NHLBI Working Group
Blood Vessel Maturation: Arteriogenesis
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
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
- 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
- Patricia A. DAmore, 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