Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
J Appl Physiol (1985). 2017 Jun 1;122(6):1388-1397. doi: 10.1152/japplphysiol.00467.2016. Epub 2017 Mar 16.
We generated a novel nanoparticle called PVAX, which has intrinsic antiapoptotic and anti-inflammatory properties. This nanoparticle was loaded with neuropeptide Y (NPY), an angiogenic neurohormone that plays a central role in angiogenesis. Subsequently, we investigated whether PVAX-NPY could act as a therapeutic agent and induce angiogenesis and vascular remodeling in a murine model of hind limb ischemia. Adult C57BL/J6 mice ( = 40) were assigned to treatment groups: control, ischemia PBS, ischemia PVAX, ischemia NPY, and Ischemia PVAX-NPY Ischemia was induced by ligation of the femoral artery in all groups except control and given relevant treatments (PBS, PVAX, NPY, and PVAX-NPY). Blood flow was quantified using laser Doppler imaging. On and posttreatment, mice were euthanized to harvest gastrocnemius muscle for immunohistochemistry and immunoblotting. Blood flow was significantly improved in the PVAX-NPY group after 14 days. Western blot showed an increase in angiogenic factors VEGF-R2 and PDGF-β ( = 0.0035 and = 0.031, respectively) and antiapoptotic marker Bcl-2 in the PVAX-NPY group compared with ischemia PBS group ( = 0.023). Proapoptotic marker Smad5 was significantly decreased in the PVAX-NPY group as compared with the ischemia PBS group ( = 0.028). Furthermore, Y receptors were visualized in endothelial cells of newly formed arteries in the PVAX-NPY group. In conclusion, we were able to show that PVAX-NPY can induce angiogenesis and arteriogenesis as well as improve functional blood flow in a murine model of hind limb ischemia. Our research project proposes a novel method for drug delivery. Our patented PVAX nanoparticle can detect areas of ischemia and oxidative stress. Although there have been studies about delivering angiogenic molecules to areas of ischemic injury, there are drawbacks of nonspecific delivery as well as short half-lives. Our study is unique because it can specifically deliver NPY to ischemic tissue and appears to extend the amount of time therapy is available, despite NPY's short half-life.
我们生成了一种新型的纳米颗粒，称为 PVAX，它具有内在的抗凋亡和抗炎特性。这种纳米颗粒负载有神经肽 Y（NPY），这是一种血管生成神经激素，在血管生成中起核心作用。随后，我们研究了 PVAX-NPY 是否可以作为治疗剂，在小鼠后肢缺血模型中诱导血管生成和血管重塑。将成年 C57BL/J6 小鼠（=40）分为以下治疗组：对照组、缺血 PBS 组、缺血 PVAX 组、缺血 NPY 组和缺血 PVAX-NPY 组。除对照组外，所有组均通过结扎股动脉诱导缺血，并给予相关治疗（PBS、PVAX、NPY 和 PVAX-NPY）。使用激光多普勒成像定量血流。在治疗后 14 天处死小鼠，采集比目鱼肌进行免疫组织化学和免疫印迹分析。PVAX-NPY 组的血流在 14 天后显著改善。Western blot 显示，与缺血 PBS 组相比，PVAX-NPY 组血管生成因子 VEGF-R2 和 PDGF-β 增加（=0.0035 和=0.031），抗凋亡标志物 Bcl-2 增加（=0.023）。与缺血 PBS 组相比，PVAX-NPY 组促凋亡标志物 Smad5 显著降低（=0.028）。此外，在 PVAX-NPY 组新形成的动脉内皮细胞中观察到 Y 受体。总之，我们能够证明 PVAX-NPY 可以在小鼠后肢缺血模型中诱导血管生成和动脉生成，并改善功能性血流。我们的研究项目提出了一种新的药物输送方法。我们的专利 PVAX 纳米颗粒可以检测到缺血和氧化应激区域。虽然已经有研究将血管生成分子递送到缺血损伤区域，但存在非特异性递送和半衰期短的缺点。我们的研究是独特的，因为它可以将 NPY 特异性递送到缺血组织，并似乎延长了治疗的可用时间，尽管 NPY 的半衰期很短。
