Abstract-Endothelial progenitor cells (EPCs) are recruited to ischemic regions and improve neovascularization. Integrins contribute to EPC homing. High-mobility group box 1 (HMGB1) is a nuclear protein that is released extracellularly on cell necrosis and tissue damage, eliciting a proinflammatory response and stimulating tissue repair. In the present study, we investigated the effects of HMGB1 on EPC homing. EPCs express the HMGB1 receptors RAGE (receptor for advanced glycation end products) and TLR2 (Toll-like receptor 2). EPC migration was stimulated by HMGB1 in a RAGE-dependent manner. In addition, the HMGB1-induced migration of EPCs on fibronectin and fibrinogen was significantly inhibited by antibodies against ␤ 1 and ␤ 2 integrins, respectively. Short-term prestimulation of EPCs with HMGB1 also increased EPC adhesion to endothelial cell monolayers, and this effect was blocked by antibodies to ␤ 2 integrins or RAGE. HMGB1 increased EPC adhesion to the immobilized integrin ligands intercellular adhesion molecule-1 and fibronectin in a RAGE-dependent manner. Strikingly, HMGB1 rapidly increased integrin affinity and induced integrin polarization. Using intravital microscopy in a tumor model of neovascularization, prestimulation of EPCs with HMGB1 enhanced the initial in vivo adhesion of EPCs to microvessels and the recruitment of EPCs in the tumor tissue. In addition, prestimulation of EPCs with HMGB1 increased the homing of EPCs to ischemic muscles. In conclusion, these data represent a link between HMGB1 and integrin functions of EPCs and demonstrate that HMGB1 stimulates EPC homing to ischemic tissues. These results may provide a platform for the development of novel therapeutic approaches to improve EPC homing. Key Words: high-mobility group box 1 Ⅲ endothelial progenitor cells Ⅲ homing Ⅲ integrins Ⅲ migration T he term vasculogenesis describes the de novo formation of new vessels from angioblasts during embryonic development. 1 Vasculogenesis, which can be mediated by circulating bone marrow (BM)-derived endothelial progenitor or hematopoietic stem cells, is important in postnatal neovascularization of adult ischemic tissues. [2][3][4][5][6] Ischemia or cytokines such as vascular endothelial growth factor (VEGF) lead to mobilization of endothelial progenitor cells (EPCs) from the BM 7 and support the neovascularization of ischemic tissues or tumors. [7][8][9] Therapeutic administration of EPCs increases the neovascularization of ischemic myocardium and limbs and improves left ventricular function after myocardial infarction. 10 -13 EPCs are preferentially recruited to sites of ischemia and improve neovascularization by being directly incorporated into vascular structures and differentiating to endothelial cells and/or by eliciting paracrine effects. 2,4,6,7,10,14 Both the paracrine effects and the differentiation of EPCs to endothelial cells depend on the homing of EPCs to ischemic sites. In an in vivo intravital microscopy study, EPCs embryonic arrested within tumor microvessels, extravasated into the...

Generation of linear roofline lesions is possible with the second-generation cryoballoon. The technique can be used in combination with PV isolation to treat persistent AF with good acute success rates, short procedure times, and acceptable safety concerns. If validated by further studies, the method would be an appealing alternative to radiofrequency ablation techniques.