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  • 1.
    Christoffersson, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lomei, Jalal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    O'Callaghan, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Engblom, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vascular sprouts induce local attraction of proangiogenic neutrophils2017In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 102, p. 741-751Article in journal (Refereed)
  • 2.
    Gabl, Michael
    et al.
    Univ Gothenburg, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden..
    Holdfeldt, Andre
    Univ Gothenburg, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden..
    Sundqvist, Martina
    Univ Gothenburg, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden..
    Lomei, Jalal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dahlgren, Claes
    Univ Gothenburg, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden..
    Forsman, Huamei
    Univ Gothenburg, Dept Rheumatol & Inflammat Res, Gothenburg, Sweden..
    FPR2 signaling without beta-arrestin recruitment alters the functional repertoire of neutrophils2017In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 145, p. 114-122Article in journal (Refereed)
    Abstract [en]

    G-protein coupled receptor (GPCR) biased agonism or functional selectivity has become an essential concept in GPCR research over the last years. Receptor-specific biased agonists selectively trigger one signaling pathway over another and induce a restricted/directed functional response. In this study, we aimed to characterize the concept of biased agonism for FPR2, a member of the formyl peptide receptor (FPR) subfamily of GPCRs. We show that the earlier described FPR2-activating pepducin F2Pal(10) is a biased FPR2 agonist. The effects of F2Pal(10) on neutrophil function differed in several aspects compared to those mediated by WKYMVM, a conventional FPR2-specific peptide agonist. Upon interaction with FPR2 expressed by neutrophils both F2Pal(10) and WKYMVM activated the PLC-PIP2-Ca2+ signaling pathway and the superoxide-generating NADPH-oxidase, but only WKYMVM activated the receptor to recruit B-arrestin. The functional consequences linked to a lack of B-arrestin recruitment were further explored, and we demonstrate that FPR2 desensitization occurred independent of B-arrestin. Despite this, reactivation of desensitized receptors achieved through a disruption of the cytoskeleton and through a novel FPR2 cross-talk mechanism with P2Y(2)R (the ATP receptor) and PAFR (the receptor for PAF) differed between F2Pal(10)-desensitized and WKYMVM-desensitized neutrophils. Further, the inability to recruit beta-arrestin was found to be associated with a reduced rate of receptor internalization and impaired chemotaxis in neutrophils. In summary, we provide experimental evidence of biased agonism for FPR2 and our data disclose critical roles of beta-arrestin in neutrophil chemotaxis and reactivation of desensitized receptors. (C) 2017 Elsevier Inc. All rights reserved.

  • 3.
    Lomei, Jalal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Characterization of pro-angiogenic neutrophils2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 81-81Article in journal (Other academic)
  • 4.
    Lomei, Jalal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Functional characterization of pro-angiogenic neutrophils2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The vascular system stretches throughout the body to provide oxygen, nutrition, and to remove waste products from cell metabolism. Angiogenesis, formation of new blood vessels by sprouting from pre-existing vessels, is one of the main mechanisms involved in blood vessel formation. A successful angiogenic process is dependent on the timely involvement of several parameters; from different cell types to anti- and pro-angiogenic soluble factors.

    White blood cells are mostly famous for being involved in host defense against pathogens, through rapid reactions by innate immunity and delayed but specific responses through adaptive immunity. The neutrophils are innate immune cells, which are the most abundant white blood cells in the circulation. In addition to their classical roles in defense against invading microorganisms, it was recently revealed that neutrophils actively contribute to angiogenesis. Neutrophils that are involved in angiogenesis comprise a specific population, namely pro-angiogenic neutrophils (PANs), that are recruited to sites of hypoxia by using different adhesion molecules compared to when they chemotax towards infection.

    The present investigations focus on characterization of PANs and comparing them to the classic neutrophil population in terms of their physical features and their functions. By modifying and applying new in vivo and in vitro models of angiogenesis, interactions between growing endothelial cells and neutrophils have been further revealed, as well as neutrophil recruitment and movement towards an active site of angiogenesis. We found that the main neutrophil contribution to angiogenesis at site of islet transplantation occurs at early stages of revascularization to establish new vessels, where after the neutrophils leave the site. Neutrophil recruitment to a site of infection relies to a large extent on macrophage signals, but this was not the case when they were recruited to sites of hypoxia. PANs are a specific sub-population of neutrophils that significantly differ from the rest of the neutrophil population not only in terms of their active contribution to angiogenesis, but also in terms of their physical features and their phagocytosis abilities. The role of vascular endothelial growth factor receptor (VEGFR1) and also chemokine CXCL12 (CXCR4/CXCL12 signaling) in neutrophil recruitment has been further revealed by our in vitro model; neutrophil migration to sprouting endothelium is directed by CXCL12 and VEGFR1. Furthermore we found that hypoxic condition boosted pro-angiogenic activities of PANs. Moreover, how vascular permeability affects neutrophil recruitment was studied; vascular permeability regulates inflammation by increasing chemokine transport into the blood vessels and thereby promotes neutrophil recruitment.

    In conclusion, functional characterization of pro-angiogenic neutrophils performed in this thesis demonstrates differences beyond marker expression when compared to classic neutrophils. Moreover, intricate interactions necessary for the formation of new blood vessels between neutrophils and the growing vasculature were shown. Increased understanding of the contribution of neutrophils to blood vessel formation in hypoxic environment or/and tumors could be exploited further to develop potential therapies.

    List of papers
    1. Vascular sprouts induce local attraction of proangiogenic neutrophils
    Open this publication in new window or tab >>Vascular sprouts induce local attraction of proangiogenic neutrophils
    Show others...
    2017 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 102, p. 741-751Article in journal (Refereed) Published
    National Category
    Physiology Bioinformatics (Computational Biology)
    Identifiers
    urn:nbn:se:uu:diva-196483 (URN)10.1189/jlb.1MA0117-018R (DOI)000413395700019 ()
    Projects
    eSSENCE
    Available from: 2017-06-05 Created: 2013-03-10 Last updated: 2018-11-12Bibliographically approved
    2. Characterization of pro-angiogenic neutrophils
    Open this publication in new window or tab >>Characterization of pro-angiogenic neutrophils
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The roles of neutrophils in immune defense have been investigated for decades. These cells are well equipped to protect the body in several ways against invaders such as microorganism. Recently it has been reported that neutrophils also contribute to angiogenesis; they are recruited to the site of hypoxia where they can promote blood vessel formation, as demonstrated both in vivo and in vitro. We found that these neutrophils with proangiogenic actions form a specific subset of the circulating neutrophils. The proangiogenic neutrophils (PANs) exclusively express the adhesion molecule CD49d and vascular endothelial growth factor receptor 1 (VEGFR1), and contribute to angiogenesis by delivering MMP-9 (matrix metalloproteinase 9). In this study, PANs were compared to classic neutrophils in respect to physical features as well as functionality. We found that PANs in humans were smaller and in human and mice PANs had higher granularity compared to the classic neutrophils. Moreover, they were more efficient phagocytes than classic neutrophils. In the aortic ring model of angiogenesis, vessel neo-formation was increased by the presence of pro-angiogenic neutrophils. Finally, by using neutrophils from mice with impaired VEGFR1 receptor (Flt-1 tk-/- mice) we demonstrated the role of VEGFR1 in neutrophil recruitment towards angiogenic endothelium. Together these results show clear differences between the pro-angiogenic subpopulation and the classic neutrophils, which further solidify the conclusion of a specific neutrophil subpopulation.

    Keywords
    Leukocytes, angiogenesis, phagocytosis, pro angiogenic neutrophils, ROS production
    National Category
    Immunology in the medical area
    Research subject
    Immunology; Biology with specialization in Molecular Immunology
    Identifiers
    urn:nbn:se:uu:diva-362053 (URN)
    Funder
    Knut and Alice Wallenberg FoundationRagnar Söderbergs stiftelse
    Available from: 2018-10-02 Created: 2018-10-02 Last updated: 2018-12-04
    3. Pro-angiogenic neutrophils are potentiated by hypoxia
    Open this publication in new window or tab >>Pro-angiogenic neutrophils are potentiated by hypoxia
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Abstract

    Hypoxia, shortage of oxygen in tissues, is closely related to injury, inflammation and tissue damage. One way to overcome this issue is increasing angiogenesis, growing new blood vessels from preexist-ing ones, at the site of hypoxia. Considerable number of cells, factors and signaling pathways are involved in regulating angiogenesis.

    Neutrophils have been detected at the site of hypoxia and it has been shown that a subpopulation of these cells, pro-angiogenic neutrophils, PANs is actively involved in increasing angiogenesis. In this study, the effect of hypoxia on PANs was studied by co-culturing PANs with growing endothelial cells using in vitro angiogenesis assay and hypoxic and normoxic incubator. Moreover, life spans of neutrophils and PANs, as well as expression of PANs specific markers have been investigated under hypoxia and normoxia.  

    Our data shows that the ability of PANs, to induce angiogenesis was increased under hypoxic conditions. Moreover larger number of PANs survived while co-culturing with active growing endothelial cells. We thereby conclude that the hypoxic microenvironment primes pro-angiogenic neutrophils increase their pro-angiogenic ability.

