Syndecan-4 proteoliposomes enhance fibroblast growth factor-2 (FGF-2)-induced proliferation, migration, and neovascularization of ischemic muscle
Syndecan-4 proteoliposomes enhance fibroblast growth factor-2 (FGF-2)-induced proliferation, migration, and neovascularization of ischemic muscle
复制标题
DOI：
10.1073/pnas.1117885109
复制
发表时间：
2012-01-31
影响因子：
11.1
通讯作者：
Baker, Aaron B.
中科院分区：
文献类型：
--
作者：
Jang, Eugene;Albadawi, Hassan;Baker, Aaron B.
心肌和下肢缺血是动脉疾病的常见后果，也是现代化国家发病率和死亡率的主要来源。诱导新血管形成治疗缺血是一种有吸引力的治疗策略，对于传统的治疗方式不能执行或无效的患者。在过去，血管生长的刺激是使用生长因子的直接递送、血管生成基因疗法或细胞疗法来追求的。虽然治疗性血管生成对于治疗缺血患者具有很大的希望，但目前的方法在临床试验中尚未取得成功。成纤维细胞生长因子-2（FGF-2）是用于治疗性血管生成的第一批被测试的生长因子之一。在这里，我们提出了一种方法，用于改善FGF-2的生物活性，通过共同交付的生长因子与脂质体嵌入的辅助受体，syndecan-4。与单独的FGF-2相比，该技术显示出增加FGF-2细胞信号传导、摄取和核定位。递送syndecan-4蛋白脂质体也增加了响应FGF-2的内皮细胞增殖、迁移和血管生成管形成。使用肢体缺血的动物模型，syndecan-4蛋白脂质体显着改善股动脉结扎后的新血管形成和缺血肢体的灌注恢复。总之，这些结果支持多配体蛋白聚糖-4的脂质体递送作为提高使用生长因子实现缺血组织的治疗性新血管形成的潜力的有效手段。
Ischemia of the myocardium and lower limbs is a common consequence of arterial disease and a major source of morbidity and mortality in modernized countries. Inducing neovascularization for the treatment of ischemia is an appealing therapeutic strategy for patients for whom traditional treatment modalities cannot be performed or are ineffective. In the past, the stimulation of blood vessel growth was pursued using direct delivery of growth factors, angiogenic gene therapy, or cellular therapy. Although therapeutic angiogenesis holds great promise for treating patients with ischemia, current methods have not found success in clinical trials. Fibroblast growth factor-2 (FGF-2) was one of the first growth factors to be tested for use in therapeutic angiogenesis. Here, we present a method for improving the biological activity of FGF-2 by codelivering the growth factor with a liposomally embedded coreceptor, syndecan-4. This technique was shown to increase FGF-2 cellular signaling, uptake, and nuclear localization in comparison with FGF-2 alone. Delivery of syndecan-4 proteoliposomes also increased endothelial proliferation, migration, and angiogenic tube formation in response to FGF-2. Using an animal model of limb ischemia, syndecan-4 proteoliposomes markedly improved the neovascularization following femoral artery ligation and recovery of perfusion of the ischemic limb. Taken together, these results support liposomal delivery of syndecan-4 as an effective means to improving the potential of using growth factors to achieve therapeutic neovascularization of ischemic tissue.