State-of-the-Art Methods for Evaluation of Angiogenesis and Tissue Vascularization

Simons, Michael; Alitalo, Kari; Annex, Brian H.; Augustin, Hellmut G.; Beam, Craig A.; Berk, Bradford C.; Byzova, Tatiana V.; Carmeliet, Peter; Chilian, William M.; Cooke, John P.; Davis, George E.; Eichmann, Anne; Iruela‐Arispe, M. Luisa; Keshet, Eli; Sinusas, Albert J.; Ruhrberg, Christiana; Woo, Y. Joseph; Dimmeler, Stefanie

doi:10.1161/res.0000000000000054

Cited by 114 publications

(84 citation statements)

References 253 publications

(211 reference statements)

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“…After treatment, perfusion was rapidly restored and a significant improvement in running endurance was observed in adult and aged mice with induced acute limb ischemia, indicating preservation of tissue structure and function. These two improvements were significantly greater than those observed for comparable HLI models after treatment with therapies currently being tested in clinical trials [3,5,10,17,37,41,42]. Biodistribution studies demonstrated excellent biocompatibility of parenterally administered SLanc.…”

Section: Discussionmentioning

confidence: 89%

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Treatment of hind limb ischemia using angiogenic peptide nanofibers

Liu²,

et al. 2016

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For a proangiogenic therapy to be successful, it must promote the development of mature vasculature for rapid reperfusion of ischemic tissue. Whole growth factor, stem cell, and gene therapies have yet to achieve the clinical success needed to become FDA-approved revascularization therapies. Herein, we characterize a biodegradable peptide-based scaffold engineered to mimic VEGF and self-assemble into a nanofibrous, thixotropic hydrogel, SLanc. We found that this injectable hydrogel was rapidly infiltrated by host cells and could be degraded while promoting the generation of neovessels. In mice with induced hind limb ischemia, this synthetic peptide scaffold promoted angiogenesis and ischemic tissue recovery, as shown by Doppler-quantified limb perfusion and a treadmill endurance test. Thirteen-month-old mice showed significant recovery within 7 days of treatment. Biodistribution studies in healthy mice showed that the hydrogel is safe when administered intramuscularly, subcutaneously, or intravenously. These preclinical studies help establish the efficacy of this treatment for peripheral artery disease due to diminished microvascular perfusion, a necessary step before clinical translation. This peptide-based approach eliminates the need for cell transplantation or viral gene transfection (therapies currently being assessed in clinical trials) and could be a more effective regenerative medicine approach to microvascular tissue engineering.

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Section: Discussionmentioning

confidence: 89%

“…For these patients and others in the early stages of PAD and that have ankle-brachial indices of 0.9–0.4, there is no FDA-approved revascularization therapy. Lower limb amputation is, therefore, often required [1–3]. …”

Section: Introductionmentioning

confidence: 99%

Treatment of hind limb ischemia using angiogenic peptide nanofibers

Liu²,

et al. 2016

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“…We determined if Nck is required for vascular development, focusing first on the postnatal mouse retina, which is a useful model to study angiogenesis 20 . Since mouse endothelial cells express Nck1 and 2 21 , we generated inducible, endothelial specific Nck2 deletions using Nck2 lox mice 22, 23 and the Cdh5Cre ERT2 line 24 (hereafter referred to as Nck2iec ) in Nck1 −/− mice .…”

Section: Resultsmentioning

confidence: 99%

Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization

et al. 2016

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Background Sprouting angiogenesis is a key process driving blood vessel growth in ischemic tissues and an important drug target in a number of diseases, including wet macular degeneration and wound healing. Endothelial cells forming the sprout must develop front-rear polarity to allow sprout extension. The adaptor proteins Nck1 and 2 are known regulators of cytoskeletal dynamics and polarity, but their function in angiogenesis is poorly understood. Here we show that the Nck adaptors are required for endothelial cell front-rear polarity and migration downstream of the angiogenic growth factors VEGF-A and Slit2. Methods and Results Mice carrying inducible, endothelial-specific Nck1/2 deletions fail to develop front-rear polarized vessel sprouts and exhibit severe angiogenesis defects in the postnatal retina and during embryonic development. Inactivation of NCK1 and 2 inhibits polarity by preventing Cdc42 and Pak2 activation by VEGF-A and Slit2. Mechanistically, NCK binding to ROBO1 is required for both Slit2 and VEGF induced front-rear polarity. Selective inhibition of polarized endothelial cell migration by targeting Nck1/2 prevents hypersprouting induced by Notch or Bmp signaling inhibition, as well as pathological ocular neovascularization and wound healing. Conclusions These data reveal a novel signal integration mechanism involving NCK1/2, ROBO1/2 and VEGFR2 that controls endothelial cell front-rear polarity during sprouting angiogenesis.

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“…Similarly, lymphatic vessels play a vital role in immune surveillance by delivering dendritic cells, macrophages, and neutrophils to lymph nodes and recycling lipids, liquids, and proteins from peripheral tissues back to the circulation system[1]. Recently, researchers have developed several lymphatic or blood vasculature-specific, promoter-driven, fluorescence-reported transgenic mice [4,5]. The transgenic fluorescence of the lymphatic or blood vasculature in Prox1-GFP [6], VEGFR3-YFP [7], Prox1-tdtomato, Flk1-mcherry[8], Flk1-GFP, and Flt1-DsRed mice is valuable because it makes it possible to characterize lymphatic or blood vessel formation in live imaging throughout the experimental time course [6] [8–10].…”

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confidence: 99%

Prox1-GFP/Flt1-DsRed transgenic mice: an animal model for simultaneous live imaging of angiogenesis and lymphangiogenesis

et al. 2017

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The roles of angiogenesis in development, health, and disease have been studied extensively; however, the studies related to lymphatic system are limited due to the difficulty in observing colorless lymphatic vessels. But recently, with the improved technique, the relative importance of the lymphatic system is just being revealed. We bred transgenic mice in which lymphatic endothelial cells express GFP (Prox1-GFP) with mice in which vascular endothelial cells express DsRed (Flt1-DsRed) to generate Prox1-GFP/Flt1-DsRed (PGFD) mice. The inherent fluorescence of blood and lymphatic vessels allows for direct visualization of blood and lymphatic vessels in various organs via confocal and two-photon microscopy and the formation, branching, and regression of both vessel types in the same live mouse cornea throughout an experimental time course. PGFD mice were bred with CDh5CreERT2 and VEGFR2lox knockout mice to examine specific knockouts. These studies showed a novel role for vascular endothelial cell VEGFR2 in regulating VEGFC-induced corneal lymphangiogenesis. Conditional deletion of vascular endothelial VEGFR2 abolished VEGFA- and VEGFC-induced corneal lymphangiogenesis. These results demonstrate the potential use of the PGFD mouse as a powerful animal model for studying angiogenesis and lymphangiogenesis.

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State-of-the-Art Methods for Evaluation of Angiogenesis and Tissue Vascularization

Cited by 114 publications

References 253 publications

Treatment of hind limb ischemia using angiogenic peptide nanofibers

Treatment of hind limb ischemia using angiogenic peptide nanofibers

Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization

Prox1-GFP/Flt1-DsRed transgenic mice: an animal model for simultaneous live imaging of angiogenesis and lymphangiogenesis

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