpolarization and phosphorylation of p42/p44MAPK. L-NAME abolished the adenosine-induced hyperpolarization and stimula- tion of L-arginine transport whereas sodium nitroprus- side activated an outward potassium current. Genistein (10 M) and PD98059 (10 M), an inhibitor of MAPK kinase 1/2 (MEK1/2), inhibited adenosine-stimulated L-arginine transport, NO production, and phosphoryla- tion of p42/p44MAPK. We found no evidence for acti-
    06/2013;
  • Kathleen M Botham, Caroline P D Wheeler-Jones
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    ABSTRACT: Blood levels of triglyceride-rich lipoproteins (TRL), increase postprandially, and a delay in their clearance results in postprandial hyperlipidemia, an important risk factor in atherosclerosis development. Atherosclerosis is a multifactorial inflammatory disease, and its initiation involves endothelial dysfunction, invasion of the artery wall by leukocytes and subsequent formation of foam cells.. TRL are implicated in several of these inflammatory processes, including the formation of damaging free radicals, leukocyte activation, endothelial dysfunction and foam cell formation. Recent studies have provided insights into the mechanisms of uptake and the signal transduction pathways mediating the interactions of TRL with leukocytes and vascular cells, and how they are modified by dietary lipids. Multiple receptor and non-receptor mediated pathways function in macrophage uptake of TRL by macrophages. TRL also induce expression of adhesion molecules, cyclooxygenase-2 and heme-oxygenase-1 in endothelial cells, and activate intracellular signalling pathways involving mitogen-activated protein kinases, NF-κB and Nrf2. Many of these effects are strongly influenced by dietary components carried in TRL. There is extensive evidence indicating that raised postprandial TRL levels are a risk factor for atherosclerosis, but the molecular mechanisms involved are only now becoming appreciated. Here, we review current understanding of the mechanisms by which TRL influence vascular cell function.
    Progress in lipid research 06/2013; · 10.67 Impact Factor
  • Cardiovascular Pathology. 01/2013; 22(3):e51–e52.
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    ABSTRACT: Following islet transplantation, islet graft revascularization is compromised due to loss of endothelial cells (ECs) during islet culture. TGF-β signaling pathways are essential for vascular homeostasis but their importance for islet EC function is unclear. We have identified a population of multipotent mesenchymal stromal cells (MSCs) within islets and investigated how modulation of TGF-β signaling by these cells influences islet EC viability. Cultured islets exhibited reduced expression of EC markers (VEGFR2; VE-cadherin; CD31) which was associated with diminished but sustained expression of endoglin a marker of both ECs and MSCs. Double fluorescent labelling of islets in situ with the EC marker CD31 disclosed a population of CD31-negative cells which were positive for endoglin. In vitro co-culture of microvascular ECs with endoglin-positive, CD31-negative islet MSCs reduced VEGFR2 protein expression, disrupted EC angiogenic behaviour and increased EC detachment. Medium conditioned by islet MSCs significantly decreased EC viability and increased EC caspase 3/7 activity. EC:MSC co-cultures showed enhanced Smad2 phosphorylation consistent with altered ALK5 signalling. Pharmacological inhibition of ALK5 activity with SB431542 (SB) improved EC survival upon contact with MSCs, and SB-treated cultured islets retained EC marker expression and sensitivity to exogenous VEGF(164) . Thus, endoglin-expressing islet MSCs influence EC ALK5 signalling in vitro, which decreases EC viability, and changes in ALK5 activity in whole cultured islets contribute to islet EC loss. Modifying TGF-β signalling may enable maintenance of islet ECs during islet isolation and thus improve islet graft revascularization post-transplantation.
