VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting.

Urology Division, Department of Surgery, and Department of Medicine, University of Hawaii 96813, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 08/2011; 108(32):13264-9. DOI: 10.1073/pnas.1101321108
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Optical-resolution photoacoustic microscopy (OR-PAM) is a high-resolution imaging technology capable of label-free imaging of the morphology and functions of the microvasculature in vivo. Previous studies of angiogenesis by OR-PAM were carried out primarily with transgenic mice and the mouse ear model. While important findings have been generated using this approach, the application of OR-PAM to the more widely used subcutaneous dorsal tumor models remains challenging, largely due to the respiratory and cardiac motion artifacts, as well as the protruding tumor contours. A noninvasive dorsal skin-fold (N-DSF) model, along with adaptive z-scanning and a corresponding experimental protocol, is developed. Mammary carcinoma cells (4T1) were administered subcutaneously to the backs of female BALB/c mice for tumor inoculation. The mice were anesthetized using a mixture of isofluorane and oxygen. In vivo OR-PAM of angiogenesis with subcutaneous dorsal tumor models in mice has been demonstrated. To test the performance of this method, we have monitored the growth of 4T1 mouse mammary carcinoma in BALB/c mice over a period of 9 days. The major features of tumor angiogenesis, including the change of vascular tortuosity, the dilation of vessel diameters, and the increase of blood supply, have been clearly captured with OR-PAM. In combination with N-DSF model, OR-PAM has demonstrated outstanding capacity to provide label-free monitoring of angiogenesis in tumor. Thus, OR-PAM is of great potential to find broad biomedical applications in the pathophysiological studies of tumor and the treatments for anti-angiogenesis.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Robust reconstructions of the three-dimensional network of blood vessels in developing embryos imaged by optical coherence tomography (OCT) are needed for quantifying the longitudinal development of vascular networks in live mammalian embryos, in support of developmental cardiovascular research. Past computational methods [such as speckle variance (SV)] have demonstrated the feasibility of vascular reconstruction, but multiple challenges remain including: the presence of vessel structures at multiple spatial scales, thin blood vessels with weak flow, and artifacts resulting from bulk tissue motion (BTM). In order to overcome these challenges, this paper introduces a robust and scalable reconstruction algorithm based on a combination of anomaly detection algorithms and a parametric dictionary based sparse representation of blood vessels from structural OCT data. Validation results using confocal data as the baseline demonstrate that the proposed method enables the detection of vessel segments that are either partially missed or weakly reconstructed using the SV method. Finally, quantitative measurements of vessel reconstruction quality indicate an overall higher quality of vessel reconstruction with the proposed method. Results suggest that sparsity-integrated speckle anomaly detection (SSAD) is potentially a valuable tool for performing accurate quantification of the progression of vascular development in the mammalian embryonic yolk sac as imaged using OCT.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Photoacoustic tomography (PAT) is an emerging imaging modality that shows great potential for preclinical research and clinical practice. As a hybrid technique, PAT is based on the acoustic detection of optical absorption from either endogenous chromophores, such as oxy-hemoglobin and deoxy-hemoglobin, or exogenous contrast agents, such as organic dyes and nanoparticles. Because ultrasound scatters much less than light in tissue, PAT generates high-resolution images in both the optical ballistic and diffusive regimes. Over the past decade, the photoacoustic technique has been evolving rapidly, leading to a variety of exciting discoveries and applications. This review covers the basic principles of PAT and its different implementations. Strengths of PAT are highlighted, along with the most recent imaging results.
    Progress In Electromagnetics Research 01/2014; 147:1-22. DOI:10.2528/PIER14032303 · 5.30 Impact Factor

Full-text (2 Sources)

Available from
May 31, 2014

Similar Publications