Hypoxia-Inducible Factors and Adenosine Signaling in Vascular Growth - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 116

differential expression and function of adenosine receptor subtypes could contribute
to functional heterogeneity in different types of endothelia.
Our understanding on the role of adenosine and its receptors during embryonic
development is still not clear. Adenosine A 1 ,A 2A ,A 2B and A 3 receptor knock-
outs are not embryonically lethal and have normal survival. Among the adenosine
receptors the adenosine A 2B receptor is present largely in the vasculature. While
both A 2A and A 2B knockout mice exhibit increased proinflammatory responses, the
A 2B knockout mouse also exhibits increased leukocyte adhesion to the vasculature.
Interestingly, these receptors are regulated differently in mouse and humans. Unlike
in mice where adenosine A 2A receptor is not regulated by hypoxia and HIFs, this
receptor is regulated by hypoxia in rat derived PC12 cells and human pulmonary
endothelial cells [3]. It appears that these receptors may play a more important role
in postnatal vascular growth and vascular diseases during adult life. Additionally,
species-specific differences can also be important and relevant in understanding
vascular growth processes in disease and development.

7.7 Conclusions

In summary, hypoxia promotes vascular growth and proliferation, in part
through hypoxia-inducible transcription factors, adenosine and adenosine recep-
tors. Furthermore, part of the HIF-mediated vascular growth is mediated through
the adenosine signaling pathway where HIFs can modulate adenosine related recep-
tors and enzymes at multiple locations. These can have important implications
in tumor growth and other diseases involving vascular growth. Understanding
of these pathways will help us target them for therapeutic benefits in

diseases.

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