Abstract
New models of angiogenesis that mimic the complexity of real microvascular networks are needed. Recently, our laboratory demonstrated that cultured rat mesentery tissues contain viable microvascular networks and could be used to probe pericyte-endothelial cell interactions. The objective of this study was to demonstrate the efficacy of the rat mesentery culture model for anti-angiogenic drug testing by time-lapse quantification of network growth. Mesenteric windows were harvested from adult rats, secured in place with an insert, and cultured for 3 days according to 3 experimental groups: 1) 10% serum (angiogenesis control), 2) 10% serum + sunitinib (SU11248), and 3) 10% serum + bevacizumab. Labeling with FITC conjugated BSI-lectin on Day 0 and 3 identified endothelial cells along blood and lymphatic microvascular networks. Comparison between day 0 (before) and 3 (after) in networks stimulated by 10% serum demonstrated a dramatic increase in vascular density and capillary sprouting. Growing networks contained proliferating endothelial cells and NG2+ vascular pericytes. Media supplementation with sunitinib (SU11248) or bevacizumab both inhibited the network angiogenic responses. The comparison of the same networks before and after treatment enabled the identification of tissue specific responses. Our results establish, for the first time, the ability to evaluate an anti-angiogenic drug based on time-lapse imaging on an intact microvascular network in an ex vivo scenario.
Highlights
Models that mimic angiogenesis, defined as the growth of new blood vessels from existing vessels, are extremely valuable for the investigation of underlying mechanisms and the pre-clinical development of therapies
Consistent with our previous characterization of the model, angiogenic networks at day 3 contained NG2-positive pericytes along the microvessels confirming that vascular pericytes remain present along endothelial cells during angiogenesis after ex vivo culture (Fig. 3 A-C)
The results of this study support the use of the rat mesentery culture model as an ex vivo tool for anti-angiogenic drug evaluation on intact microvascular networks based on time-lapse doi:10.1371/journal.pone.0119227.g001
Summary
Models that mimic angiogenesis, defined as the growth of new blood vessels from existing vessels, are extremely valuable for the investigation of underlying mechanisms and the pre-clinical development of therapies. Ex Vivo Model for Anti-Angiogenic Drug Testing microvascular scenario, i.e., cells, vessels and network, has motivated the development of three-dimensional culture systems [1], ex vivo tissue explant models [2], microfluidic platforms [3,4], and the use of integrated computational approaches [5]. Since angiogenesis involves multiple cell types and is related to the growth of other systems, such as lymphatic networks [6,7], a need still exists for a model of angiogenesis from intact microvascular networks that more closely reflects an in vivo scenario
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