COMP-angiopoietin-1 promotes wound healing through enhanced angiogenesis, lymphangiogenesis, and blood flow in a diabetic mouse model

Cho, Chung Hyun; Sung, Hoon‐Ki; Kim, Young Ho; Cheon, Hyae Gyeong; Oh, Goo Taeg; Hong, Hyo Jeong; Yoo, Ook Joon; Koh, Gou Young

doi:10.1073/pnas.0506352103

Cited by 148 publications

(117 citation statements)

References 34 publications

(34 reference statements)

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“…Cho et al also showed an increase in wound closure after treatment with cartilage oligomeric matrix protein-Angpt1 (COMPAngpt1) and attributed this to increased angiogenesis, lymphangiogenesis, and blood flow (29). How can loss of Angpt1 and exaggerated levels of COMP-Angpt1 produce apparently similar phenotypes?…”

Section: Discussionmentioning

confidence: 98%

Angiopoietin-1 is essential in mouse vasculature during development and in response to injury

et al. 2011

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Angiopoietin-1/Tek signaling is a critical regulator of blood vessel development, with conventional knockout of angiopoietin-1 or Tek in mice being embryonically lethal due to vascular defects. In addition, angiopoietin-1 is thought to be required for the stability of mature vessels. Using a Cre-Lox conditional gene targeting approach, we have studied the role of angiopoietin-1 in embryonic and adult vasculature. We report here that angiopoietin-1 is critical for regulating both the number and diameter of developing vessels but is not required for pericyte recruitment. Cardiac-specific knockout of angiopoietin-1 reproduced the phenotype of the conventional knockout, demonstrating that the early vascular abnormalities arise from flow-dependent defects. Strikingly, deletion in the entire embryo after day E13.5 produced no immediate vascular phenotype. However, when combined with injury or microvascular stress, angiopoietin-1 deficiency resulted in profound organ damage, accelerated angiogenesis, and fibrosis. These findings redefine our understanding of the biological roles of angiopoietin-1: it is dispensable in quiescent vessels but has a powerful ability to modulate the vascular response after injury.

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Section: Discussionmentioning

confidence: 98%

Angiopoietin-1 is essential in mouse vasculature during development and in response to injury

et al. 2011

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“…We used another acute wound healing model, the ear punch wound model, in which vessel growth is known to profoundly affect the epidermal closure 31,34 ( Figure 3A-B). Four days after wounding, GFP ϩ BMDCs were abundant at wound healing edges compared with the area distant from the wounds (Figure 3C-D).…”

Section: Bmdcs Do Not Differentiate Into Endothelial Cells In Ear Punmentioning

confidence: 99%

Bone marrow-derived cells serve as proangiogenic macrophages but not endothelial cells in wound healing

Okuno¹,

Nakamura‐Ishizu²,

Kishi³

et al. 2011

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102

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Bone marrow-derived cells (BMDCs) contribute to postnatal vascular growth by differentiating into endothelial cells or secreting angiogenic factors. However, the extent of their endothelial differentiation highly varies according to the angiogenic models used. Wound healing is an intricate process in which the skin repairs itself after injury. As a process also observed in cancer progression, neoangiogenesis into wound tissues is profoundly involved in this healing process, suggesting the contribution of BMDCs. However, the extent of the differentiation of BMDCs to endothelial cells in wound healing is unclear. In this study, using the green fluorescent protein-bone marrow chimeric experiment and high resolution confocal microscopy at a single cell level, we observed no endothelial differentiation of BMDCs in 2 acute wound healing models (dorsal excisional wound and ear punch) and a chronic wound healing model (decubitus ulcer). Instead, a major proportion of BMDCs were macrophages. Indeed, colony-stimulating factor 1 (CSF-1) inhibition depleted approximately 80% of the BMDCs at the wound healing site. CSF-1-mutant (CSF-1 op/op ) mice showed significantly reduced neoangiogenesis into the wound site, supporting the substantial role of BMDCs as macrophages. Our data show that the proangiogenic effects of macrophages, but not the endothelial differentiation, are the major contribution of

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“…2 However, proangiogenic stimuli, including nitric oxide, hypoxia, TNF␣, and VEGF, cause Ang-1 up-regulation. [18][19][20] In addition, Ang-1 triggers neovascularization in vivo 4,5 and modulates EC sprouting and vascular network formation in vitro. 3 Here, we demonstrate the capacity of the proangiogenic factor Drm to increase Ang-1 production in murine and human ECs.…”

