Mast-cell-mediated angiogenesis: a novel experimental model using the rat mesentery

VEGF165b, an Inhibitory Vascular Endothelial Growth Factor Splice Variant

“…The diameter and length of each vessel were measured. Branch point density, sprout density, and proliferating endothelial cell density were calculated as the number per unit area within five randomly selected fields of view (ϫ40 objective) containing vessels as described previously (31).…”

Rat Mesentery Angiogenesis Assay

“…The assay was introduced in 1986 3 and has successively been further developed and refined in our laboratory 7,[10][11][12] . As discussed in review papers (invited) 1,2 , the assay compares well with other mammalian in vivo angiogenesis assay in regard particularly to important features such as the adult test tissue is natively vascularized and lacks physiologic angiogenesis; minimal trauma, if any, is inflicted upon the tissue; truly quantitative variables are measured, which allows sound statistical analysis regarding dose-response and molecular-activity studies; sprouting angiogenesis occurs, which is predominating in normal tissues and tumors; and toxicity data are easily accumulated in rats that grow robustly physiologically in adulthood.…”

“…treatment with modifying agents of choice. Each membranous part of the mesentery is translucent and framed by fatty tissue, giving it a window-like appearance.The assay has the following advantageous features: (i) the test tissue is natively vascularized, albeit sparsely, and since it is extremely thin, the microvessel network is virtually two-dimensional, which allows the entire network to be assessed microscopically in situ; (ii) in adult rats the test tissue lacks significant physiologic angiogenesis, which characterizes most normal adult mammalian tissues; the degree of native vascularization is, however, correlated with age, as discussed in 1 ; (iii) the negligible level of trauma-induced angiogenesis ensures high sensitivity; (iv) the assay replicates the clinical situation, as the angiogenesis-modulating test drugs are administered systemically and the responses observed reflect the net effect of all the metabolic, cellular, and molecular alterations induced by the treatment; (v) the assay allows assessments of objective, quantitative, unbiased variables of microvascular spatial extension, density, and network pattern formation, as well as of capillary sprouting, thereby enabling robust statistical analyses of the dose-effect and molecular structure-activity relationships; and (vi) the assay reveals with high sensitivity the toxic or harmful effects of treatments in terms of decreased rate of physiologic body-weight gain, as adult rats grow robustly.Mast-cell-mediated angiogenesis was first demonstrated using this assay 3,4 . The model demonstrates a high level of discrimination regarding dosage-effect relationships and the measured effects of systemically administered chemically or functionally closely related drugs and proteins, including: (i) low-dosage, metronomically administered standard chemotherapeutics that yield diverse, drug-specific effects (i.e., angiogenesissuppressive, neutral or angiogenesis-stimulating activities 5 ); (ii) natural iron-unsaturated human lactoferrin, which stimulates VEGF-A-mediated angiogenesis 6 , and natural iron-unsaturated bovine lactoferrin, which inhibits VEGF-A-mediated angiogenesis 7 ; and (iii) low-molecular-weight heparin fractions produced by various means 8,9 .…”

“…Mast-cell-mediated angiogenesis was first demonstrated using this assay 3,4 . The model demonstrates a high level of discrimination regarding dosage-effect relationships and the measured effects of systemically administered chemically or functionally closely related drugs and proteins, including: (i) low-dosage, metronomically administered standard chemotherapeutics that yield diverse, drug-specific effects (i.e., angiogenesissuppressive, neutral or angiogenesis-stimulating activities 5 ); (ii) natural iron-unsaturated human lactoferrin, which stimulates VEGF-A-mediated angiogenesis 6 , and natural iron-unsaturated bovine lactoferrin, which inhibits VEGF-A-mediated angiogenesis 7 ; and (iii) low-molecular-weight heparin fractions produced by various means 8,9 .…”

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

“…Many existing angiogenesis models fell short in this regard as their site of angiogenesis was difficult to distinguish from already existing vessels on noninvasive imaging modalities (19)(20)(21). Harvesting of tissue for histology was also difficult in these models, making them less favorable as animal models for our purpose.…”