Angiopoietin-1 and vascular endothelial growth factor induce expression of inflammatory cytokines before angiogenesis

Aplin, Alfred C.; Gelati, Maurizio; Fogel, Eric; Carnevale, Edvige; Nicosia, Roberto F.

doi:10.1152/physiolgenomics.00048.2006

Cited by 64 publications

(75 citation statements)

References 50 publications

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“…(B) Pharmacologic inhibition or genetic disruption of CXCR2, the receptor of CXCL1, CXCL2, and CXCL3, reduces aortic angiogenesis (Gelati et al, 2008). (C) A cocktail of cytokines and chemokines upregulated in aortic ring cultures (TNF, IL1-a, CXCL1, CCL3, CCL4,) synergistically stimulates the angiogenic response of aortic rings to a low dose of VEGF which is minimally stimulatory when used alone (Aplin et al, 2006). (D) Aortic rings lose their ability to spontaneously sprout if embedded in collagen when they are no longer releasing growth factors, i.e.…”

Section: Angiogenesis In the Aortic Ring Model Is Induced By Injurymentioning

confidence: 99%

“…Upregulated genes include many macrophage-stimulatory cytokines and chemokines (Table 1). Immunohistochemical studies show that the angiogenic response is associated with mobilization from the aortic adventitia of CD45+ CD11b+ and CD68+ macrophages (Aplin et al, 2006). Ablation of macrophages in rat aortic cultures with liposomal clodronate, a toxic compound that selectively kills phagocytic cells, markedly impairs VEGF production and angiogenic sprouting.…”

Section: Role Of Adventitial Macrophages As Injury Sensors and Transdmentioning

confidence: 99%

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Paracrine regulation of angiogenesis by different cell types in the aorta ring model

Nicosia¹,

Zorzi²,

Ligresti³

et al. 2011

Int. J. Dev. Biol.

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The development of blood vessels during angiogenesis is the result of paracrine interactions between tube-forming endothelial cells and angiogenic factor-producing nonendothelial cells. This process can be reproduced and studied under chemically defined culture conditions by culturing vascular explants in three-dimensional gels of extracellular matrix. Rings of rat or mouse aorta cultured in collagen, fibrin or basement membrane gels produce angiogenic outgrowths composed of a mixed population of endothelial cells and nonendothelial cells. Aortic angiogenesis is regulated by endogenous angiogenic factors, inflammatory cytokines, chemokines, extracellular matrix molecules, and proteolytic enzymes produced by cells of the vessel wall in response to the injury of the dissection procedure. In this paper, we review how macrophages, mural cells and fibroblasts regulate different stages of the angiogenic process, from the formation of immature endothelial sprouts to the reabsorption of the neovessels. We also describe how aortic cultures can be used to study interactions between angiogenic outgrowths and nonvascular cell types such as bone marrow macrophages, platelets or cancer cells. Morphologic, genetic and functional studies of this model have provided invaluable information on how vessels form, mature, interact with nonvascular cell types, and are eventually reabsorbed. Further analysis of the paracrine cross-talk between aortic endothelial and nonendothelial cells is likely to provide new insights into the angiogenic process and its key mechanisms.

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Section: Angiogenesis In the Aortic Ring Model Is Induced By Injurymentioning

confidence: 99%

Section: Role Of Adventitial Macrophages As Injury Sensors and Transdmentioning

confidence: 99%

Paracrine regulation of angiogenesis by different cell types in the aorta ring model

Nicosia¹,

Zorzi²,

Ligresti³

et al. 2011

Int. J. Dev. Biol.

Self Cite

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show abstract

“…[5][6][7] However, angiogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), and fibroblast growth factor-2 (FGF2), may elicit proinflammatory responses in ECs by upregulating the expression of cell adhesion molecules and inflammatory mediators involved in leukocyte recruitment and activation. [8][9][10] Thus, neovascularization and inflammation share several common signaling pathways and molecular mediators.…”

