Our results demonstrate that enhanced somatostatinergic function at sst
2 limited the hypoxia-induced VEGF increase, whereas sst
2 loss upregulated this increase. Thus, sst
1-KO retinas were protected to some extent from hypoxia which, in contrast, had a more serious influence after sst
2 loss. An SRIF-induced regulation of VEGF has been suggested,
16 18 although there are also studies demonstrating that SRIF does not influence VEGF levels, as it does GH or IGF-1.
39 Our additional finding that sst
2 loss upregulated the hypoxia-induced increase of IGF-1R mRNA suggests the possibility that sst
2 may regulate VEGF expression through an increased expression of IGF-1R. In this respect, results from human RPE cells demonstrate that activation of sst
2 inhibits IGF-1R phosphorylation and the downstream VEGF synthesis.
16 Our finding that normoxic levels of IGF-1 mRNA were drastically decreased by sst
2 loss is difficult to explain, since activation of sst
2 is known to decrease IGF-1.
17 One possibility is that sst
2 loss causes excessive stimulation of IGF-1R which would in turn elicit feedback mechanisms to decrease IGF-1 expression. These mechanisms would be removed in hypoxia, as we observed that, in the absence of sst
2, IGF-1 mRNA expression was enhanced, and it reached levels that were comparable to those in WT or in sst
1-KO retinas. As also shown by our results, sst
2 levels appeared to influence the effects of hypoxia on the Ang/Tie system. Ang-1, acting on Tie-2, is known to promote vascular integrity and maturation, whereas Ang-2 is an antagonist of Ang-1 and promotes VEGF-induced proliferation of endothelial cells.
40 In addition, Tie-1 promotes structural integrity of endothelial cells.
41 We found that, after hypoxia, Ang-1, Tie-1, and Tie-2 mRNAs were decreased in the absence of sst
2, whereas Tie-1 mRNA was increased when sst
2 was overexpressed, as in sst
1-KO retinas. Together, these results add further evidence to the possibility that sst
2 may be beneficial in limiting hypoxia-induced neovascularization in the retina.