Figure 6.

The proposed signaling pathway involved in VEGF₁₆₅ and flow/shear stress-induced dilations of retinal arterioles. Evidence from our studies provides support for ligand-dependent and ligand-independent activation of VEGFR2 in the endothelium mediating NO-dependent dilations of retinal arterioles in response to VEGF₁₆₅ and increased flow/shear stress, respectively. The activation of endothelial VEGFR2 leads to stimulation of PI3K and downstream link to calpain proteases and subsequent SIRT1-dependent deacetylation of NOS for NO production and arteriolar dilation. Bradykinin also can elicit a calpain/SIRT1-dependent vasodilator response, whereas resveratrol activates SIRT1 downstream from calpain leading to NO-mediated vasodilation. Blockade of the proposed signaling pathways by their respective inhibitors is indicated with vertical lines in reference to the direction of the arrows. AB, antibody.