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

Nicosia RF - J. Cell. Mol. Med. (2009)

Bottom Line: Many factors have contributed to its popularity including reproducibility, cost effectiveness, ease of use and good correlation with in vivo studies.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.

View Article: PubMed Central - PubMed

Affiliation: Pathology and Laboratory Medicine Services, Veterans Administration Puget Sound Health Care System, Seattle, WA 98108, USA. roberto.nicosia@va.gov

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

The aortic ring model has been extensively used to test the activity of angiogenic regulators. This drawing lists many of the stimulators and inhibitors of aortic angiogenesis that have been reported to date. Note: ECM molecules such as laminin and type IV collagen have the capacity to promote angiogenesis, but become inhibitory at concentrations comparable to those found in mature basement membranes. Netrin-1 has been reported to inhibit or stimulate angiogenesis by different groups. PAI-1 inhibits angiogenesis when administered to aortic cultures at high dose but it is also required for vessel growth because angiogenesis is impaired in cultures of PAI-1 deficient mouse aortas.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4496118&req=5

fig07: The aortic ring model has been extensively used to test the activity of angiogenic regulators. This drawing lists many of the stimulators and inhibitors of aortic angiogenesis that have been reported to date. Note: ECM molecules such as laminin and type IV collagen have the capacity to promote angiogenesis, but become inhibitory at concentrations comparable to those found in mature basement membranes. Netrin-1 has been reported to inhibit or stimulate angiogenesis by different groups. PAI-1 inhibits angiogenesis when administered to aortic cultures at high dose but it is also required for vessel growth because angiogenesis is impaired in cultures of PAI-1 deficient mouse aortas.

Mentions: More than a quarter century after we first reported that explants of rat aorta have the capacity to generate vessels ex vivo[170] the aortic ring model has become one the most commonly used assays of angiogenesis. Many factors have contributed to its popularity including reproducibility, cost effectiveness, ease of use and good correlation with in vivo studies. An important milestone in the establishment of this model was the discovery that endothelial sprouting from the aortic explants does not require serum or exogenous growth factors and is driven by endogenous mechanisms triggered by the injury of the dissection procedure [112, 168]. This fundamental observation has enabled investigators to analyse mechanisms of angiogenesis in a chemically defined culture environment in which native macrophages, dendritic cells, fibroblasts, pericytes and endothelial cells interact through paracrine and juxtacrine mechanisms comparable to those operating in the live animal. The relative ease with which the soluble and solid phases of the culture system can be modified has facilitated the molecular analysis of specific steps of the angiogenic process from the induction of endothelial sprouting to the recruitment of pericytes and the reabsorption (regression) of the newly formed vasculature. These studies have helped define the role in angiogenesis of many growth factors, inflammatory cytokines and chemokines, axonal guidance molecules, tyrosine kinase receptors, integrin receptors, ECM molecules, MMPs, as well signal transduction pathways and transcription factors (Fig. 7). Co-cultures of aortic rings with different cell types have provided novel insights on the angiogenic role of fibroblasts, smooth muscle cells, macrophages, platelets and cancer cells [28, 70, 168, 174, 231, 232]. The self-limited nature of the angiogenic process and the induction of angiogenic quiescence have facilitated the analysis of the angiogenic cascade from its earliest inductive events to its final resolution through vascular regression. Studies with aortic rings from young and old animals and different animal strains have demonstrated that the angiogenic process is greatly influenced by age and genetic background. The adaptation of the aortic ring model to different species and vessel types has broadened its use to genetically modified mice and human beings. Finally the development of methods to virally transduce the aortic rings has facilitated the study of genes involved in the regulation of the angiogenic process.


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

Nicosia RF - J. Cell. Mol. Med. (2009)

The aortic ring model has been extensively used to test the activity of angiogenic regulators. This drawing lists many of the stimulators and inhibitors of aortic angiogenesis that have been reported to date. Note: ECM molecules such as laminin and type IV collagen have the capacity to promote angiogenesis, but become inhibitory at concentrations comparable to those found in mature basement membranes. Netrin-1 has been reported to inhibit or stimulate angiogenesis by different groups. PAI-1 inhibits angiogenesis when administered to aortic cultures at high dose but it is also required for vessel growth because angiogenesis is impaired in cultures of PAI-1 deficient mouse aortas.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4496118&req=5

fig07: The aortic ring model has been extensively used to test the activity of angiogenic regulators. This drawing lists many of the stimulators and inhibitors of aortic angiogenesis that have been reported to date. Note: ECM molecules such as laminin and type IV collagen have the capacity to promote angiogenesis, but become inhibitory at concentrations comparable to those found in mature basement membranes. Netrin-1 has been reported to inhibit or stimulate angiogenesis by different groups. PAI-1 inhibits angiogenesis when administered to aortic cultures at high dose but it is also required for vessel growth because angiogenesis is impaired in cultures of PAI-1 deficient mouse aortas.
Mentions: More than a quarter century after we first reported that explants of rat aorta have the capacity to generate vessels ex vivo[170] the aortic ring model has become one the most commonly used assays of angiogenesis. Many factors have contributed to its popularity including reproducibility, cost effectiveness, ease of use and good correlation with in vivo studies. An important milestone in the establishment of this model was the discovery that endothelial sprouting from the aortic explants does not require serum or exogenous growth factors and is driven by endogenous mechanisms triggered by the injury of the dissection procedure [112, 168]. This fundamental observation has enabled investigators to analyse mechanisms of angiogenesis in a chemically defined culture environment in which native macrophages, dendritic cells, fibroblasts, pericytes and endothelial cells interact through paracrine and juxtacrine mechanisms comparable to those operating in the live animal. The relative ease with which the soluble and solid phases of the culture system can be modified has facilitated the molecular analysis of specific steps of the angiogenic process from the induction of endothelial sprouting to the recruitment of pericytes and the reabsorption (regression) of the newly formed vasculature. These studies have helped define the role in angiogenesis of many growth factors, inflammatory cytokines and chemokines, axonal guidance molecules, tyrosine kinase receptors, integrin receptors, ECM molecules, MMPs, as well signal transduction pathways and transcription factors (Fig. 7). Co-cultures of aortic rings with different cell types have provided novel insights on the angiogenic role of fibroblasts, smooth muscle cells, macrophages, platelets and cancer cells [28, 70, 168, 174, 231, 232]. The self-limited nature of the angiogenic process and the induction of angiogenic quiescence have facilitated the analysis of the angiogenic cascade from its earliest inductive events to its final resolution through vascular regression. Studies with aortic rings from young and old animals and different animal strains have demonstrated that the angiogenic process is greatly influenced by age and genetic background. The adaptation of the aortic ring model to different species and vessel types has broadened its use to genetically modified mice and human beings. Finally the development of methods to virally transduce the aortic rings has facilitated the study of genes involved in the regulation of the angiogenic process.

Bottom Line: Many factors have contributed to its popularity including reproducibility, cost effectiveness, ease of use and good correlation with in vivo studies.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.

View Article: PubMed Central - PubMed

Affiliation: Pathology and Laboratory Medicine Services, Veterans Administration Puget Sound Health Care System, Seattle, WA 98108, USA. roberto.nicosia@va.gov

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus