Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence

Oladipupo, Sunday S.; Hu, Song; Santeford, Andrea; Yao, Junjie; Kovalski, Joanna; Shohet, Ralph V.; Maslov, Konstantin; Wang, Lihong V.; Arbeit, Jeffrey M.

doi:10.1182/blood-2010-09-307538

Cited by 77 publications

(60 citation statements)

References 52 publications

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“…An outstanding feature of the TetON-HIF-1 model is the ability to dissect discrete stages of neovascular network development and its maintenance due to temporal control of HIF-1 gain of function (11). Here, we tested the necessity of VEGF for HIF-1 induction of the earliest stages of neovascularization, endothelial sprouting, and proliferation.…”

Section: Loss Of Hif-1-induced Vegf Produces Sprouting Without Endothmentioning

confidence: 99%

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

Oladipupo¹,

Kovalski³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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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Section: Loss Of Hif-1-induced Vegf Produces Sprouting Without Endothmentioning

confidence: 99%

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

Oladipupo¹,

Kovalski³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

156

116

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“…However, emerging evidence exists for the involvement of the hypoxia-inducible factor 1-␣ and its downstream products like stromal cell-derived factor-1␣ (SDF-1␣/CXCL12) and VEGF-A in recruitment and retention of leukocytes in angiogenic environments. [24][25][26][27][28] The ␤-cells of the islet of Langerhans are reported to endogenously produce high levels of the growth factor VEGF-A to uphold the dense angioarchitecture and the fenestrated phenotype of islet capillaries. [29][30][31] In this study, we used nonvascularized transplanted pancreatic islets as a model of angiogenesis, explored the signals attracting leukocytes to a site of vascular development, and studied the identities of these proangiogenic leukocytes.…”

Section: Introductionmentioning

confidence: 99%

VEGF-A recruits a proangiogenic MMP-9–delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue

Christoffersson

Vågesjö

Vandooren

et al. 2012

Blood

287

231

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Recruitment and retention of leukocytes at a site of blood vessel growth are crucial for proper angiogenesis and subsequent tissue perfusion. Although critical for many aspects of regenerative medicine, the mechanisms of leukocyte recruitment to and actions at sites of angiogenesis are not fully understood. In this study, we investigated the signals attracting leukocytes to avascular transplanted pancreatic islets and leukocyte actions at the engraftment site. Expression of the angiogenic stimulus VEGF-A by mouse pancreatic islets was elevated shortly after syngeneic transplantation to muscle. High levels of leukocytes, predominantly CD11b ؉ /Gr-1 ؉ /CXCR4 hi neutrophils, were observed at the site of engraftment, whereas VEGF-A-deficient islets recruited only half of the amount of leukocytes when transplanted. Acute VEGF-A exposure of muscle increased leukocyte extravasation but not the levels of SDF-1␣. VEGF-A-recruited neutrophils expressed 10 times higher amounts of MMP-9 than neutrophils recruited to an inflammatory stimulus. Revascularization of islets transplanted to MMP-9-deficient mice was impaired because blood vessels initially failed to penetrate grafts, and after 2 weeks vascularity was still disturbed. This study demonstrates that VEGF-A recruits a proangiogenic circulating subset of CD11b ؉ /Gr-1 ؉ neutrophils that are CXCR4 hi and deliver large amounts of the effector protein MMP-9, required for islet revascularization and functional integration after transplantation. (Blood. 2012; 120(23):4653-4662)

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“…As a result, it is becoming a powerful tool for studying the microcirculation in many physiological and pathological conditions [6]. For example, recently, OR-PAM has been applied to the longitudinal study of angiogenesis (the imaging of angiogenesis at a series of time points over a period of timedays or weeks-to monitoring the evolution of angiogenesis) [7,8], which plays a critical role in tumor growth, invasion, and metastasis [9,10]. Such studies may open up new opportunities to better understand the dynamics of the tumor microenvironment, as well as to assess the efficacy of anti-angiogenic and/or combined tumor therapies in the early stages [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…Quantitative imaging of these parameters in vivo at different time points can provide us insights into the dynamics of tumor angiogenesis [13][14][15][16][17][18]. In previous studies, we used a simple thresholding approach, together with cross-section vessel tracking, to segment the microvasculature in OR-PAM images [7,8]. However, to offer truly accurate quantification for the intricate microvascular images acquired by OR-PAM, a more rigorous vascular segmentation and quantification algorithm is needed.…”

Section: Introductionmentioning

confidence: 99%

Multi-parametric quantitative microvascular imaging with optical-resolution photoacoustic microscopy in vivo

Yang¹,

Chen²,

Yao³

et al. 2014

Opt. Express

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Many diseases involve either the formation of new blood vessels (e.g., tumor angiogenesis) or the damage of existing ones (e.g., diabetic retinopathy) at the microcirculation level. Optical-resolution photoacoustic microscopy (OR-PAM), capable of imaging microvessels in 3D in vivo down to individual capillaries using endogenous contrast, has the potential to reveal microvascular information critical to the diagnosis and staging of microcirculation-related diseases. In this study, we have developed a dedicated microvascular quantification (MQ) algorithm for OR-PAM to automatically quantify multiple microvascular morphological parameters in parallel, including the vessel diameter distribution, the microvessel density, the vascular tortuosity, and the fractal dimension. The algorithm has been tested on in vivo OR-PAM images of a healthy mouse, demonstrating high accuracy for microvascular segmentation and quantification. The developed MQ algorithm for OR-PAM may greatly facilitate quantitative imaging of tumor angiogenesis and many other microcirculation related diseases in vivo. M. Arbeit, "VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting," Proc. Natl. Acad. Sci. U. S. A. 108(32), 13264-13269 (2011). 9. J. Folkman, "Angiogenesis in cancer, vascular, rheumatoid and other disease," Nat. Med. 1(1), 27-30 (1995 1182-1186 (1971). 11. J. W. Baish and R. K. Jain, "Cancer, angiogenesis and fractals," Nat. Med. 4(9), 984 (1998). 12. R. K. Jain, "Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy," Nat. Med. 7(9), 987-989 (2001)

show abstract

Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence

Cited by 77 publications

References 52 publications

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

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

VEGF-A recruits a proangiogenic MMP-9–delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue

Multi-parametric quantitative microvascular imaging with optical-resolution photoacoustic microscopy in vivo

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