1. Conditional HIF-1 induction produces multistage neovascularization with stage-specific sensitivity to VEGFR inhibitors and myeloid cell independence.
- Author
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Oladipupo SS, Hu S, Santeford AC, Yao J, Kovalski JR, Shohet RV, Maslov K, Wang LV, and Arbeit JM
- Subjects
- Angiogenesis Inhibitors pharmacology, Animals, Endothelium, Vascular cytology, Endothelium, Vascular physiology, Hemodynamics physiology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Mice, Mice, Transgenic, Microcirculation physiology, Myeloid Cells physiology, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic metabolism, Neovascularization, Physiologic drug effects, Pericytes physiology, Signal Transduction physiology, Transcriptional Activation physiology, Tumor Microenvironment physiology, Vascular Endothelial Growth Factor Receptor-1 metabolism, Vascular Endothelial Growth Factor Receptor-2 metabolism, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Neovascularization, Pathologic physiopathology, Neovascularization, Physiologic physiology, Vascular Endothelial Growth Factor Receptor-1 antagonists & inhibitors, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
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.
- Published
- 2011
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