Overcoming disease-induced growth factor resistance in therapeutic angiogenesis using recombinant co-receptors delivered by a liposomal system.
Overcoming disease-induced growth factor resistance in therapeutic angiogenesis using recombinant co-receptors delivered by a liposomal system.
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DOI：
10.1016/j.biomaterials.2013.09.105
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发表时间：
2014-01
期刊：
影响因子：
14
通讯作者：
Baker, Aaron B.
中科院分区：
文献类型：
--
作者：
Das, Subhamoy;Singh, Gunjan;Baker, Aaron B.
关键词：
目前对缺血的治疗选择包括经皮介入、外科搭桥术或旨在减缓血管疾病进展的药物干预。不幸的是，虽然这些治疗方式中的每一种都在短期内为患者提供了一些好处，但许多患者患有耐药或复发的疾病，这些治疗方法处理不善。治疗缺血性疾病的一个非常有吸引力的策略是刺激组织的血管重建以恢复血液流动。虽然在这方面已经探索了许多技术，但临床上有效的血管生成疗法仍然难以捉摸。在这里，我们假设，共病状态的存在内在地改变了身体对血管生成治疗的反应能力。利用糖尿病和肥胖的小鼠模型，我们检测了在正常和高脂肪饮食条件下，成纤维细胞生长因子-2、血管内皮生长因子-A和血小板衍生生长因子信号通路的主要成分的变化。在骨骼肌中，高脂肪饮食增加了野生型小鼠的生长因子受体和辅助受体的水平，包括Syndecan-1，Syndecan-4和PDGFR-。这些增加在高脂肪饮食的Ob/Ob小鼠中没有发生，这些小鼠的神经菌素-1和乙酰肝素酶的蛋白质水平显著下降。为了在疾病的背景下增加生长因子的有效性，我们检查了海藻酸凝胶递送的成纤维细胞生长因子-2和Syndecan-4蛋白脂质体的局部治疗是否可以克服这些小鼠的生长因子抵抗。与单独注射成纤维细胞生长因子-2相比，该治疗可使Ob/Ob小鼠体内新血管的形成增加6倍。我们的研究支持疾病状态导致生长因子信号通路的深刻变化，基于共受体的治疗有可能在疾病状态的背景下克服生长因子抵抗。
Current treatment options for ischemia include percutaneous interventions, surgical bypass or pharmacological interventions aimed at slowing the progression of vascular disease. Unfortunately, while each of these treatment modalities provides some benefit for patients in the short-term, many patients have resistant or recurrent disease that is poorly managed by these therapies. A highly appealing strategy for treating ischemic disease is to stimulate the revascularization of the tissue to restore blood flow. While many techniques have been explored in this regard, clinically effective angiogenic therapies remain elusive. Here, we hypothesized that the presence of co-morbid disease states inherently alters the ability of the body to respond to angiogenic therapies. Using a mouse model of diabetes and obesity, we examined alterations in the major components for the signaling pathways for FGF-2, VEGF-A and PDGF under normal and high fat dietary conditions. In skeletal muscle, a high fat diet increased levels of growth factor receptors and co-receptors including syndecan-1, syndecan-4 and PDGFR-□in wild-type mice. These increases did not occur in Ob/Ob mice on a high fat diet and there was a significant decrease in protein levels for neuropilin-1 and heparanase in these mice. With the aim of increasing growth factor effectiveness in the context of disease, we examined whether local treatment with alginate gel-delivered FGF-2 and syndecan-4 proteoliposomes could overcome the growth factor resistance in these mice. This treatment enhanced the formation of new blood vessels in Ob/Ob mice by 6 fold in comparison to FGF-2 delivered alone. Our studies support that disease states cause a profound shift in growth factor signaling pathways and that co-receptor-based therapies have potential to overcome growth factor resistance in the context of disease states.
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影响因子：
2.8
作者：
Lederman, RJ;Tenaglia, AN;Annex, BH
通讯作者：
Annex, BH
DOI：
10.1152/ajpheart.00379.2008
发表时间：
2008-10-01
影响因子：
4.8
作者：
Bouhidel, Omar;Pons, Sandrine;Ghaleh, Bijan
通讯作者：
Ghaleh, Bijan
DOI：
10.1073/pnas.1117885109
发表时间：
2012-01-31
影响因子：
11.1
作者：
Jang, Eugene;Albadawi, Hassan;Baker, Aaron B.
通讯作者：
Baker, Aaron B.
影响因子：
4.3
作者：
Adeghate, E
通讯作者：
Adeghate, E
影响因子：
20.1
作者：
Baker AB;Groothuis A;Jonas M;Ettenson DS;Shazly T;Zcharia E;Vlodavsky I;Seifert P;Edelman ER
通讯作者：
Edelman ER