Grote Karsten, Salguero Gustavo, Ballmaier Matthias, Dangers Marc, Drexler Helmut, Schieffer Bernhard
Department of Cardiology, Medical School Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.
Blood. 2007 Aug 1;110(3):877-85. doi: 10.1182/blood-2006-07-036202. Epub 2007 Apr 11.
Tissue regeneration involves the formation of new blood vessels regulated by angiogenic factors. We reported recently that the expression of the angiogenic factor CCN1 is up-regulated under various pathophysiologic conditions within the cardiovascular system. Because CD34+ progenitor cells participate in cardiovascular tissue regeneration, we investigated whether CCN1-detected for the first time in human plasma-promotes the recruitment of CD34+ progenitor cells to endothelial cells, thereby enhancing endothelial proliferation and neovascularization. In this study, we demonstrated that CCN1 and supernatants from CCN1-stimulated human CD34+ progenitor cells promoted proliferation of endothelial cells and angiogenesis in vitro and in vivo. In addition, CCN1 induced migration and transendothelial migration of CD34+ cells and the release of multiple growth factors, chemokines, and matrix metalloproteinase-9 (MMP-9) from these cells. Moreover, the CCN1-specific integrins alpha(M)beta(2) and alpha(V)beta(3) are expressed on CD34+ cells and CCN1 stimulated integrin-dependent signaling. Furthermore, integrin antagonists (RGD-peptides) suppressed both binding of CCN1 to CD34+ cells and CCN1-induced adhesion of CD34+ cells to endothelial cells. These data suggest that CCN1 promotes integrin-dependent recruitment of CD34+ progenitor cells to endothelial cells, which may contribute to paracrine effects on angiogenesis and tissue regeneration.
组织再生涉及由血管生成因子调节的新血管形成。我们最近报道，血管生成因子CCN1在心血管系统的各种病理生理条件下表达上调。由于CD34+祖细胞参与心血管组织再生，我们研究了首次在人血浆中检测到的CCN1是否促进CD34+祖细胞向内皮细胞的募集，从而增强内皮细胞增殖和新血管形成。在本研究中，我们证明CCN1以及CCN1刺激的人CD34+祖细胞的上清液在体外和体内均促进内皮细胞增殖和血管生成。此外，CCN1诱导CD34+细胞迁移和跨内皮迁移，并促使这些细胞释放多种生长因子、趋化因子和基质金属蛋白酶-9（MMP-9）。而且，CCN1特异性整合素α(M)β(2)和α(V)β(3)在CD34+细胞上表达，CCN1刺激整合素依赖性信号传导。此外，整合素拮抗剂（RGD肽）抑制CCN1与CD34+细胞的结合以及CCN1诱导的CD34+细胞与内皮细胞的粘附。这些数据表明，CCN1促进整合素依赖性的CD34+祖细胞向内皮细胞的募集，这可能有助于对血管生成和组织再生的旁分泌作用。
