Hershey James C, Baskin Elizabeth P, Corcoran Halea A, Bett Andrew, Dougherty Nancy M, Gilberto David B, Mao Xianzhi, Thomas Kenneth A, Cook Jacquelynn J
Department of Pharmacology, Merck Research Laboratories, Merck & Co, Inc., WP46-200, West Point, PA 19454, USA.
Heart Vessels. 2003 Jul;18(3):142-9. doi: 10.1007/s00380-003-0694-z.
This study was designed to test the ability of adenovirus-delivered vascular endothelial growth factor (Ad-VEGF) to stimulate angiogenesis and arteriogenesis in the rabbit hindlimb following the induction of ischemia and to evaluate the functional changes in the collateral circulation. Ten days after the surgical induction of hindlimb ischemia, either a control virus (1 x 10(9) pfu) or an adenovirus containing the gene for VEGF(165) (1 x 10(6), 1 x 10(7), 1 x 10(8), or 1 x 10(9) pfu) was administered intramuscularly into the ischemic limb. Thirty days after administration of the adenoviral vectors, skeletal muscle capillary density was assessed and angiography was performed as markers of angiogenesis and arteriogenesis, respectively. Hindlimb blood flow was directly measured and hyperemic tests were performed to evaluate the functional improvements in collateral blood flow. Animals treated with Ad-VEGF at 1 x 10(8) and 1 x 10(9) pfu showed elevated levels of circulating VEGF and dose-dependent hindlimb edema. These doses also led to a robust angiogenic response (i.e., increase in capillary density), but failed to improve collateral blood flow. Consistent with the lack of a functional response, there was no angiographic evidence of enhanced arteriogenesis with any dose of Ad-VEGF. Following the induction of hindlimb ischemia, administration of Ad-VEGF stimulated capillary sprouting (i.e., angiogenesis), but did not increase the growth and development of larger conduit vessels (i.e., arteriogenesis) or improve collateral blood flow. These results support the concept that VEGF may not be expected to have therapeutic utility for the treatment of peripheral or myocardial ischemia.
本研究旨在测试腺病毒介导的血管内皮生长因子（Ad-VEGF）在兔后肢缺血诱导后刺激血管生成和动脉生成的能力，并评估侧支循环的功能变化。在手术诱导后肢缺血10天后，将对照病毒（1×10⁹ pfu）或含有VEGF(165)基因的腺病毒（1×10⁶、1×10⁷、1×10⁸或1×10⁹ pfu）肌肉注射到缺血肢体中。在给予腺病毒载体30天后，分别评估骨骼肌毛细血管密度并进行血管造影，作为血管生成和动脉生成的标志物。直接测量后肢血流量并进行充血试验，以评估侧支血流的功能改善情况。用1×10⁸和1×10⁹ pfu的Ad-VEGF治疗的动物循环VEGF水平升高且后肢出现剂量依赖性水肿。这些剂量还导致强烈的血管生成反应（即毛细血管密度增加），但未能改善侧支血流。与缺乏功能反应一致，任何剂量的Ad-VEGF均无血管造影证据表明动脉生成增强。在诱导后肢缺血后，给予Ad-VEGF刺激了毛细血管芽生（即血管生成），但并未增加较大导管血管的生长和发育（即动脉生成），也未改善侧支血流。这些结果支持了这样一种观点，即VEGF可能无法用于治疗外周或心肌缺血。