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confidence: 99%

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Corsini

Moroni

Ravelli

et al. 2014

ATVB

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Objective-Angiogenesis and inflammation are closely related processes. Gremlin is a novel noncanonical vascular endothelial growth factor receptor-2 (VEGFR2) ligand that induces a proangiogenic response in endothelial cells (ECs).Here, we investigated the role of the cyclic adenosine monophosphate-response element (CRE)-binding protein (CREB) in mediating the proinflammatory and proangiogenic responses of ECs to gremlin. Approach and Results-Gremlin induces a proinflammatory response in ECs, leading to reactive oxygen species and cyclic adenosine monophosphate production and the upregulation of proinflammatory molecules involved in leukocyte extravasation, including chemokine (C-C motif) ligand-2 (Ccl2) and Ccl7, chemokine (C-X-C motif) ligand-1 (Cxcl1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1). Accordingly, gremlin induces the VEGFR2-dependent phosphorylation, nuclear translocation, and transactivating activity of CREB in ECs. CREB activation mediates the early phases of the angiogenic response to gremlin, including stimulation of EC motility and permeability, and leads to monocyte/macrophage adhesion to ECs and their extravasation. All these effects are inhibited by EC transfection with a dominant-negative CREB mutant or with a CREB-binding protein-CREB interaction inhibitor that competes for CREB/CRE binding. Also, both recombinant gremlin and gremlin-expressing tumor cells induce proinflammatory/proangiogenic responses in vivo that are suppressed by the anti-inflammatory drug hydrocortisone. Corsini et al CREB in Gremlin Activity 137diseases 24 and cancer. [25][26][27] Gremlin acts as a bone morphogenic protein (BMP) antagonist by binding BMP2, BMP4, and BMP7. 28 Also, gremlin stimulates EC intracellular signaling and motility in a BMP-independent manner, leading to a potent angiogenic response in vivo. 27,29 This is because of the capacity of gremlin to bind and activate VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals. 30,31 Also, gremlin interacts with heparan-sulfate proteoglycans that act as functional gremlin coreceptors in ECs, affecting its productive interaction with VEGFR2.32 However, at variance with heparin-binding VEGFs, gremlin does not interact with the coreceptor neuropilin-1. 32 Thus, gremlin is a novel proangiogenic VEGFR2 agonist distinct from canonical VEGFs.Here, we demonstrate that gremlin induces a proinflammatory response in ECs by inducing the expression of various chemokines and cell adhesion molecules, causing a VEGFR2-mediated activation of CREB. In turn, CREB activation mediates the early phases of the angiogenic response to gremlin, including stimulation of EC motility and permeability, and leads to leukocyte-adhesion to ECs and their extravasation. In keeping with these observations, gremlin and gremlin-expressing tumor cells induce a proinflammatory or proangiogenic response in vivo that is suppressed by the anti-inflammatory drug hydrocortisone. These data point to a nonredundant role of CRE...

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“…Ang-1 is an oligomeric-secreted glycoprotein that binds to the Tie-2 receptor and induces Tie-2 phosphorylation (3)(4)(5). Accumulating data demonstrate that dominant Ang-1/Tie-2 signaling is essential for the maintenance of endothelial integrity and vessel maturation (3,(5)(6)(7)(8)(9)(10). VEGF is required to initiate immature vascular formation, whereas Ang-1 is required for further remodeling and maturation of VEGFinitiated immature vessels during postischemic angiogenesis (1,2).…”

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confidence: 99%

Ang-1 Gene Therapy Inhibits Hypoxia-Inducible Factor-1α (HIF-1α)-Prolyl-4-Hydroxylase-2, Stabilizes HIF-1α Expression, and Normalizes Immature Vasculature in db/db Mice

Chen

Stinnett

2008

Diabetes

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OBJECTIVE— Diabetic impaired angiogenesis is associated with impairment of hypoxia-inducible factor-1α (HIF-1α) as well as vasculature maturation. We investigated the potential roles and intracellular mechanisms of angiopoietin-1 (Ang-1) gene therapy on myocardial HIF-1α stabilization and vascular maturation in db/db mice. RESEARCH DESIGN AND METHODS— db/db mice were systemically administrated adenovirus Ang-1 (Ad-CMV-Ang-1). Myocardial HIF-1α, vascular endothelial growth factor (VEGF), hemeoxygenase-1 (HO-1), endothelial nitric oxide synthase (eNOS), Akt, and HIF-1α–prolyl-4-hydroxylase-2 (PHD)2 expression were measured. Vasculature maturation, capillary and arteriole densities, and cardiac interstitial fibrosis were analyzed in the border zone of infarcted myocardium. RESULTS— Systemic administration of Ad-CMV-Ang-1 results in overexpression of Ang-1 in db/db mice hearts. Ang-1 gene therapy causes a significant increase in Akt and eNOS expression and HIF-1α stabilization. This is accompanied by a significant upregulation of VEGF and HO-1 expression. Intriguingly, Ang-1 gene therapy also leads to a significant inhibition of PHD2 expression. Smooth muscle recruitment and smooth muscle coverage in the neovessels of the border zone of infarcted myocardium are severely impaired in db/db mice compared with wild-type mice. Ang-1 gene therapy rescues these abnormalities, which leads to a dramatic increase in capillary and arteriole densities and a significant reduction of cardiac hypertrophy and interstitial fibrosis at 14 days after ischemia. Taken together, our data show that Ang-1 increases myocardial vascular maturation and angiogenesis together with suppression of PHD2 and the upregulation of HIF-1α signaling. CONCLUSIONS— Normalization of immature vasculature by Ang-1 gene therapy may represent a novel therapeutic strategy for treatment of the diabetes-associated impairment of myocardial angiogenesis.

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Angiopoietin-1 and vascular endothelial growth factor induce expression of inflammatory cytokines before angiogenesis

Cited by 64 publications

References 50 publications

Paracrine regulation of angiogenesis by different cell types in the aorta ring model

Paracrine regulation of angiogenesis by different cell types in the aorta ring model

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Ang-1 Gene Therapy Inhibits Hypoxia-Inducible Factor-1α (HIF-1α)-Prolyl-4-Hydroxylase-2, Stabilizes HIF-1α Expression, and Normalizes Immature Vasculature in db/db Mice

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