Section: Resultsmentioning

confidence: 99%

“…Accordingly, Ang-1 enhances survival, migration, and network formation of endothelial cells (ECs) in vitro 3 and induces neovascularization in vivo. 4,5 Drm, a member the Dan family of bone morphogenic protein (BMP) antagonists, 6,7 interacts with signaling EC receptors in a BMP-independent manner. 8 The productive interaction stimulates EC sprouting and migration in vitro and induces angiogenesis in vivo.…”

mentioning

confidence: 99%

Angiopoietin-1 mediates the proangiogenic activity of the bone morphogenic protein antagonist Drm

Mitola

Moroni

Ravelli

et al. 2008

Blood

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IntroductionThe angiopoietin/Tie receptor system, which consists of 4 angiopoietin (Ang) ligands and the Tie-1 and Tie-2 receptors, plays a nonredundant role in embryonic vascularization and tumor angiogenesis. 1,2 An autocrine Ang-1/Tie-2 axis modulates blood vessel plasticity and contributes to vascular maintenance. Accordingly, Ang-1 enhances survival, migration, and network formation of endothelial cells (ECs) in vitro 3 and induces neovascularization in vivo. 4,5 Drm, a member the Dan family of bone morphogenic protein (BMP) antagonists, 6,7 interacts with signaling EC receptors in a BMP-independent manner. 8 The productive interaction stimulates EC sprouting and migration in vitro and induces angiogenesis in vivo. 8 Drm is overexpressed in human cancers by tumor and stromal cells, thus suggesting that Drm may contribute to tumor neovascularization. [8][9][10] Here, we investigated the role of the Ang/Tie-2 system in mediating the angiogenic activity of Drm. The results demonstrate that Drm up-regulates Ang-1 expression in EC via activation of the transcription factor NF-B. This leads to an autocrine loop of stimulation that mediates Drm-induced EC sprouting in vitro and angiogenesis in vivo. Methods Cell culturesApproval for these studies was obtained from the Ethical Committee of the School of Medicine of the University of Brescia. Subcutaneous murine microvascular EC (SIE cells) and vascular endothelial growth factor (VEGF) receptor-2-transduced murine aortic EC (VEGFR2-MAE cells) were cultured in DMEM supplemented with 10% calf serum (Invitrogen, Carlsbad, CA). Human umbilical vein ECs (HUVECs) were grown as described. 11 ECs were transfected (70%-80% efficiency) with siRNAs using the SiRNA Transfection Reagent (Santa Cruz Biotechnology, Santa Cruz, CA) according to the manufacturer's instructions. Western blottingWestern blotting was performed according to standard procedures on the conditioned media (0.5 mL), total cell lysates (20 g), nuclear extracts (5 g), and cytoplasmic fractions (10 g) from serum-starved EC cultures stimulated with 50 ng/mL of recombinant Drm (rDrm, R&D Systems, Minneapolis, MN). Electrophoretic mobility shift assayNuclear extracts (2 g) were incubated with biotin-labeled NF-B doublestranded DNA oligonucleotide probe (5Ј-AGTTGAGGGGACTTTCCCAGGC) according to LightShift Chemiluminescent EMSA Kit instructions (Pierce, Rockford, IL) and analyzed on a native 6% polyacrylamide gel. EC sproutingFibrin gel and type I collagen gel invasion assays were performed on VEGFR2-MAE and HUVEC cell aggregates, respectively. 12,13 In addition, HUVEC cell aggregates were immunostained with anti-Ang-1 antibodies (Santa Cruz Biotechnology) and analyzed under a confocal laser microscope. Artery ring assayOne-millimeter human umbilical artery rings were embedded in fibrin gel 14 and cultured in human EC medium SFM (Invitrogen) with different stimuli. After 3 days, EC sprouts were counted under an inverted microscope at ϫ10 magnification. Gene expression analysiscDNA was generated from total RNA using t...

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COMP-angiopoietin-1 promotes wound healing through enhanced angiogenesis, lymphangiogenesis, and blood flow in a diabetic mouse model

Cited by 148 publications

References 34 publications

Angiopoietin-1 is essential in mouse vasculature during development and in response to injury

Angiopoietin-1 is essential in mouse vasculature during development and in response to injury

Bone marrow-derived cells serve as proangiogenic macrophages but not endothelial cells in wound healing

Angiopoietin-1 mediates the proangiogenic activity of the bone morphogenic protein antagonist Drm

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