Chandraratne Sue, von Bruehl Marie-Luise, Pagel Judith-Irina, Stark Konstantin, Kleinert Eike, Konrad Ildiko, Farschtschi Said, Coletti Raffaele, Gärtner Florian, Chillo Omari, Legate Kyle R, Lorenz Michael, Rutkowski Simon, Caballero-Martinez Amelia, Starke Richard, Tirniceriu Anca, Pauleikhoff Laurenz, Fischer Silvia, Assmann Gerald, Mueller-Hoecker Josef, Ware Jerry, Nieswandt Bernhard, Schaper Wolfgang, Schulz Christian, Deindl Elisabeth, Massberg Steffen
From the Medizinische Klinik und Poliklinik I, Department of Cardiology (S.C., M.-L.v.B., K.S., I.K., S.F., R.C., F.G., K.R.L., M.L., A.T., C.S., S.M.), Walter-Brendel-Centre of Experimental Medicine (S.C., M.-L.v.B., J.-I.P., K.S., E.K., I.K., S.F., R.C., F.G., O.C., K.R.L., M.L., S.R., A.C.-M., A.T., L.P., C.S., E.D., S.M.), Department of Anaesthesiology (J.-I.P.), Department of Applied Physics (K.R.L.), and Institute of Pathology (G.A., J.M.-H.), Ludwig-Maximilians-Universität, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Berlin, Germany (S.C., M.-L.v.B., K.S., I.K., S.F., R.C., F.G., K.R.L., M.L., A.T., C.S., S.M); Department of Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany (S.F.); Vascular Sciences, National Heart and Lung Institute, Faculty of Medicine, Hammersmith Campus, Imperial College London, South Kensington Campus, London, United Kingdom (R.S.); Department of Physiology and Biophysics, University of Arkansas for Medical Science, Little Rock (J.W.); Rudolf Virchow Center and DFG Research Center for Experimental Biomedicine, Universität Würzburg, Würzburg, Germany (B.N.); and Max Planck Institute for Heart and Lung Research, Giessen, Germany (W.S.).
Arterioscler Thromb Vasc Biol. 2015 Mar;35(3):589-97. doi: 10.1161/ATVBAHA.114.304447. Epub 2014 Dec 30.
Arteriogenesis is strongly dependent on the recruitment of leukocytes, especially monocytes, into the perivascular space of growing collateral vessels. On the basis of previous findings that platelets are central players in inflammatory processes and mediate the recruitment of leukocytes, the aim of this study was to assess the role of platelets in a model of arterial remodeling.
C57Bl6 wild-type mice, IL4-R/Iba mice lacking the extracellular domain of the glycoprotein Ibα (GPIbα) receptor, and mice treated with antibodies to block GPIbα or deplete circulating platelets were studied in peripheral arteriogenesis. Using a novel model of intravital 2-photon and epifluorescence imaging, we visualized and quantified the interaction of platelets with leukocytes and the vascular endothelium in vivo. We found that transient platelet adhesion to the endothelium of collateral vessels was a major event during arteriogenesis and depended on GPIbα. Furthermore, leukocyte recruitment was obviously affected in animals with defective platelet GPIbα function. In IL4-R/Iba mice, transient and firm leukocyte adhesion to the endothelium of collateral vessels, as well as leukocyte accumulation in the perivascular space, were significantly reduced. Furthermore, we detected platelet-leukocyte aggregates within the circulation, which were significantly reduced in IL4-R/Iba animals. Finally, platelet depletion and loss of GPIbα function resulted in poor reperfusion recovery as determined by laser Doppler imaging.
Thus, GPIbα-mediated interactions between platelets and endothelial cells, as well as leukocytes, support innate immune cell recruitment and promote arteriogenesis-establishing platelets as critical players in this process.
动脉生成强烈依赖于白细胞，尤其是单核细胞募集到正在生长的侧支血管的血管周围间隙。基于先前的研究发现血小板是炎症过程的核心参与者并介导白细胞募集，本研究旨在评估血小板在动脉重塑模型中的作用。
研究了C57Bl6野生型小鼠、缺乏糖蛋白Ibα（GPIbα）受体胞外域的IL4-R/Iba小鼠以及用抗体阻断GPIbα或消耗循环血小板的小鼠的外周动脉生成情况。使用一种新型的活体双光子和落射荧光成像模型，我们在体内可视化并量化了血小板与白细胞以及血管内皮之间的相互作用。我们发现，侧支血管内皮上短暂的血小板黏附是动脉生成过程中的一个主要事件，并且依赖于GPIbα。此外，血小板GPIbα功能有缺陷的动物中白细胞募集明显受到影响。在IL4-R/Iba小鼠中，侧支血管内皮上短暂而牢固的白细胞黏附以及血管周围间隙中的白细胞积聚均显著减少。此外，我们在循环中检测到血小板-白细胞聚集体，在IL4-R/Iba动物中其显著减少。最后，通过激光多普勒成像测定，血小板消耗和GPIbα功能丧失导致再灌注恢复不良。
因此，GPIbα介导的血小板与内皮细胞以及白细胞之间的相互作用支持先天免疫细胞募集并促进动脉生成，确立了血小板在这一过程中的关键作用。
