September 21, 2005
The National Heart, Lung, and Blood Institute convened a Working Group of expert basic and clinical vascular biologists to discuss blood vessel maturation (arteriogenesis) on September 21, 2005, in Bethesda, Maryland. Their goal was to assess the state of knowledge in this field, identify gaps in our understanding (including the barriers that impede progress and novel approaches to overcome these barriers), and to provide the NHLBI with a list of recommendations for future research activities.
The working group determined that our knowledge of the chemical factors and physical forces that initiate arteriogenesis is limited compared to our understanding of the factors that initiate the angiogenic process. Arteriogenesis involves the laying down of the different layers that constitute the wall of the blood vessel, the elaboration of the extracellular matrix, and the intra- and extra-cellular signals that initiate and promote this complex stage of blood vessel development. It has not been operationally defined, which has confounded this area of investigation because the scientific community uses arteriogenesis, arterialization, and collaterization interchangeably, even though each of these may be different processes not only during development, but also in the adult. Further, our understanding of the chemical mediators and other factors (such as inflammatory cells and hemodynamic forces) that initiate arteriogenesis is far from resolved and these mediators and factors need to be characterized during the different stages of arteriogenesis. Finally, it is uncertain if there is a distinct separation between angiogenesis and arteriogenesis, or if it is a continuum.
Arteriogenesis is complex and its onset and development may be affected by a number of factors: clinical (age, type, and severity of disease; and rapidity of onset), genetic (mutations in key pathways involved in arteriogenesis, as well as epigenetic factors), and systemic/local stimuli (the presence or absence of arteriogenesis/angiogenesis stimulators and inhibitors). The importance of the extracellular matrix is usually overlooked. It is a dynamic structure in that its phenotype is constantly changing during the course of vessel development. Further, the components of the extracellular matrix may act as signaling molecules, directing the differentiation of vascular cells during the development of the vessel wall.
The involvement of bone marrow-derived precursor cells in arteriogenesis is becoming more controversial since there is no conclusive evidence to show that these cells incorporate and expand within the vessel wall. High-resolution imaging suggests that these cells assume a perivascular location, where they may provide an important paracrine role by stimulating vessel remodeling.
Translating animal studies to the clinical setting is fraught with many difficulties due to a number of technical barriers that include: the type of animal model and its appropriateness (as representative of human disease), inter-animal variability regarding preexisting collateral flow (even in genetically identical animals), and the inter- and intra-variability of physiological measurements.
After comprehensive discussion, the working group made four recommendations:
- Elucidate the factors involved in regulation of the various steps of vessel wall assembly involved in arteriogenesis, including: the role of the extracellular matrix, inflammatory cells, shear stress, small molecules, growth factors, cytokines, cell-to-cell interactions, and intracellular signaling pathways.
- Determine the effect of risk factors (e.g., hypertension, diabetes, and hyperlipidemia) and disease (such as atherosclerosis) on vessel development, including their effects on the temporal changes in the expression of genes and gene products involved in the various stages of arteriogenesis.
- Investigate therapeutic approaches, such as cell-based and non-cell based therapies, to induce and/or stimulate vessel maturation and determine how the therapeutic approach is affected by aging, epigenetic factors, disease state, and risk factors.
- Develop reliable animal models that reflect human clinical phenotypes, novel methods, and biomarkers to study vessel maturation.
Possibility of a journal publication.
Stephen S. Goldman, Ph.D., NHLBI, NIH
Working Group Members
Chair: Timothy T. Hla, Ph.D. University of Connecticut Health Science Center
- Patricia A. D?Amore, Ph.D., Schepens Eye Research Institute
- Harold F. Dvorak, M.D., Beth Israel Deaconess Medical Center
- Stephen E. Epstein, M.D., Medstar Research Institute
- Robert P. Mecham, M.D. Ph.D., Washington University
- Louis M. Messina, M.D., University of California, San Francisco
- Gary K. Owens, Ph.D., University of Virginia School of Medicine
- William K. Sessa, Ph.D. Yale University School of Medicine
- Michael Simons, M.D. Dartmouth College School of Medicine
- Ronald L. Terjung, Ph.D., University of Missouri
Last updated: December 31, 2005