    Keywords
    Neutrophils, angiogenesi, hypoxia
    National Category
    Immunology in the medical area
    Research subject
    Immunology; Biology with specialization in Molecular Immunology
    Identifiers
    urn:nbn:se:uu:diva-362052 (URN)
    Funder
    Ragnar Söderbergs stiftelseKnut and Alice Wallenberg FoundationSwedish Research Council
    Available from: 2018-10-02 Created: 2018-10-02 Last updated: 2018-10-03
    4. Chemokine transport across the vessel wall and presentation to circulation leukocytes are regulated by vascular permeability, DARC and PAD released during inflammation
    Open this publication in new window or tab >>Chemokine transport across the vessel wall and presentation to circulation leukocytes are regulated by vascular permeability, DARC and PAD released during inflammation
    Show others...
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Increased vascular permeability and consequent leakage of plasma and macromolecules through endothelial cell junctions is a hallmark of inflammation. The physiological importance of this event for leukocyte recruitment has been controversial, but it might have a role in chemokine transport into blood vessels and consequently for the recruitment of circulating leukocytes. Elevated amounts of peptidyl arginine deiminases (PAD) and of their citrullinated products associate with autoimmune disorders, chronic inflammation and cancer. The role of citrullination in the inflamed microenvironment is debated, but it might be an innate mechanism for infiltrating leukocytes to resolve inflammation. In this study we investigated if increased vascular permeability facilitated the influx of chemokines from tissue into post-capillary venules, thereby affecting leukocyte recruitment. Vascular permeability and chemokine influx into post-capillary venules were simultaneously monitored by real-time in vivo confocal microscopy of the mouse cremaster muscle. We found that increased venular permeability induced by histamine, correlated with accelerated influx of the fluorescently labeled chemokine CXC ligand 2 (CXCL2/MIP-2) into post-capillary venules, which accumulated predominantly at endothelial cell junctions. Consequently, neutrophil adhesion was accelerated leading to increased neutrophil extravasation. In situ inhibition of caveolae-mediated transcytosis by filipin had no significant effect on chemokine influx to post-capillary venules, indicating that chemokine traffic across the venular wall is independent of caveolar transport. Nevertheless, neutrophil recruitment was prevented in filipin-treated mice as transmigrating neutrophils were trapped on endothelial cell domes and failed to finalize transmigration. Furthermore, we used this real-time in vivo model for studying the role of the atypical chemokine receptor 1 (DARC/ACKR1) in chemokine transport and availability. We show that the absence of DARC/ACKR1 (ACKR1-/- mice) does not impair chemokine transport. Instead it leads to increased seric levels of chemokine and increased intravascular chemokine sequestration. As a result, high numbers of firmly adherent neutrophils were found in post-capillary venules. Intraluminal neutrophil crawling was though abrogated and neutrophil transmigration prevented. Finally, we studied the role of chemokine citrullination by leukocyte-derived PAD in the inflamed tissue. The transport of citrullinated CXC ligand 8 (CXCL8/IL-8) across the venular wall, its immobilization on the luminal endothelium, and subsequent leukocyte recruitment, were monitored by real time imaging. Chemokine citrullination inhibited its transport from the inflamed tissue into blood vessels, impeding their immobilization on the luminal endothelium. Reduced intravascular chemokine bioavailability dampened leukocyte recruitment. Altogether these findings demonstrate that changes in vascular permeability regulate inflammation by affecting abluminal-to-luminal chemokine transport and thereby leukocyte recruitment to tissue. Furthermore, DARC/ACKR1 plays an important role in neutrophil recruitment by controlling intravascular chemokine availability and by shaping the intravascular chemokine gradient necessary for efficient neutrophil recruitment. Finally, citrullination of chemokines by PAD in the inflamed tissue inhibits chemokine transport into blood vessels and luminal presentation to circulating leukocytes, which dampens leukocyte recruitment

    Keywords
    Vascular permeability, chemokine transport, DARC, Leukocyte recruitment
    National Category
    Immunology in the medical area
    Research subject
    Biology with specialization in Molecular Immunology; Biology with specialization in Molecular Immunology; Biology with specialization in Molecular Immunology
    Identifiers
    urn:nbn:se:uu:diva-362055 (URN)
    Funder
    Ragnar Söderbergs stiftelseKnut and Alice Wallenberg Foundation
    Available from: 2018-10-02 Created: 2018-10-02 Last updated: 2018-10-03
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  • 5.
    Lomei, Jalal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Pro-angiogenic neutrophils are potentiated by hypoxiaManuscript (preprint) (Other academic)
    Abstract [en]

    Abstract

    Hypoxia, shortage of oxygen in tissues, is closely related to injury, inflammation and tissue damage. One way to overcome this issue is increasing angiogenesis, growing new blood vessels from preexist-ing ones, at the site of hypoxia. Considerable number of cells, factors and signaling pathways are involved in regulating angiogenesis.

