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January 23, 2024 article Open access Aachen paper

Myeloid PHD2 Conditional Knockout Improves Intraplaque Angiogenesis and Vascular Remodeling in a Murine Model of Venous Bypass Grafting

Journal of the American Heart Association, vol. 13, pp. e033109

DOI: 10.1161/jaha.123.033109 Full text (OA) OpenAlex

Abstract

BACKGROUND: Intraplaque angiogenesis occurs in response to atherosclerotic plaque hypoxia, which is driven mainly by highly metabolically active macrophages. Improving plaque oxygenation by increasing macrophage hypoxic signaling, thus stimulating intraplaque angiogenesis, could restore cellular function and neovessel maturation, and decrease plaque formation. Prolyl hydroxylases (PHDs) regulate cellular responses to hypoxia. We therefore aimed to elucidate the role of myeloid PHD2, the dominant PHD isoform, on intraplaque angiogenesis in a murine model for venous bypass grafting. METHODS AND RESULTS: background underwent vein graft surgery (n=11-15/group) by interpositioning donor caval veins into the carotid artery of genotype-matched mice. At postoperative day 28, vein grafts were harvested for morphometric and compositional analysis, and blood was collected for flow cytometry. Myeloid PHD2cko induced and improved intraplaque angiogenesis by improving neovessel maturation, which reduced intraplaque hemorrhage. Intima/media ratio was decreased in myeloid PHD2cko vein grafts. In addition, PHD2 deficiency prevented dissection of vein grafts and resulted in an increase in vessel wall collagen content. Moreover, the macrophage proinflammatory phenotype in the vein graft wall was attenuated in myeloid PHD2cko mice. In vitro cultured PHD2cko bone marrow-derived macrophages exhibited an increased proangiogenic phenotype compared with control. CONCLUSIONS: Myeloid PHD2cko reduces vein graft disease and ameliorates vein graft lesion stability by improving intraplaque angiogenesis.

Authors 12

  1. Thijs J. Sluiter Aachen Department of Surgery Leiden University Medical Centre Leiden The Netherlands Department of Surgery, Leiden University Medical Centre Einthoven Laboratory for Experimental Vascular Medicine

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Surgery Leiden University Medical Centre Leiden The Netherlands

    Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Centre Leiden The Netherlands

    Thijs J. Sluiter https://orcid.org/0000-0003-0199-2729 , Department of Surgery, , Leiden University Medical Centre, , Leiden, , The Netherlands, , Einthoven Laboratory for Experimental Vascular Medicine, , Leiden University Medical Centre, , Leiden, , The Netherlands,

  2. Renée J. H. A. Tillie

    Maastricht University Medical Centre

    Affiliation as printed

    Department of Pathology, CARIM School for Cardiovascular Sciences Maastricht University Medical Centre Maastricht The Netherlands

  3. Alwin de Jong Aachen Department of Surgery Leiden University Medical Centre Leiden The Netherlands Department of Surgery, Leiden University Medical Centre Einthoven Laboratory for Experimental Vascular Medicine

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Surgery Leiden University Medical Centre Leiden The Netherlands

    Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Centre Leiden The Netherlands

    Alwin de Jong https://orcid.org/0000-0002-4556-5393 , Department of Surgery, , Leiden University Medical Centre, , Leiden, , The Netherlands, , Einthoven Laboratory for Experimental Vascular Medicine, , Leiden University Medical Centre, , Leiden, , The Netherlands,

  4. J Bruijn

    Maastricht University Medical Centre

    Affiliation as printed

    Department of Pathology, CARIM School for Cardiovascular Sciences Maastricht University Medical Centre Maastricht The Netherlands

    Jenny B. G. de Bruijn , Department of Pathology, CARIM School for Cardiovascular Sciences, , Maastricht University Medical Centre, , Maastricht, , The Netherlands,

  5. Hendrika A. B. Peters Aachen Department of Surgery Leiden University Medical Centre Leiden The Netherlands Hendrika A. B. Peters Department of Surgery, Leiden University Medical Centre Einthoven Laboratory for Experimental Vascular Medicine

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Surgery Leiden University Medical Centre Leiden The Netherlands

    Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Centre Leiden The Netherlands

    Hendrika A. B. Peters , Department of Surgery, , Leiden University Medical Centre, , Leiden, , The Netherlands, , Einthoven Laboratory for Experimental Vascular Medicine, , Leiden University Medical Centre, , Leiden, , The Netherlands,

  6. Remco van de Leijgraaf Aachen Department of Surgery Leiden University Medical Centre Leiden The Netherlands Remco van de Leijgraaf Department of Surgery, Leiden University Medical Centre

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Surgery Leiden University Medical Centre Leiden The Netherlands

    Remco van de Leijgraaf , Department of Surgery, , Leiden University Medical Centre, , Leiden, , The Netherlands,

  7. Raghed Halawani Aachen Department of Surgery Leiden University Medical Centre Leiden The Netherlands Raghed Halawani Department of Surgery, Leiden University Medical Centre

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Surgery Leiden University Medical Centre Leiden The Netherlands

    Raghed Halawani , Department of Surgery, , Leiden University Medical Centre, , Leiden, , The Netherlands,

  8. Michelle Westmaas Aachen Department of Surgery Leiden University Medical Centre Leiden The Netherlands Michelle Westmaas Department of Surgery, Leiden University Medical Centre

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Surgery Leiden University Medical Centre Leiden The Netherlands

    Michelle Westmaas , Department of Surgery, , Leiden University Medical Centre, , Leiden, , The Netherlands,

  9. Lineke I. W. Starink Aachen Department of Surgery Leiden University Medical Centre Leiden The Netherlands Lineke I. W. Starink Department of Surgery, Leiden University Medical Centre

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Surgery Leiden University Medical Centre Leiden The Netherlands

    Lineke I. W. Starink , Department of Surgery, , Leiden University Medical Centre, , Leiden, , The Netherlands,

  10. Paul H.A. Quax Aachen Department of Surgery Leiden University Medical Centre Leiden The Netherlands Department of Surgery, Leiden University Medical Centre Einthoven Laboratory for Experimental Vascular Medicine

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Surgery Leiden University Medical Centre Leiden The Netherlands

    Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Centre Leiden The Netherlands

    Paul H. A. Quax https://orcid.org/0000-0002-6853-5760 , Department of Surgery, , Leiden University Medical Centre, , Leiden, , The Netherlands, , Einthoven Laboratory for Experimental Vascular Medicine, , Leiden University Medical Centre, , Leiden, , The Netherlands,

  11. Judith C. Sluimer

    Maastricht University Medical Centre · University of Edinburgh

    Affiliation as printed

    Centre for Cardiovascular Sciences University of Edinburgh Edinburgh United Kingdom

    Department of Pathology, CARIM School for Cardiovascular Sciences Maastricht University Medical Centre Maastricht The Netherlands

    Judith C. Sluimer https://orcid.org/0000-0002-0269-4582 , Department of Pathology, CARIM School for Cardiovascular Sciences, , Maastricht University Medical Centre, , Maastricht, , The Netherlands, , Centre for Cardiovascular Sciences, , University of Edinburgh, , Edinburgh, , United Kingdom,

  12. Margreet R. de Vries Aachen Department of Surgery Leiden University Medical Centre Leiden The Netherlands

    Leiden University · Brigham and Women's Hospital · Harvard University · Leiden University Medical Center

    Affiliation as printed

    Department of Surgery Brigham and Women’s Hospital, Harvard Medical School Boston MA

    Department of Surgery Leiden University Medical Centre Leiden The Netherlands

    Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Centre Leiden The Netherlands

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References 44