Bidirectional regulation of angiogenesis by phytoestrogens through estrogen receptor-mediated signaling networks.
Sex hormone estrogen is one of the most active intrinsic angiogenesis regulators; its therapeutic use has been limited due to its carcinogenic potential. Plant-derived phytoestrogens are attractive alternatives, but reports on their angiogenic activities often lack in-depth analysis and sometimes are controversial. Herein, we report a data-mining study with the existing literature, using IPA system to classify and characterize phytoestrogens based on their angiogenic properties and pharmacological consequences. We found that pro-angiogenic phytoestrogens functioned predominantly as cardiovascular protectors whereas anti-angiogenic phytoestrogens played a role in cancer prevention and therapy. This bidirectional regulation were shown to be target-selective and, for the most part, estrogen-receptor-dependent. The transactivation properties of ERα and ERβ by phytoestrogens were examined in the context of angiogenesis-related gene transcription. ERα and ERβ were shown to signal in opposite ways when complexed with the phytoestrogen for bidirectional regulation of angiogenesis. With ERα, phytoestrogen activated or inhibited transcription of some angiogenesis-related genes, resulting in the promotion of angiogenesis, whereas, with ERβ, phytoestrogen regulated transcription of angiogenesis-related genes, resulting in inhibition of angiogenesis. Therefore, the selectivity of phytoestrogen to ERα and ERβ may be critical in the balance of pro- or anti-angiogenesis process.
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300457, China; Research and Development Center of Traditional Chinese Medicine, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, China.
Hai-Xin
HX
Liu
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300457, China; Research and Development Center of Traditional Chinese Medicine, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, China.
Yu
Y
Wang
Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington St. Boston, MA 02111, USA.
Qing
Q
Lu
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300457, China; Research and Development Center of Traditional Chinese Medicine, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, China.
Ming-Zhu
MZ
Yang
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300457, China.
Guan-Wei
GW
Fan
Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington St. Boston, MA 02111, USA.
Richard H
RH
Karas
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300457, China.
Xiu-Mei
XM
Gao
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300457, China; Research and Development Center of Traditional Chinese Medicine, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin 300457, China; Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington St. Boston, MA 02111, USA. Electronic address: yanzhu.harvard@gmail.com.
Yan
Y
Zhu
D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D048789:Phytoestrogens / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D048789:Phytoestrogens; D011960:Receptors, Estrogen
Bidirectional regulation of angiogenesis; ERα; ERβ; IPA; Phytoestrogen; Selective estrogen receptor modifies (SERMs)