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  • Massena, SaraUppsala universitet,Institutionen för medicinsk cellbiologi (author)

Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans

  • Article/chapterEnglish2015

Publisher, publication year, extent ...

  • American Society of Hematology,2015
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-265201
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-265201URI
  • https://doi.org/10.1182/blood-2015-03-631572DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Christoffersson, GustafUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)guchr179 (author)
  • Vågesjö, EvelinaUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)eveva858 (author)
  • Seignez, CédricUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)seice516 (author)
  • Gustafsson, KarinUppsala universitet,Experimentell och klinisk onkologi(Swepub:uu)kargu861 (author)
  • Binet, FrançoisUppsala universitet,Institutionen för medicinsk cellbiologi (author)
  • Herrera Hidalgo, CarmenUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)carca670 (author)
  • Giraud, AntoineUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)antgi368 (author)
  • Lomei, JalalUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)jallo420 (author)
  • Weström, SimoneUppsala universitet,Dermatologi och venereologi(Swepub:uu)simku408 (author)
  • Shibuya, MasabumiJobu Univ, Gakubunkan Inst Physiol & Med, Gunma, Japan (author)
  • Claesson-Welsh, LenaUppsala universitet,Vaskulärbiologi(Swepub:uu)lcl04207 (author)
  • Gerwins, PärUppsala universitet,Institutionen för medicinsk cellbiologi,Radiologi(Swepub:uu)pargerwi (author)
  • Welsh, MichaelUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)michwels (author)
  • Kreuger, JohanUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)jkr07842 (author)
  • Phillipson, MiaUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)mjo07958 (author)
  • Uppsala universitetInstitutionen för medicinsk cellbiologi (creator_code:org_t)

Related titles

  • In:Blood: American Society of Hematology126:17, s. 2016-20260006-49711528-0020

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