    Stem Cells 12/2012; · 7.70 Impact Factor
  • Diabetologia 10/2012; · 6.49 Impact Factor
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    ABSTRACT: C-type natriuretic peptide (CNP/Nppc) is expressed at high levels in the anterior pituitary of rats and mice and activates guanylyl cyclase B receptors (GC-B/Npr2) to regulate hormone secretion. Mutations in NPR2/Npr2 can cause achondroplasia, GH deficiency, and female infertility, yet the normal expression profile within the anterior pituitary remains to be established in humans. The current study examined the expression profile and transcriptional regulation of NPR2 and GC-B protein in normal human fetal pituitaries, normal adult pituitaries, and human pituitary adenomas using RT-PCR and immunohistochemistry. Transcriptional regulation of human NPR2 promoter constructs was characterized in anterior pituitary cell lines of gonadotroph, somatolactotroph, and corticotroph origin. NPR2 was detected in all human fetal and adult pituitary samples regardless of age or sex, as well as in all adenoma samples examined regardless of tumor origin. GC-B immunoreactivity was variable in normal pituitary, gonadotrophinomas, and somatotrophinomas. Maximal transcriptional regulation of the NPR2 promoter mapped to a region within -214 bp upstream of the start site in all anterior pituitary cell lines examined. Electrophoretic mobility shift assays revealed that this region contains Sp1/Sp3 response elements. These data are the first to show NPR2 expression in normal human fetal and adult pituitaries and adenomatous pituitary tissue and suggest a role for these receptors in both pituitary development and oncogenesis, introducing a new target to manipulate these processes in pituitary adenomas.
    Endocrine Related Cancer 05/2012; 19(4):497-508. · 5.26 Impact Factor
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    ABSTRACT: Atherosclerosis is known to be an inflammatory disease and there is increasing evidence that chylomicron remnants (CMR), the lipoproteins which carry dietary fats in the blood, cause macrophage foam cell formation and inflammation. In early atherosclerosis the frequency of activated monocytes in the peripheral circulation is increased, and clearance of CMR from blood may be delayed, however, whether CMR contribute directly to monocyte activation and subsequent egress into the arterial wall has not been established. Here, the contribution of CMR to activation of monocyte pro-inflammatory pathways was assessed using an in vitro model. Primary human monocytes and CMR-like particles (CRLP) were used to measure several endpoints of monocyte activation. Treatment with CRLP caused rapid and prolonged generation of reactive oxygen species by monocytes. The pro-inflammatory chemokines MCP-1 and IL-8 were secreted in nanogram quantities by the cells in the absence of CRLP. IL-8 secretion was transiently increased after CRLP treatment, and CRLP maintained secretion in the presence of pharmacological inhibitors of IL-8 production. In contrast, exposure to CRLP significantly reduced MCP-1 secretion. Chemotaxis towards MCP-1 was increased in monocytes pre-exposed to CRLP and was reversed by addition of exogenous MCP-1. Our findings indicate that CRLP activate human monocytes and augment their migration in vitro by reducing cellular MCP-1 expression. Our data support the current hypothesis that CMR contribute to the inflammatory milieu of the arterial wall in early atherosclerosis, and suggest that this may reflect direct interaction with circulating blood monocytes.
    Nutrition, metabolism, and cardiovascular diseases: NMCD 11/2011; 21(11):871-8. · 3.52 Impact Factor
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    ABSTRACT: Surgical attenuation of a congenital portosystemic shunt (CPSS) results in increased liver mass, development of intrahepatic portal vasculature and improved liver function. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis. The aim of this study was to investigate the role of VEGF and its receptor in the hepatic response to CPSS surgery. The study included 99 dogs with CPSS treated with either partial or complete suture attenuation. Forty-four dogs with partial attenuation underwent a second surgery for complete attenuation. The expression of VEGF and VEGF receptor 2 (VEGFR2) in biopsy samples of liver was assessed by immunohistochemistry with rabbit anti-human VEGF polyclonal antibody and mouse anti-human VEGFR2 monoclonal antibody. Expression of these molecules was graded. The proportion of samples expressing VEGF was significantly greater in samples from dogs with CPSS compared with control samples (P=0.04) and the proportion of samples expressing VEGFR2 was significantly greater in control samples compared with samples from dogs with CPSS (P=0.04). VEGF labelling grade decreased significantly (P=0.038) and VEGFR2 increased significantly (P=0.046) between first and second surgery. The decrease in VEGF may reflect transient expression, preferential expression of other factors, reperfusion of existing vessels and/or increased angiogenesis before surgery in the form of arterialization and subsequent reduction due to improved portal blood flow. Partial suture attenuation was associated with a degree of 'normalization' of VEGF and VEGFR2 expression when compared with the control samples. Further investigation is needed to provide more information on the hepatic response to CPSS surgery.
