Hypoxia-Inducible Factors and Adenosine Signaling in Vascular Growth - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 115

A 2B receptor can be regulated by hypoxia in specific cell types. Cells expressing
either of these receptors may have differential sensitivities based, in part, on local
adenosine concentrations. Specifically, (a) adenosine A 2B receptor has a much lower
affinity for adenosine relative to the adenosine A 2A receptor and would likely be
activated in areas where adenosine concentrations are high, and (b) higher adeno-
sine concentrations, while activating A 2B receptor, can simultaneously desensitize
the high affinity A 2A receptor [57]. Thus, adenosine A 2A receptors would likely be
more important and active at lower adenosine concentrations. Consistent with this
hypothesis, constitutively high levels of adenosine were found to have an adverse
effect on lung growth and maturation. In a study using ADA − / − mice (adenosine
deaminase; ADA), global increases in adenosine levels were linked to abnormal
alveolar development [7]. Interestingly there were decreased A 2A receptor mRNA
levels in the ADA − / − mice compared to the control mice suggesting a likely role
for the A 2A receptor. Thus, optimal levels of adenosine, together with activation of
specific receptors like A 2A , are likely to be critical in supporting lung growth and
development .

7.6 Adenosine and Adenosine Receptors in Vascular Growth and
Development

Several studies have shown that adenosine and its analogs can promote endothelial
cell proliferation and migration [18, 22, 23, 30, 44, 47]. Adenosine and its analogues
can also promote angiogenesis in a number of models through upregulation of pro-
angiogenic cytokines. Adenosine can induce expression of VEGF in a number of
cell types including aortic smooth muscle cells [61], coronary artery smooth mus-
cle cells [32] and myocardial myoblasts [33]. Adenosine has also been shown to
increase expression of VEGF in chick embryo heart and skeletal muscle and also in
humans (reviewed in [2]). NECA, an adenosine analog and activator of adenosine
A 2A and A 2B receptor increased levels of VEGF in human retinal endothelial cells
[31], umbilical vein endothelial cells [26], skin microvascular endothelial cells [25]
mast cells [24], macrophages [35, 43] and retinal pericytes [71]. These effects are
predominantly mediated through the A 2B receptor and in some cases through the
A 2A receptor as well. Additionally, activation of A 3 receptor also increased expres-
sion of VEGF through a HIF-1 -dependent mechanism [48, 49]. Other than VEGF,

adenosine and its analogues have also been shown to increase expression of insulin-
like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), interleukin-8
(IL-8) and angiopoietin-2 (Ang-2) [31, 63, 64]. Thus multiple angiogenic path-
ways are regulated by adenosine and its analogues through activation of its
receptors.
In human dermal microvascular endothelial cells, activation of A 2B , but not
A 2A , receptor promotes angiogenesis [25]. By contrast, activation of A 2A , but not
A 2B , receptor promotes angiogenesis in human umbilical vein endothelial cells
and human lung microvascular endothelial cells (HLMVEC) [3, 16]. Therefore

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