Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13444-9. doi: 10.1073/pnas.1110121108. Epub 2011 Aug 1.
Enhancing the maturity of the newly formed blood vessels is critical for the success of therapeutic angiogenesis. The maturation of vasculature relies on active participation of mural cells to stabilize endothelium and a basal level of relevant growth factors. We set out to design and successfully achieved robust angiogenesis using an injectable polyvalent coacervate of a polycation, heparin, and fibroblast growth factor-2 (FGF2). FGF2 was loaded into the coacervate at nearly 100% efficiency. In vitro assays demonstrated that the matrix protected FGF2 from proteolytic degradations. FGF2 released from the coacervate was more effective in the differentiation of endothelial cells and chemotaxis of pericytes than free FGF2. One injection of 500 ng of FGF2 in the coacervate elicited comprehensive angiogenesis in vivo. The number of endothelial and mural cells increased significantly, and the local tissue contained more and larger blood vessels with increased circulation. Mural cells actively participated during the whole angiogenic process: Within 7 d of the injection, pericytes were recruited to close proximity of the endothelial cells. Mature vasculature stabilized by vascular smooth muscle cells persisted till at least 4 wk. On the other hand, bolus injection of an identical amount of free FGF2 induced weak angiogenic responses. These results demonstrate the potential of polyvalent coacervate as a new controlled delivery platform.
提高新形成血管的成熟度对于治疗性血管生成的成功至关重要。血管成熟依赖于壁细胞的积极参与，以稳定内皮细胞和相关生长因子的基础水平。我们设计并成功地使用多价凝聚体实现了强大的血管生成，该凝聚体由聚阳离子、肝素和成纤维细胞生长因子 2（FGF2）组成。FGF2 以接近 100%的效率加载到凝聚体中。体外实验表明，基质保护 FGF2 免受蛋白水解降解。与游离 FGF2 相比，从凝聚体中释放的 FGF2 更有效地促进内皮细胞分化和周细胞趋化性。在凝聚体中注射 500 ng 的 FGF2 可引发体内全面的血管生成。内皮细胞和壁细胞的数量显著增加，局部组织含有更多和更大的血管，循环增加。壁细胞在整个血管生成过程中积极参与：在注射后的 7 天内，周细胞被募集到内皮细胞的附近。由血管平滑肌细胞稳定的成熟血管至少持续到 4 周。另一方面，相同数量的游离 FGF2 的单次注射引起了较弱的血管生成反应。这些结果表明多价凝聚体作为一种新的控制释放平台具有潜力。
