title: VEGF signaling is disrupted in the hearts of mice lacking estrogen receptor alpha.
abstract: Estrogen has widely been credited for cardioprotection in women. However, the exact mechanisms that underlie these beneficial estrogenic effects are not completely understood. Here, we sought to: 1) elucidate estrogen's influence on levels of vascular endothelial growth factor (VEGF), a key regulator of cardiovascular processes, and components of its basic signaling machinery (VEGF receptors, Akt, and eNOS) in the heart, and 2) delineate the specific estrogen receptor signaling pathway that mediates its beneficial effects using mice lacking either estrogen receptor alpha or estrogen receptor beta. We analyzed pattern of VEGF signaling and the associated coronary capillary density in the hearts of wild-type (WT), estrogen receptor alpha knockout (ERalpha-KO), and estrogen receptor beta knockout (ERbeta-KO) female mice. Deletion of estrogen receptor alpha causes a marked decrease in coronary capillary density compared to wild-type (WT) mice, while that of estrogen receptor beta had a minimal effect. Consistent with reduced coronary capillary density, cardiac expression levels of VEGF and its signaling molecules (two receptors, phosphorylated Akt, and eNOS) in ERalpha-KO mice were reduced to half of WT, in contrast to ERbeta-KO mice that only showed a slight decrease. Moreover, activity of eNOS was greatly lowered in ERalpha-KO mice. These data suggest that estrogen acts largely via estrogen receptor alpha to regulate VEGF transcription and possibly components of its basic signaling and ultimately, the development of coronary microvasculature in the heart. This molecular and histological data, in part, sheds some insights into potential mechanisms that may likely underlie estrogen's cardioprotective effects.
authors.affiliation: Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, 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: Nobutake
authors.initials: N
authors.lastname: Shimojo
authors.forename: Hiroko
authors.initials: H
authors.lastname: Togashi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Iwashima
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kato
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sakuma
authors.forename: Michiaki
authors.initials: M
authors.lastname: Hiroe
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D047628:Estrogen Receptor alpha / Q000378:metabolism / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt