ABSTRACT
Nearly all of the non-classical pro-angiogenic factors modulate the expression of VEGF, VEGF receptors, or both in promoting angiogenesis. The question that has not been adequately addressed is whether there is crosstalk between pathways induced by different non-classical proangiogenic factors that may lead to enhanced or attenuated angiogenesis. For example, current data suggests that there is a reciprocal relationship
between NOS activity and VEGF expression. There is also limited studies that examined possible crosstalk between estrogen (and other steroid hormone), COX2 (and prostaglandins), NOS (NO) and VEGF pathways in mediating tumor angiogenesis. Kim and coworkers (Kim et al. 2008) have reported steroid receptor signaling through the activation of eNOS in endothelial cells. These researchers found estrogen receptor-46, a shortened isoform of estrogen receptor-a, which mediates rapid responses to estradiol by forming a complex with c-Src, PI3K, Akt and eNOS within caveolar membranes of endothelial cells leading to the activation of eNOS. This results in increase production of NO. Kimura and Esumi (Kimura and Esumi 2003) reported that some NO donors, other than SNP, was able to induce VEGF expression by stabilizing HIF-1 levels in tumor cell lines, independent from the cGMP pathway.
