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

Oladipupo, Sunday S. and Hu, Song and Santeford, Andrea C. and Yao, Junjie and Kovalski, Joanna R. and Shohet, Ralph V. and Maslov, Konstantin and Wang, Lihong V. and Arbeit, Jeffrey M. (2011) Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence. Blood, 117 (15). pp. 4142-4153. ISSN 0006-4971. PMCID PMC3087536.

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Neovascularization is a crucial component of tumor growth and ischemia. Although prior work primarily used disease models, delineation of neovascularization in the absence of disease can reveal intrinsic mechanisms of microvessel regulation amenable to manipulation in illness. We created a conditional model of epithelial HIF-1 induction in adult mice (TetON-HIF-1 mice). Longitudinal photoacoustic microscopy (L-PAM) was coincidentally developed for noninvasive, label-free serial imaging of red blood cell-perfused vasculature in the same mouse for weeks to months. TetON-HIF-1 mice evidenced 3 stages of neovascularization: development, maintenance, and transgene-dependent regression. Regression occurred despite extensive and tight pericyte coverage. L-PAM mapped microvascular architecture and quantified volumetric changes in neocapillary morphogenesis, arteriovenous remodeling, and microvessel regression. Developmental stage endothelial proliferation down-regulation was associated with a DNA damage checkpoint consisting of p53, p21, and endothelial γ-H2AX induction. The neovasculature was temporally responsive to VEGFR2 immuno-blockade, with the developmental stage sensitive, and the maintenance stage resistant, to DC101 treatment. L-PAM analysis also pinpointed microvessels ablated or resistant to VEGFR2 immuno-blockade. HIF-1–recruited myeloid cells did not mediate VEGFR2 inhibitor resistance. Thus, HIF-1 neovascularization in the absence of disease is self-regulated via cell autonomous endothelial checkpoints, and resistant to angiogenesis inhibitors independent of myeloid cells.

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URLURL TypeDescription CentralArticle PublisherData Supplements
Maslov, Konstantin0000-0003-3408-8840
Wang, Lihong V.0000-0001-9783-4383
Additional Information:© 2011 The American Society of Hematology. Submitted September 23, 2010; accepted January 18, 2011. Prepublished online as Blood First Edition paper, February 9, 2011. The authors thank Rebecca Sohn for mouse husbandry; Rick Bruick for the gift of the TRE-HIF-1α^(P402A/P464A/N803A) plasmid for construction of the TRE-HIF-1α^(P402/464A/N803A) transgenic mice; Adam Glick for the gift of the K5-rtTA transgenic mice; ImClone for the generous gift of the DC101 and MF1 antibodies; Fulu Liu, Alyssa Gregory, Kyle Eash, and Dan Link for help with bone marrow transplantation and advice on AMD3100 experiments; and Professor James Ballard for reading the manuscript. Authorship: Contribution: S.S.O. contributed to experimental design, coordinated the research project, performed most of the biology experiments, analyzed data, prepared figures, and wrote the manuscript; S.H. contributed to the experimental design, performed all L-PAM imaging and data analysis, prepared figures, and wrote the manuscript; A.C.S. performed ear whole-mount and confocal microcopy experiments and edited the manuscript; J.Y. performed L-PAM data analysis, assisted with L-PAM experiments, organized figures, and wrote the manuscript; J.R.K. performed the myeloid cell immunofluorescence experiments; R.V.S. provided the TRE-HIF-1α^(Pro402A/564A/Asn803A) mice and edited the manuscript; K.M. contributed to L-PAM technology development and the L-PAM experiments; L.V.W. conceived and designed L-PAM experiments and wrote the manuscript; and J.M.A. conceived, designed, and directed the overall research project, analyzed data, and wrote and edited the manuscript. L.V.W. has financial interest in Microphotoacoustics Inc and Endra Inc, which, however, did not support this work. The other authors declare no competing financial interests.
Funding AgencyGrant Number
NIHR01 CA90722
NIHR01 EB000712
NIHR01 NS46214
NIHR01 EB008085
NIHU54 CA136398
Issue or Number:15
PubMed Central ID:PMC3087536
Record Number:CaltechAUTHORS:20160817-090507356
Persistent URL:
Official Citation:Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence Sunday S. Oladipupo, Song Hu, Andrea C. Santeford, Junjie Yao, Joanna R. Kovalski, Ralph V. Shohet, Konstantin Maslov, Lihong V. Wang, Jeffrey M. Arbeit Blood Apr 2011, 117 (15) 4142-4153; DOI: 10.1182/blood-2010-09-307538
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:69690
Deposited By: Tony Diaz
Deposited On:17 Aug 2016 18:43
Last Modified:03 Mar 2020 13:01

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