    Journal of comparative pathology 10/2011; 147(1):55-61. · 1.73 Impact Factor
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    ABSTRACT: Current evidence suggests that consumption of virgin olive oil (VOO) helps to protect against the development of atherosclerosis and that minor components such as oleanolic acid contribute to this effect. In this study, the effects of triacylglycerol-rich lipoproteins (TRLs) derived from olive oil on inflammatory processes in macrophages and how they are modulated by oleanolic acid was investigated. TRLs isolated from healthy volunteers 2 and 4 h after a test meal containing VOO, pomace olive oil (POO) (the second pressing of olive oil, enriched in minor components) or POO enriched with oleanolic acid (OPOO) were incubated with macrophages derived from the human monocyte cell line, THP-1. All types of TRLs caused a decrease of about 50% in the secretion of monocyte chemoattractant protein-1 (MCP-1) by the cells. Interleukin (IL)-6 secretion was also significantly decreased by 2 and 4 h VOO TRLs and by 4 h OPOO TRLs. In contrast, increased IL-1β secretion was observed with all 2 h TRL types, and increased tumour necrosis factor-α (TNF-α) production with 2 h VOO and POO, but not OPOO, TRLs. TRLs isolated after 4 h, however, had no significant effects on TNF-α secretion and increased IL-1β secretion only when they were derived from VOO. Cyclooxygenase-2 (COX-2) mRNA expression was strongly down-regulated by all types of TRLs, but protein expression was significantly depressed only by 4 h OPOO TRLs. These findings demonstrate that TRLs derived from olive oil influence inflammatory processes in macrophages and suggest that oleanolic acid may have beneficial effects.
    European Journal of Nutrition 06/2011; 51(3):301-9. · 3.13 Impact Factor
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    ABSTRACT: Secretion of pro-inflammatory chemokines and cytokines by macrophages is a contributory factor in the pathogenesis of atherosclerosis. In this study, the effects of chylomicron remnants (CMR), the lipoproteins which transport dietary fat in the blood, on the production of pro-inflammatory chemokine and cytokine secretion by macrophages was investigated using CMR-like particles (CRLPs) together with THP-1 macrophages or primary human macrophages (HMDM). Incubation of CRLPs or oxidized CRLPs (oxCRLPs) with HMDM or THP-1 macrophages for up to 24h led to a marked decrease in the secretion of the pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) and the pro-inflammatory cytokines tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β (-50-90%), but these effects were reduced or abolished when CRLPs protected from oxidation by incorporation of the antioxidant drug, probucol, (pCRLPs) were used. In macrophages transfected with siRNA targeted to the low density lipoprotein receptor (LDLr), neither CRLPs nor pCRLPs had any significant effect on chemokine/cytokine secretion, but in cells transfected with siRNA targeted to the LDLr-related protein 1 (LRP1) both types of particles inhibited secretion to a similar extent to that observed with CRLPs in mock transfected cells. These findings demonstrate that macrophage pro-inflammatory chemokine/cytokine secretion is down-regulated by CMR, and that these effects are positively related to the lipoprotein oxidative state. Furthermore, uptake via the LDLr is required for the down-regulation, while uptake via LRP1 does not bring about this effect. Thus, the receptor-mediated route of uptake of CMR plays a crucial role in modulating their effects on inflammatory processes in macrophages.
