In vivo models of angiogenesis

Norrby, Klas

doi:10.1111/j.1582-4934.2006.tb00423.x

Cited by 253 publications

(245 citation statements)

References 134 publications

(220 reference statements)

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“…Images were acquired for every third day as 53 5 montages with a 310 objective and quantified with the parameter tube total length (BD Attovision software). Once the network is formed at day 3, this parameter reflects the stability of the network (day [3][4][5][6][7][8][9][10][11][12], and inhibition of network formation due to drug treatment can be measured. (b) Images from a developing network acquired every third day during a 12-day period showing fluorescent EC (gray).…”

Section: Ic 50 Calculationsmentioning

confidence: 99%

A novel imaging‐based high‐throughput screening approach to anti‐angiogenic drug discovery

et al. 2009

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The successful progression to the clinic of angiogenesis inhibitors for cancer treatment has spurred interest in developing new classes of anti-angiogenic compounds. The resulting surge in available candidate therapeutics highlights the need for robust, highthroughput angiogenesis screening systems that adequately capture the complexity of new vessel formation while providing quantitative evaluation of the potency of these agents. Available in vitro angiogenesis assays are either cumbersome, impeding adaptation to high-throughput screening formats, or inadequately model the complex multistep process of new vessel formation. We therefore developed an organotypic endothelial-mural cell co-culture assay system that reflects several facets of angiogenesis while remaining compatible with high-throughput/high-content image screening. Co-culture of primary human endothelial cells (EC) and vascular smooth muscle cells (vSMC) results in assembly of a network of tubular endothelial structures enveloped with vascular basement membrane proteins, thus, comprising the three main components of blood vessels. Initially, EC are dependent on vSMC-derived VEGF and sensitive to clinical anti-angiogenic therapeutics. A subsequent phenotypic VEGFswitch renders EC networks resistant to anti-VEGF therapeutics, demarcating a mature vascular phenotype. Conversely, mature EC networks remain sensitive to vascular disrupting agents. Therefore, candidate anti-angiogenic compounds can be interrogated for their relative potency on immature and mature networks and classified as either vascular normalizing or vascular disrupting agents. Here, we demonstrate that the EC-vSMC co-culture assay represents a robust high-content imaging high-throughput screening system for identification of novel anti-angiogenic agents. A pilot highthroughput screening campaign was used to define informative imaging parameters and develop a follow-up dose-response scheme for hit characterization. High-throughput screening using the EC-vSMC co-culture assay establishes a new platform to screen for novel anti-angiogenic compounds for cancer therapy. ' 2009 International Society for Advancement of Cytometry Key termshigh-throughput screening; endothelial/mural cell co-culture; angiogenesis INHIBITING angiogenesis is a validated therapeutic modality for cancer (1). Hence, new agents that potently inhibit pathological angiogenesis are a critical component of future combination cancer therapies (2). The identification of candidate therapeutics relies on current in vitro angiogenesis assays that measure effects on endothelial cell migration, proliferation, apoptosis and tube formation, and in vivo models such as the chick chorioallantoic membrane assay, corneal neovascularization assay, and Matrigel plug assays (3-5). Current in vitro angiogenesis assays are generally focused on specific behaviors of monocultured endothelial cells (EC) (e.g., migration, proliferation) and fail to model heterotypic perivascular interactions, whereas in vivo systems are not compatible ...

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Section: Ic 50 Calculationsmentioning

confidence: 99%

A novel imaging‐based high‐throughput screening approach to anti‐angiogenic drug discovery

et al. 2009

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“…To date, there is no consensus on the optimal protocol for the induction of corneal angiogenesis in rats 10 . The implantation of pellets containing drugs or pro-angiogenic molecules are emerging in the literature as reliable strategies.…”

Section: ■ Discussionmentioning

confidence: 99%

“…The reproducibility of corneal cauterization protocols using alkali remains controversial. While in some studies, alkaline cauterization appears to be very effective in the induction of corneal neovascularization, in others, the lack of reproducibility in the vascular response represented a limiting factor for the validation of the results 10 .…”

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Corneal angiogenesis based on different protocols of alkaline cauterization in murine models

et al. 2017

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Purpose: To establish and compare protocols of alkaline cauterization for inducing corneal angiogenesis in murine models. Methods: Twenty-four adult Wistar rats were distributed into four groups (G1, G2, G3, and G4). The right eye cornea from each rat was cauterized using filter paper (3 mm), soaked in a solution of silver and potassium nitrates (3:1). Cauterization times were 10 (G1 and G4), or 20 seconds (G2 and G3). Cauterized corneas were washed with Ringer's lactate solution. The filter paper was either removed before washing (G1 and G2), or kept on the corneas (G3 and G4). Corneas were photographed at multiple time points (2, 4, 6, 8, 11, 13, and 15 days after the procedure), and neovascularization parameters were assayed. Results: Neovascularization was observed in 66% of G1 corneas, and 100% of G2, G3, and G4 corneas. On day 15, G1 corneas showed smaller vascularized areas (12.63 ± 12.59%) compared to those in the G3 (41.95 ± 17.32%) and G4 (33 ± 11.74%) (P < 0.05) groups. Conclusions: The silver and potassium nitrate solution effectively induced corneal angiogenesis. The G2, G3, and G4 protocols showed excellent reproducibility, and induced vascularization in 100% of corneas.

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“…Animal models of angiogenesis were reported earlier, but those presently available have many important shortcomings (11). An ideal model should be reproducible and allow discrimination between preexisting and newly formed vessels to provide conclusions about angiogenesis.…”

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confidence: 99%

Ultrahigh‐field DCE‐MRI of angiogenesis in a novel angiogenesis mouse model

Wittenborn

Nielsen

Nygaard

et al. 2011

Magnetic Resonance Imaging

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Purpose: To be able to screen and identify potential candidate agents for noninvasive imaging of diseases involving angiogenesis, a standardized in vivo angiogenesis model is needed. Angiogenesis is a common feature of many pathological conditions and has become an important target for diagnosis and treatment, with many noninvasive imaging agents emerging. Materials and Methods:Uniform scaffolds consisting of porous and flexible polycaprolactone were implanted subcutaneously in mice and studied after 1 to 6 weeks to describe the time course of angiogenesis. The model was characterized by histology and dynamic contrastenhanced magnetic resonance imaging (DCE-MRI).Results: Microscopic examination revealed progressive ingrowth of new vessels from the periphery, leading to a fully vascularized scaffold within 6 weeks. Blood flow through the new vessels, assessed by DCE-MRI, revealed peripheral vascularization corresponding to 12.3% (SD 6.1%) of scaffold area at week 1 and a more uniform and complete distribution of vessels corresponding to 84.1% (SD 16.2%) of scaffold area at week 4. Conclusion:In agreement with microscopic examination, noninvasive DCE-MRI visualized progressive development of new vessels in a novel and standardized murine angiogenesis model, making this model suitable for screening angiogenesis-related drugs and contrast agents.

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In vivo models of angiogenesis

Abstract: The process of building new blood vessels (angiogenesis) and controlling the propagation of blood vessels (anti-angiogenesis) are fundamental to human health, as they play key roles in wound healing and tissue growth. More than 500 million people may stand to benefit from anti-or

Cited by 253 publications

References 134 publications

A novel imaging‐based high‐throughput screening approach to anti‐angiogenic drug discovery

A novel imaging‐based high‐throughput screening approach to anti‐angiogenic drug discovery

Corneal angiogenesis based on different protocols of alkaline cauterization in murine models

Ultrahigh‐field DCE‐MRI of angiogenesis in a novel angiogenesis mouse model

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