title: Inhibition of protein tyrosine phosphatases enhances cerebral collateral growth in rats.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Ivo
authors.initials: I
authors.lastname: Buschmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Hackbusch
authors.forename: Nora
authors.initials: N
authors.lastname: Gatzke
authors.forename: André
authors.initials: A
authors.lastname: Dülsner
authors.forename: Manuela
authors.initials: M
authors.lastname: Trappiel
authors.forename: Markus
authors.initials: M
authors.lastname: Dagnell
authors.forename: Arne
authors.initials: A
authors.lastname: Ostman
authors.forename: Rob
authors.initials: R
authors.lastname: Hooft van Huijsduijnen
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000201:enzymology; D002536:Cerebral Arteries / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D020797:Receptor, Platelet-Derived Growth Factor beta; D017027:Protein Tyrosine Phosphatases