Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 641, Issue 2-3, Pages 168-178Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2010.05.020
Keywords
Heart; Estrogen; Estrogen receptors; VEGF and its signaling cascade; Coronary capillary density; Apoptosis
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [18300215, 18650186, 1705488, 21249086]
- Japan Society for the Promotion of Science [21300234]
- Kanzawa Medical Research Foundation (Japan)
- Grants-in-Aid for Scientific Research [21249086, 18650186] Funding Source: KAKEN
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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 (ER alpha-KO), and estrogen receptor beta knockout (ER beta-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 ER alpha-KO mice were reduced to half of WT, in contrast to ER beta-KO mice that only showed a slight decrease. Moreover, activity of eNOS was greatly lowered in ER alpha-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. (C) 2010 Elsevier B.V. All rights reserved.
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