In Vivo and in Vitro Studies of Progesterone-Induced Anti-Angiogenesis

The cardiovascular protection effects of female sex hormones have been documented. For instance, it has been reported that female sex hormones can protect the development of atherosclerosis and subarachnoid hemorrhage-induced cerebral vasospasm. However, the effects of sex hormones on angiogenesis are still not clear. Angiogenesis, the formation of new blood vessels as extensions of existing vessels, is essential for many physiological processes and important in the pathogenesis of many disorders. Normally, vascular proliferation occurs only during embryonic development, the female reproductive cycle and wound healing. By contrast, many pathological conditions (eg, atherosclerosis, diabetic retinopathy and cancer) are characterized by persistent, unregulated angiogenesis. Control of vascular development could permit new therapeutic approaches to these disorders. Lately, angiogenesis has become an important research subject. It has been well documented that estrogen can stimulate angiogenesis. As for progesterone, however, there has been little information about an angiogenic or anti-angiogenic effect. Our previous studies have shown that progesterone could inhibit endothelial cell proliferation through increase of p53, which in turn up-regulate p21 and p27 expression, subsequently inhibit the CDK2 activity, and finally interrupt the progress of cell cycle (Hsu et al., 2008). To delineate the molecular mechanisms underlying progesterone-induced up-regulation of p53 expression, we further demonstrated that the cSrc/Kras/Raf-1/Erk2/NF-B signaling pathway contributes to the progesterone-induced up-regulation of p53 in vascular endothelial cells (Hsu et al., 2010). This proposed project is the extension of our previous findings. Once the effects of sex hormones on angiogenesis have been established, we will further investigate the molecular mechanisms underlying. The findings of these studies will help us getting inside how female sex hormones regulate the angiogenesis in endometrium and ovary during menstrual cycle and influence the tumor development.