A Vascular Endothelial Growth Factor-Dependent Sprouting Angiogenesis Assay Based on an In Vitro Human Blood Vessel Model for the Study of Anti-Angiogenic Drugs

• Published in: EBioMedicine Vol. 27; no. C; pp. 225 - 236
• Main Authors: Pauty, Joris, Usuba, Ryo, Cheng, Irene Gayi, Hespel, Louise, Takahashi, Haruko, Kato, Keisuke, Kobayashi, Masayoshi, Nakajima, Hiroyuki, Lee, Eujin, Yger, Florian, Soncin, Fabrice, Matsunaga, Yukiko T.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2018; Elsevier
• Subjects: Angiogenesis inhibitors; Angiogenesis Inhibitors - pharmacology; Biological Assay; Biotechnology; Blood Vessels - drug effects; Blood Vessels - physiology; Computer Science; DLL4; Gene Knockdown Techniques; Human umbilical vein endothelial cell; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; In vitro 3D model; Indoles - pharmacology; Life Sciences; Microvessel; Microvessels - metabolism; Models, Biological; Neovascularization, Physiologic - drug effects; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Notch; Phenylurea Compounds - pharmacology; Pyrroles - pharmacology; Research Paper; Signal Transduction - drug effects; Sorafenib; Sprouting angiogenesis; Sunitinib; Tomography, Optical Coherence; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Microvessel; DMSO; kDa; NOCTH1; mRNA; PFA; DLL4; BSA; Sunitinib; HUVEC; Sprouting angiogenesis; CLSM; Vascular endothelial growth factor; PBS; UV; In vitro 3D model; VEGF; Notch; Human umbilical vein endothelial cell; siRNA; VE-Cad; LSFM; ECM; 3D; Sorafenib; VEGFR-2; Angiogenesis inhibitors; EGM-2; PDMS
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2017.12.014

Angiogenesis is the formation of new capillaries from pre-existing blood vessels and participates in proper vasculature development. In pathological conditions such as cancer, abnormal angiogenesis takes place. Angiogenesis is primarily carried out by endothelial cells, the innermost layer of blood vessels. The vascular endothelial growth factor-A (VEGF-A) and its receptor-2 (VEGFR-2) trigger most of the mechanisms activating and regulating angiogenesis, and have been the targets for the development of drugs. However, most experimental assays assessing angiogenesis rely on animal models. We report an in vitro model using a microvessel-on-a-chip. It mimics an effective endothelial sprouting angiogenesis event triggered from an initial microvessel using a single angiogenic factor, VEGF-A. The angiogenic sprouting in this model is depends on the Notch signaling, as observed in vivo. This model enables the study of anti-angiogenic drugs which target a specific factor/receptor pathway, as demonstrated by the use of the clinically approved sorafenib and sunitinib for targeting the VEGF-A/VEGFR-2 pathway. Furthermore, this model allows testing simultaneously angiogenesis and permeability. It demonstrates that sorafenib impairs the endothelial barrier function, while sunitinib does not. Such in vitro human model provides a significant complimentary approach to animal models for the development of effective therapies. •We report an efficient model of VEGF-induced sprouting angiogenesis based on a human blood-vessel on-a-chip.•The model enables to simultaneously study sprouting angiogenesis and endothelial barrier function in a human-related model.•We describe differential effects of the anti-angiogenic drugs sorafenib and sunitinib on endothelium integrity. We present a method to study in vitro the formation of new capillaries from a pre-existing blood vessel, a phenomenon known as sprouting angiogenesis. The method is based on the relatively easy fabrication of a human blood vessel mimic within a collagen gel embedded in a small silicone device, which enables the combination of biological analytic methods for obtaining multiple information at once. This method can be used to develop and study drugs in a more relevant way than classical in vitro methods. It should contribute to improving research and development of anti-angiogenic therapies.