School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biological Inspired Engineering, Harvard University, Boston, MA 02115, USA.
Biomaterials. 2013 Dec;34(36):9201-9. doi: 10.1016/j.biomaterials.2013.08.007. Epub 2013 Aug 22.
Therapeutic stimulation of angiogenesis to re-establish blood flow in ischemic tissues offers great promise as a treatment for patients suffering from cardiovascular disease or trauma. Since angiogenesis is a complex, multi-step process, different signals may need to be delivered at appropriate times in order to promote a robust and mature vasculature. The effects of temporally regulated presentation of pro-angiogenic and pro-maturation factors were investigated in vitro and in vivo in this study. Pro-angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) cooperatively promoted endothelial sprouting and pericyte detachment in a three-dimensional in vitro EC-pericyte co-culture model. Pro-maturation factors platelet-derived growth factor B (PDGF) and angiopoietin 1 (Ang1) inhibited the early stages of VEGF- and Ang2-mediated angiogenesis if present simultaneously with VEGF and Ang2, but promoted these behaviors if added subsequently to the pro-angiogenesis factors. VEGF and Ang2 were also found to additively enhance microvessel density in a subcutaneous model of blood vessel formation, while simultaneously administered PDGF/Ang1 inhibited microvessel formation. However, a temporally controlled scaffold that released PDGF and Ang1 at a delay relative to VEGF/Ang2 promoted both vessel maturation and vascular remodeling without inhibiting sprouting angiogenesis. Our results demonstrate the importance of temporal control over signaling in promoting vascular growth, vessel maturation and vascular remodeling. Delivering multiple growth factors in combination and sequence could aid in creating tissue engineered constructs and therapies aimed at promoting healing after acute wounds and in chronic conditions such as diabetic ulcers and peripheral artery disease.
治疗性刺激血管生成以重新建立缺血组织的血流，为患有心血管疾病或创伤的患者提供了巨大的治疗希望。由于血管生成是一个复杂的、多步骤的过程，因此需要在适当的时间传递不同的信号，以促进强健和成熟的血管生成。本研究在体外和体内研究了时空调节的促血管生成和促成熟因子的作用。促血管生成因子血管内皮生长因子（VEGF）和血管生成素 2（Ang2）协同促进了三维体外 EC-周细胞共培养模型中的内皮细胞出芽和周细胞分离。促成熟因子血小板衍生生长因子 B（PDGF）和血管生成素 1（Ang1）如果与 VEGF 和 Ang2 同时存在，则会抑制 VEGF 和 Ang2 介导的血管生成的早期阶段，但如果随后添加到促血管生成因子中，则会促进这些行为。VEGF 和 Ang2 还被发现可在血管形成的皮下模型中附加地增加微血管密度，而同时给予 PDGF/Ang1 抑制微血管形成。然而，与 VEGF/Ang2 相比，延迟释放 PDGF 和 Ang1 的时空控制支架可促进血管成熟和血管重塑，而不会抑制出芽血管生成。我们的研究结果表明，在促进血管生长、血管成熟和血管重塑方面，对信号进行时空控制非常重要。联合和序贯递送多种生长因子可能有助于创建组织工程构建体和治疗方法，以促进急性伤口愈合以及慢性疾病（如糖尿病溃疡和外周动脉疾病）的愈合。
