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Inhibition of protein tyrosine phosphatases enhances cerebral collateral growth in rats

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Abstract

Arteriogenesis involves the rapid proliferation of preexisting arterioles to fully functional arteries as a compensatory mechanism to overcome circulatory deficits. Stimulation of arteriogenesis has therefore been considered a treatment concept in arterial occlusive disease. Here, we investigated the impact of inhibition of protein tyrosine phosphatases (PTPs) on cerebral arteriogenesis in rats. Arteriogenesis was induced by occlusion of one carotid and both vertebral arteries (three-vessel occlusion (3-VO)). Collateral growth and functional vessel perfusion was assessed 3–35 days following 3-VO. Furthermore, animals underwent 3-VO surgery and were treated with the pan-PTP inhibitor BMOV, the SHP-1 inhibitor sodium stibogluconate (SSG), or the PTP1B inhibitor AS279. Cerebral vessel diameters and cerebrovascular reserve capacity (CVRC) were determined, together with immunohistochemistry analyses and proximity ligation assays (PLA) for determination of tissue proliferation and phosphorylation patterns after 7 days. The most significant changes in vessel diameter increase were present in the ipsilateral posterior cerebral artery (PCA), with proliferative markers (PCNA) being time-dependently increased. The CVRC was lost in the early phase after 3-VO and partially recovered after 21 days. PTP inhibition resulted in a significant increase in the ipsilateral PCA diameter in BMOV-treated animals and rats subjected to PTP1B inhibition. Furthermore, CVRC was significantly elevated in AS279-treated rats compared to control animals, along with hyperphosphorylation of the platelet-derived growth factor-β receptor in the vascular wall in vivo. In summary, our data indicate PTPs as hitherto unrecognized negative regulators in cerebral arteriogenesis. Further, PTP inhibition leading to enhanced collateral growth and blood perfusion suggests PTPs as novel targets in anti-ischemic treatment.

Key Messages

  • PTPs exhibit negative regulatory function in cerebral collateral growth in rats.

  • Inhibition of pan-PTP/PTP1B increases vessel PDGF-β receptor phosphorylation.

  • PTP1B inhibition enhances arteriogenesis and cerebrovascular reserve capacity.

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Acknowledgments

KK was supported by the Deutsche Forschungsgemeinschaft (DFG) (KA1820/4-1), the Charité-University Medicine Berlin, and receives funding from the Marga und Walter Boll-Stiftung (210-04-10). IB was supported by the Deutsche Forschungsgemeinschaft (BU1151/6-1). This work was supported by a grant of the Japanese Society for the Promotions of Science (JSPS) to DH (PE11501). Studies were supported by grants to AÖ from Swedish Research Council.

Disclosure

RH was employed by Merck Serono International S.A., Geneva, Switzerland.

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Authors and Affiliations

  1. Center for Cardiovascular Research (CCR), Department of Internal Medicine/Cardiology, Richard-Thoma-Laboratories for Arteriogenesis, Charité–University Medicine Berlin, Hessische Str. 3-4, 10115, Berlin, Germany

    Ivo Buschmann, Nora Gatzke & André Dülsner

  2. Center for Cardiovascular Research (CCR), Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité–University Medicine Berlin, Hessische Str. 3-4, 10115, Berlin, Germany

    Daniel Hackbusch, Manuela Trappiel & Kai Kappert

  3. Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden

    Markus Dagnell

  4. Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institutet, 171 76, Stockholm, Sweden

    Arne Östman

  5. Merck Serono SA, Chemin des Mines, 9, 1202, Geneva, Switzerland

    Rob Hooft van Huijsduijnen

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  1. Ivo Buschmann
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  2. Daniel Hackbusch
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Correspondence to Kai Kappert.

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Ivo Buschmann, Daniel Hackbusch, and Nora Gatzke contributed equally.

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Buschmann, I., Hackbusch, D., Gatzke, N. et al. Inhibition of protein tyrosine phosphatases enhances cerebral collateral growth in rats. J Mol Med 92, 983–994 (2014). https://doi.org/10.1007/s00109-014-1164-z

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  • DOI: https://doi.org/10.1007/s00109-014-1164-z

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