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: 9.67). 08/2011; 108(32):13264-9. DOI: 10.1073/pnas.1101321108
Source: PubMed


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.

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    • "nM vs. 52±9 nM for manassantin A) (Fig 2C). Consistent with its HIF-1 inhibitory activity, hypoxia-induced expression of vascular endothelial growth factor (VEGF), a known HIF-1 target gene [20], was significantly down-regulated by LXY6006 (Fig 2D). "
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    ABSTRACT: The dineolignan manassantin A from Saururaceae was recently identified as a hypoxia-inducible factor 1 (HIF-1) inhibitor, but its in-vivo anti-tumor effect has not been explored. We synthesized a series of manassantin A derivatives, and found that replacing the central tetrahydrofuran moiety with a cyclopentane ring yielded a compound (LXY6006) with increased HIF-1-inhibitory activity yet decreased stereochemically complexity amenable to a simplified synthesis scheme. LXY6006 inhibited HIF-1α nuclear accumulation induced by hypoxia, and inhibited cancer cell growth as a consequence of G2/M arrest. Oral administration of LXY6006 significantly inhibited growth of breast, lung, and pancreatic tumors implanted in nude mice. These results indicate that LXY6006 represents a novel class of agents targeting a broad range of human cancers.
    PLoS ONE 06/2014; 9(6):e99584. DOI:10.1371/journal.pone.0099584 · 3.23 Impact Factor
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    • "Further studies suggested that hypoxia also upregulates the expression and secretion of ADM by macrophages (50), which are often regulated by HIF and VEGF (51, 52). A recent study showed that TAM-induced endothelial cell migration and tubule formation are inhibited by treatment with an ADM neutralizing antibody (53). "
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    ABSTRACT: Angiogenesis, the formation of new blood vessels, as well as inflammation with massive infiltration of leukocytes are hallmarks of various tumor entities. Various epidemiological, clinical, and experimental studies have not only demonstrated a link between chronic inflammation and cancer onset but also shown that immune cells from the bone marrow such as tumor-infiltrating macrophages significantly influence tumor progression. Tumor angiogenesis is critical for tumor development as tumors have to establish a blood supply in order to progress. Although tumor cells were first believed to fuel tumor angiogenesis, numerous studies have shown that the tumor microenvironment and infiltrating immune cell subsets are important for regulating the process of tumor angiogenesis. These infiltrates involve the adaptive immune system including several types of lymphocytes as well as cells of the innate immunity such as macrophages, neutrophils, eosinophils, mast cells, dendritic cells, and natural killer cells. Besides their known immune function, these cells are now recognized for their crucial role in regulating the formation and the remodeling of blood vessels in the tumor. In this review, we will discuss for each cell type the mechanisms that regulate the vascular phenotype and its impact on tumor growth and metastasis.
    Frontiers in Oncology 04/2014; 4:69. DOI:10.3389/fonc.2014.00069
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    • "Absorption spectra of hemoglobin differ with oxygenation and therefore offer the additional possibility of functional analysis 8: Dual-wavelength PA can be used to separately measure tissue concentration of hemoglobin (HbO2) and deoxyhemoglobin (Hb) and as such to calculate focal tissue oxygen saturation 9,10. By imaging HbO2 in blood vessels, three dimensional blood vasculature networks have been studied in superficial tissues such as subcutaneous xenografts, rodent ears, as well as endoscopically in rat intestine 9,11,12. "
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    ABSTRACT: Purpose: In preclinical cancer studies, non-invasive functional imaging has become an important tool to assess tumor development and therapeutic effects. Tumor hypoxia is closely associated with tumor aggressiveness and is therefore a key parameter to be monitored. Recently, photoacoustic (PA) imaging with inherently co-registered high-frequency ultrasound (US) has reached preclinical applicability, allowing parallel collection of anatomical and functional information. Dual-wavelength PA imaging can be used to quantify tissue oxygen saturation based on the absorbance spectrum differences between hemoglobin and deoxyhemoglobin. Experimental Design: A new bi-modal PA/US system for small animal imaging was employed to test feasibility and reliability of dual-wavelength PA for measuring relative tissue oxygenation. Murine models of pancreatic and colon cancer were imaged, and differences in tissue oxygenation were compared to immunohistochemistry for hypoxia in the corresponding tissue regions. Results: Functional studies proved feasibility and reliability of oxygenation detection in murine tissue in vivo. Tumor models exhibited different levels of hypoxia in localized regions, which positively correlated with immunohistochemical staining for hypoxia. Contrast-enhanced imaging yielded complementary information on tissue perfusion using the same system. Conclusion: Bimodal PA/US imaging can be utilized to reliably detect hypoxic tumor regions in murine tumor models, thus providing the possibility to collect anatomical and functional information on tumor growth and treatment response live in longitudinal preclinical studies.
    Theranostics 03/2014; 4(6):604-13. DOI:10.7150/thno.7996 · 8.02 Impact Factor
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