The aortic ring model of angiogenesis: a quarter century of search and discovery.

• Introduction - Early history of the aortic ring model - Morphology of the angiogenic response - Source of microvessels in aortic cultures - Stimulatory effect of angiogenesis on cancer spread - Regulation of angiogenesis by the extracellular matrix - Role of integrin receptors in aortic angiogenesis - Paracrine regulation of angiogenesis: role of endogenous growth factors - Paracrine regulation of angiogenesis: role of resident macrophages and inflammatory cytokines and chemokines - Expression and function of neural related genes - Signal transduction pathways - Pericyte origin and recruitment mechanisms - Role of proteolytic enzymes in angiogenesis and vascular regression - Influence of genetic background and aging on angiogenic response - Adaptation of the aortic ring model to different species and vessel types - Limitations of the aortic ring assay • Summary and conclusion The aortic ring model has become one of the most widely used methods to study angiogenesis and its mechanisms. Many factors have contributed to its popularity including reproducibility, cost effectiveness, ease of use and good correlation with in vivo studies. In this system aortic rings embedded in biomatrix gels and cultured under chemically defined conditions generate arborizing vascular outgrowths which can be stimulated or inhibited with angiogenic regulators. Originally based on the rat aorta, the aortic ring model was later adapted to the mouse for the evaluation of specific molecular alterations in genetically modified animals. Viral transduction of the aortic rings has enabled investigators to overexpress genes of interest in the aortic cultures. Experiments on angiogenic mechanisms have demonstrated that formation of neovessels in aortic cultures is regulated by macrophages, pericytes and fibroblasts through a complex molecular cascade involving growth factors, inflammatory cytokines, axonal guidance cues, extracellular matrix (ECM) molecules and matrix-degrading proteolytic enzymes. These studies have shown that endothelial sprouting can be effectively blocked by depleting the aortic explants of macrophages or by interfering with the angiogenic cascade at multiple levels including growth factor signalling, cell adhesion and proteolytic degradation of the ECM. In this paper, we review the literature in this field and retrace the journey from our first morphological descriptions of the aortic outgrowths to the latest breakthroughs in the cellular and molecular regulation of aortic vessel growth and regression. [ABSTRACT FROM AUTHOR]