    Biochimica et Biophysica Acta 03/2011; 1811(3):209-20. · 4.66 Impact Factor
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    ABSTRACT: Glycosaminoglycans (GAGs) are critical for extracellular matrix (ECM) integrity in cartilage but mechanisms regulating their synthesis are not defined. UDP-glucose dehydrogenase (UGDH) catalyses UDP-glucose oxidation to UDP-glucuronic acid, an essential monosaccharide in many GAGs. Our previous studies in articular surface (AS) cells from embryonic joints have established pivotal roles for mitogen-activated protein kinases (MAPK) in synthesis of the unsulfated GAG, hyaluronan (HA). We investigated the functional significance of UGDH in GAG production and chondrogenesis, and determined roles for MEK-ERK and p38MAPK pathways in regulating UGDH expression and function. Inhibitors of MEK and p38MAPK reduced UGDH protein in AS cells. Treatment with TGF-β (archetypal growth factor) increased UGDH expression, sulfated (s)-GAG/HA release and pericellular matrix formation in a p38MAPK-dependent manner. Retroviral overexpression of UGDH augmented HA/sGAG release and pericellular matrix elaboration, which were blocked by inhibiting MEK but not p38MAPK. UGDH overexpression increased cartilage nodule size in bone marrow culture, promoted chondrogenesis in limb bud micromass culture and selectively suppressed medium HA levels and modified GAG sulfation, as assessed by FACE analysis. Our data provide evidence that: (i) TGF-β regulates UGDH expression via p38MAPK to modulate sGAG/HA secretion, (ii) MEK-ERK, but not p38MAPK facilitates UGDH-induced HA and sGAG release, and (iii) increased UGDH expression promotes chondrogenesis directly and differential modifies GAG levels and sulfation. These results indicate a more diverse role for UGDH in the support of selective GAG production than previously described. Factors regulating UGDH may provide novel candidates for restoring ECM integrity in degenerative cartilage diseases, such as osteoarthritis.Arthritis Research Campaign.
    Journal of Cellular Physiology 03/2011; 226(3):749-61. · 4.22 Impact Factor
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    ABSTRACT: 4-Methylumbelliferone (4-MU) is described as a selective inhibitor of hyaluronan (HA) production. It is thought that 4-MU depletes UDP-glucuronic acid (UDP-GlcUA) substrate for HA synthesis and also suppresses HA-synthase expression. The possibility that 4-MU exerts at least some of its actions via regulation of UDP-glucose dehydrogenase (UGDH), a key enzyme required for both HA and sulphated-glycosaminoglycan (sGAG) production, remains unexplored. We therefore examined the effects of 4-MU on basal and retroviral UGDH-driven HA and sGAG release in cells derived from chick articular cartilage and its influence upon UGDH protein and mRNA expression and HA and sGAG production. We found that 4-MU: i) suppressed UGDH mRNA and protein expression and chondrogenic matrix accumulation in chick limb bud micromass culture, ii) significantly reduced both HA and sGAG production and iii) more selectively reversed the potentiating effects of UGDH overexpression on the production of HA than sGAG. Understanding how GAG synthesis is controlled and the mechanism of 4-MU action may inform its future clinical success.
    Matrix biology: journal of the International Society for Matrix Biology 02/2011; 30(3):163-8. · 3.56 Impact Factor
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    ABSTRACT: The adipocyte-derived hormone leptin influences the behaviour of a wide range of cell types and is now recognised as a pro-angiogenic and pro-inflammatory factor. In the vasculature, these effects are mediated in part through its direct leptin receptor (ObRb)-driven actions on endothelial cells (ECs) but the mechanisms responsible for these activities have not been established. In this study we sought to more fully define the molecular links between inflammatory and angiogenic responses of leptin-stimulated human ECs. Immunoblotting studies showed that leptin increased cyclo-oxygenase-2 (COX-2) expression (but not COX-1) in cultured human umbilical vein ECs (HUVEC) through pathways that depend upon activation of both p38 mitogen-activated protein kinase (p38(MAPK)) and Akt, and stimulated rapid phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) on Tyr(1175). Phosphorylation of VEGFR2, p38(MAPK) and Akt, and COX-2 induction in cells challenged with leptin were blocked by a specific leptin peptide receptor antagonist. Pharmacological inhibitors of COX-2, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and p38(MAPK) abrogated leptin-induced EC proliferation (assessed by quantifying 5-bromo-2'-deoxyuridine incorporation, calcein fluorescence and propidium iodide staining), slowed the increased migration rate of leptin-stimulated cells (in vitro wound healing assay) and inhibited leptin-induced capillary-like tube formation by HUVEC on Matrigel. Inhibition of VEGFR2 tyrosine kinase activity reduced leptin-stimulated p38(MAPK) and Akt activation, COX-2 induction, and pro-angiogenic EC responses, and blockade of VEGFR2 or COX-2 activities abolished leptin-driven neo-angiogenesis in a chick chorioallantoic membrane vascularisation assay in vivo. We conclude that a functional endothelial p38(MAPK)/Akt/COX-2 signalling axis is required for leptin's pro-angiogenic actions and that this is regulated upstream by ObRb-dependent activation of VEGFR2. These studies identify a new function for VEGFR2 as a mediator of leptin-stimulated COX-2 expression and angiogenesis and have implications for understanding leptin's regulation of the vasculature in both non-obese and obese individuals.
