dcyphr | P2y Receptor-Mediated Angiogenesis via Vascular Endothelial Growth Factor Receptor 2 Signaling


Both disease causing and healthy angiogenesis are regulated by nucleotides and Vascular Endothelial Growth Factor (VEGF). The activated P2Y nucleotide receptors (P2YR) can interact with VEGF Receptor 2 (VEGFR2). This tells us that the P2YR may mediate VEGFR, called P2YR-VEGFR2 signaling. Inhibiting P2YR can increase angiogenesis in endothelial cells. But treating the cells with a VEGFR2 inhibitor lowered the levels of angiogenesis back to the baseline before P2YR was inhibited. The findings of this study lead researchers to believe that the P2RY-VEGFR2 signaling is important for both disease causing and healthy angiogenesis.


Nucleoside diphosphate kinase (NDPK) may have a role in cancer and tumor angiogenesis. The researchers of this lab recently published another study showing that angiogenesis could be regulated by a cancer that secreted NDPK. Activated P2YR have been shown to interact with VEGFR2. This shows that there is a direct link to nucleotide regulation outside of the cell, to the regulation of tumor angiogenesis. P2YR-VEGFR2 signaling may be important for outlining nucleotides in angiogenesis signaling, like ATP.

The researchers hypothesize that P2YR activation uses VEGFR2 to increase angiogenesis, and cancer uses NDPK to exploit this pathway and obtain a blood supply.

An antibody that binds to VEGF and stops its function is approved for the treatment of many types of cancer. This is due to the role of VEGF in angiogenesis. VEGFR2 regulates and increases the angiogenic effects of VEGF. Also, VEGFR2 and P2YR are known to be located on the surface of endothelial cells, meaning they are in close proximity and are likely to be involved in the same angiogenesis signaling pathway. This study provides evidence that P2YR interacts with VEGFR2 to increase endothelial capillary like tube formation, or tubulogenesis, in the lab setting.

Materials and Methods

This study used a tissue culture of human cardiac endothelial cells. Tubulogenesis and angiogenesis were determined by the number of branch points, length, and cell surface area of the sample. 

Results and Discussion

The cells treated with the P2YR1 and P2YR1/2 inhibitors showed 1.9 and 1.5 times higher angiogenesis than the control samples. The addition of the VEGFR2 kinase inhibitor to the samples returned the angiogenesis levels back to control levels. The positive control sample had 2.4 times higher angiogenesis than the negative control.

These results, combined with the results of the previous studies done by this research team, directly linking VEGFR2 signaling to cancer secreted NDPK and angiogenesis. The P2YR tubulogenesis was consistent with previous findings. These results suggest that VEGFR2 cell signaling plays a role in P2YR regulated angiogenesis.

This study allows the research team to expand their previous study. Their hypothesis says that cancer cells exploit the P2YR-VEGFR2 signaling pathway by secreting NDPK and increasing angiogenesis. The P2YR-VEGFR2 signaling pathway may also help us understand angiogenesis and vessel formation in both tumors and healthy vasculature.