Urology Division, Department of Surgery, and Department of Medicine, University of Hawaii 96813, USA.
Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13264-9. doi: 10.1073/pnas.1101321108. Epub 2011 Jul 22.
Although our understanding of the molecular regulation of adult neovascularization has advanced tremendously, vascular-targeted therapies for tissue ischemia remain suboptimal. The master regulatory transcription factors of the hypoxia-inducible factor (HIF) family are attractive therapeutic targets because they coordinately up-regulate multiple genes controlling neovascularization. Here, we used an inducible model of epithelial HIF-1 activation, the TetON-HIF-1 mouse, to test the requirement for VEGF in HIF-1 mediated neovascularization. TetON-HIF-1, K14-Cre, and VEGF(flox/flox) alleles were combined to create TetON-HIF-1:VEGF(Δ) mice to activate HIF-1 and its target genes in adult basal keratinocytes in the absence of concomitant VEGF. HIF-1 induction failed to produce neovascularization in TetON-HIF-1:VEGF(Δ) mice despite robust up-regulation of multiple proangiogenic HIF targets, including PlGF, adrenomedullin, angiogenin, and PAI-1. In contrast, endothelial sprouting was preserved, enhanced, and more persistent, consistent with marked reduction in Dll4-Notch-1 signaling. Optical-resolution photoacoustic microscopy, which provides noninvasive, label-free, high resolution, and wide-field vascular imaging, revealed the absence of both capillary expansion and arteriovenous remodeling in serially imaged individual TetON-HIF-1:VEGF(Δ) mice. Impaired TetON-HIF-1:VEGF(Δ) neovascularization could be partially rescued by 12-O-tetradecanoylphorbol-13-acetate skin treatment. These data suggest that therapeutic angiogenesis for ischemic cardiovascular disease may require treatment with both HIF-1 and VEGF.
尽管我们对成人血管新生的分子调控机制有了深入的了解，但针对组织缺血的血管靶向治疗仍然不尽如人意。缺氧诱导因子 (HIF) 家族的主调控转录因子是有吸引力的治疗靶点，因为它们协同上调多个控制血管新生的基因。在这里，我们使用上皮细胞 HIF-1 激活的诱导模型，TetON-HIF-1 小鼠，来测试 VEGF 在 HIF-1 介导的血管新生中的必要性。TetON-HIF-1、K14-Cre 和 VEGF(flox/flox) 等位基因被组合在一起，创建了 TetON-HIF-1:VEGF(Δ) 小鼠，以在没有伴随的 VEGF 的情况下，在成年基底角质形成细胞中激活 HIF-1 和其靶基因。尽管多种促血管生成的 HIF 靶基因（包括 PlGF、肾上腺髓质素、血管生成素和 PAI-1）都被强烈上调，但 HIF-1 的诱导未能在 TetON-HIF-1:VEGF(Δ) 小鼠中产生血管新生。相比之下，内皮芽生得到了保留、增强和更持久，这与 Dll4-Notch-1 信号的显著减少一致。光分辨率光声显微镜提供了非侵入性、无标记、高分辨率和宽视场的血管成像，显示在连续成像的单个 TetON-HIF-1:VEGF(Δ) 小鼠中，既没有毛细血管扩张，也没有动静脉重塑。12-O-十四烷酰佛波醇-13-乙酸酯皮肤处理可以部分挽救 TetON-HIF-1:VEGF(Δ) 血管新生的缺陷。这些数据表明，缺血性心血管疾病的治疗性血管生成可能需要同时使用 HIF-1 和 VEGF 进行治疗。