    PLoS ONE 01/2011; 6(4):e18823. · 3.73 Impact Factor
  • Caroline P D Wheeler-Jones, Charlotte E Farrar, Andrew A Pitsillides
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    ABSTRACT: The endothelial glycocalyx (EG) is an extracellular matrix (ECM) coating the luminal surface of the vascular endothelium. Hyaluronan (HA), a glycosaminoglycan, is an important constituent of the EG that regulates inflammation and repair. By providing a direct link between the endothelium and its ECM, HA contributes to maintaining glycocalyx integrity; emerging evidence indicates a close association between EG deterioration, concomitant loss of HA and the onset of endothelial dysfunction, a phenomenon that is involved in many disorders, including atherosclerosis, diabetes, hypertension and dyslipidemia. This review provides an overview of glycocalyx modification by pathological stimuli and considers the potential of the pharmacological targeting of HA synthesis and binding to limit endothelial dysfunction and to improve vasculoprotection.
    Current opinion in investigational drugs (London, England: 2000) 09/2010; 11(9):997-1006. · 3.55 Impact Factor
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    ABSTRACT: Micromolar concentrations of the proangiogenic metabolite deoxyribose-1-phosphate (dRP) were detected in platelet supernatants by mass spectrometry. In this study, we assessed whether the release of dRP by platelets stimulates endothelial cell migration and angiogenesis. Protein-free supernatants from thrombin-stimulated platelets increased human umbilical vein endothelial cell migratory activity in transmigration and monolayer repair assays. This phenomenon was ablated by genetic silencing of dRP-generating uridine phosphorylase (UP) and thymidine phosphorylase (TP) or pharmacological inhibition of UP and restored by exogenous dRP. The stimulation of endothelial cell migration by platelet-derived dRP correlated with upregulation of integrin β(3), which was induced in a reactive oxygen species-dependent manner, and was mediated by the activity of the integrin heterodimer α(v)β(3). The physiological relevance of dRP release by platelets was confirmed in a chick chorioallantoic membrane assay, where the presence of this metabolite in platelet supernatants strongly induced capillary formation. Platelet-derived dRP stimulates endothelial cell migration by upregulating integrin β(3) in a reactive oxygen species-dependent manner. As demonstrated by our in vivo experiments, this novel paracrine regulatory pathway is likely to play an important role in the stimulation of angiogenesis by platelets.
    Arteriosclerosis Thrombosis and Vascular Biology 09/2010; 30(12):2631-8. · 6.34 Impact Factor

Publication Stats

1k Citations
378.02 Total Impact Points

Institutions

  • 2002–2013
    • University of Concepción
      Ciudad de Concepcion, Biobío, Chile
  • 2001–2013
    • Royal Veterinary College
      • • Department of Veterinary Basic Sciences
      • • Department of Comparative Biomedical Sciences
      London, ENG, United Kingdom
  • 2012
    • University of London
      Londinium, England, United Kingdom
  • 2004
    • Imperial College London
      • Faculty of Medicine
      London, ENG, United Kingdom
  • 1989–1998
    • King's College London
      • School of Biomedical Sciences
      London, ENG, United Kingdom
  • 1991–1992
    • Thrombosis Research Institute
      Londinium, England, United Kingdom