    Neutrophils have been detected at the site of hypoxia and it has been shown that a subpopulation of these cells, pro-angiogenic neutrophils, PANs is actively involved in increasing angiogenesis. In this study, the effect of hypoxia on PANs was studied by co-culturing PANs with growing endothelial cells using in vitro angiogenesis assay and hypoxic and normoxic incubator. Moreover, life spans of neutrophils and PANs, as well as expression of PANs specific markers have been investigated under hypoxia and normoxia.  

    Our data shows that the ability of PANs, to induce angiogenesis was increased under hypoxic conditions. Moreover larger number of PANs survived while co-culturing with active growing endothelial cells. We thereby conclude that the hypoxic microenvironment primes pro-angiogenic neutrophils increase their pro-angiogenic ability.

  • 6.
    Lomei, Jalal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Giraud, Antoine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Herrera Hidalgo, Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Shibuya, Masabumi
    Jobu University, Gunma, Japan..
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Characterization of pro-angiogenic neutrophilsManuscript (preprint) (Other academic)
    Abstract [en]

    The roles of neutrophils in immune defense have been investigated for decades. These cells are well equipped to protect the body in several ways against invaders such as microorganism. Recently it has been reported that neutrophils also contribute to angiogenesis; they are recruited to the site of hypoxia where they can promote blood vessel formation, as demonstrated both in vivo and in vitro. We found that these neutrophils with proangiogenic actions form a specific subset of the circulating neutrophils. The proangiogenic neutrophils (PANs) exclusively express the adhesion molecule CD49d and vascular endothelial growth factor receptor 1 (VEGFR1), and contribute to angiogenesis by delivering MMP-9 (matrix metalloproteinase 9). In this study, PANs were compared to classic neutrophils in respect to physical features as well as functionality. We found that PANs in humans were smaller and in human and mice PANs had higher granularity compared to the classic neutrophils. Moreover, they were more efficient phagocytes than classic neutrophils. In the aortic ring model of angiogenesis, vessel neo-formation was increased by the presence of pro-angiogenic neutrophils. Finally, by using neutrophils from mice with impaired VEGFR1 receptor (Flt-1 tk-/- mice) we demonstrated the role of VEGFR1 in neutrophil recruitment towards angiogenic endothelium. Together these results show clear differences between the pro-angiogenic subpopulation and the classic neutrophils, which further solidify the conclusion of a specific neutrophil subpopulation.

  • 7.
    Massena, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Seignez, Cédric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gustafsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Binet, François
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Herrera Hidalgo, Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Giraud, Antoine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lomei, Jalal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Weström, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Shibuya, Masabumi
    Jobu Univ, Gakubunkan Inst Physiol & Med, Gunma, Japan.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gerwins, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 17, p. 2016-2026Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor A (VEGF-A) is upregulated during hypoxia and is the major regulator of angiogenesis. VEGF-A expression has also been found to recruit myeloid cells to ischemic tissues where they contribute to angiogenesis. This study investigates the mechanisms underlying neutrophil recruitment to VEGF-A as well as the characteristics of these neutrophils. A previously undefined circulating subset of neutrophils shown to be CD49d(+)VEGFR1(high)CXCR4(high) was identified in mice and humans. By using chimeric mice with impaired VEGF receptor 1 (VEGFR1) or VEGFR2 signaling (Flt-1tk(-/-), tsad(-/-)), we found that parallel activation of VEGFR1 on neutrophils and VEGFR2 on endothelial cells was required for VEGF-A-induced recruitment of circulating neutrophils to tissue. Intravital microscopy of mouse microcirculation revealed that neutrophil recruitment by VEGF-A versus by the chemokine macrophage inflammatory protein 2 (MIP-2 [CXCL2]) involved the same steps of the recruitment cascade but that an additional neutrophil integrin (eg, VLA-4 [CD49d/CD29]) played a crucial role in neutrophil crawling and emigration to VEGF-A. Isolated CD49d(+) neutrophils featured increased chemokinesis but not chemotaxis compared with CD49d(-) neutrophils in the presence of VEGF-A. Finally, by targeting the integrin α4 subunit (CD49d) in a transplantation-based angiogenesis model that used avascular pancreatic islets transplanted to striated muscle, we demonstrated that inhibiting the recruitment of circulating proangiogenic neutrophils to hypoxic tissue impairs vessel neoformation. Thus, angiogenesis can be modulated by targeting cell-surface receptors specifically involved in VEGF-A-dependent recruitment of proangiogenic neutrophils without compromising recruitment of the neutrophil population involved in the immune response to pathogens.

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