Angiogenesis is critical to
wound repair due to its role in providing
oxygen and nutrients that are required to support the growth and function of reparative cells in damaged tissues.
Adenosine receptors are claimed to be of paramount importance in driving
wound angiogenesis by inducing
VEGF. However, the underlying mechanisms for the regulation of
adenosine receptors in
VEGF as well as eNOS remain poorly understood. In the present study, we found that
adenosine and the non-selective
adenosine receptor agonists (
NECA) induced tube formation in HMEC-1 in a dose-dependent manner.
Adenosine or
NECA (10 µmol/L) significantly augmented the number and length of the segments in comparison with the control. Simultaneously,
VEGF and eNOS were significantly upregulated following the administration of 10 µmol/L
NECA, while they were suppressed after A2B AR genetic silencing and pharmacological inhibition by
MRS1754. In addition,
VEGF expression and eNOS bioavailability elimination significantly reduced the formation of capillary-like structures. Furthermore, the activation of A2B AR by
NECA significantly increased the intracellular cAMP levels and concomitant CREB phosphorylation, eventually leading to the production of
VEGF in HMEC-1. However, the activated PKA-CREB pathway seemed to be invalidated in the induction of eNOS. Moreover, we found that the elicited PI3K/AKT signaling in response to the induction of
NECA assisted in regulating eNOS but failed to impact on
VEGF generation. In conclusion, the A2B AR activation-driven angiogenesis via cAMP-PKA-CREB mediated
VEGF production and PI3K/AKT-dependent upregulation of eNOS in HMEC-1.