title: Estrogen receptor alpha and beta are both involved in the cerebral VEGF/Akt/NO pathway and cerebral angiogenesis in female mice.
abstract: We have previously demonstrated that vascular endothelial growth factor (VEGF) is critical for cerebral angiogenesis in middle-aged female rats and may play a role in the flow-preserving neuroprotective actions of estrogen through its angiogenic and antiapoptotic properties. Here, we attempt to elucidate the effects of estrogen and the specific estrogen receptor (ER) subtype in cerebral VEGF/Akt/NO pathways and cerebral angiogenesis using 15-week old female mice that are either wild-type (WT), lack estrogen receptor α (ERαKO) or β (ERβKO). Protein levels of VEGF and basic signaling molecules of VEGF angiogenic pathway in the frontal cortex were expressed as follows, as revealed by ELISA and immunoblotting : a) VEGF; WT: ERαKO: ERβKO, 47 ± 15: 27 ± 5: 28 ± 5 pg/mg, respectively (P < 0.01); b) KDR decreased about 40% in both ERαKO and ERβKO compared to WT; c) Akt was significantly down-regulated in both ERαKO and ERβKO compared to WT; d) phosphorylated Akt (pAkt); WT: ERαKO: ERβKO, 0.6 ± 0.2: 0.3 ± 0.01: 0.3 ± 0.1 units/mg, respectively; e) phosphorylated eNOS significantly decreased about 45% in both ERαKO and ERβKO compared to WT. Cerebral capillary density decreased in both ERαKO and ERβKO compared to WT. Thus, it can be concluded that in female mice, VEGF/Akt/eNOS pathway plays an important role in cerebral angiogenesis and that both ER subtypes are involved in the regulation of VEGF and its signaling molecule expression in the frontal cortex.
authors.affiliation: Division of Gene Therapeutics, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, Japan. jsubrina@gmail.com
authors.forename: Subrina
authors.initials: S
authors.lastname: Jesmin
authors.forename: Chishimba N
authors.initials: CN
authors.lastname: Mowa
authors.forename: Sayeeda Nusrat
authors.initials: SN
authors.lastname: Sultana
authors.forename: Sohag
authors.initials: S
authors.lastname: Mia
authors.forename: Reazul
authors.initials: R
authors.lastname: Islam
authors.forename: Sohel
authors.initials: S
authors.lastname: Zaedi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sakuma
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
authors.forename: Michiaki
authors.initials: M
authors.lastname: Hiroe
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D001927:Brain Diseases / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism; D002540:Cerebral Cortex / Q000098:blood supply; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D007178:Inbreeding; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt