Non-nuclear estrogen receptor alpha signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice
- Ken L Chambliss 1, Qian Wu , Sarah Oltmann , Eddy S Konaniah , Michihisa Umetani , Kenneth S Korach , Gail D Thomas , Chieko Mineo , Ivan S Yuhanna , Sung Hoon Kim , Zeynep Madak-Erdogan , Adriana Maggi , Sean P Dineen , Christina L Roland , David Y Hui , Rolf A Brekken , John A Katzenellenbogen , Benita S Katzenellenbogen , Philip W Shaul
- 1Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063, USA.
- 0Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063, USA.
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View abstract on PubMed
Summary
This summary is machine-generated.An estrogen-dendrimer conjugate (EDC) activates non-nuclear estrogen receptors (ERs) to promote cardiovascular protection. This selective ER modulator offers vascular benefits without increasing cancer risk.
Area Of Science
- Endocrinology
- Cardiovascular Biology
- Molecular Pharmacology
Background
- Steroid hormone receptors, including estrogen receptors (ERs), classically act as nuclear transcription factors.
- Emerging evidence suggests non-nuclear ER subpopulations mediate membrane-initiated signaling with incompletely understood mechanisms.
- The significance of non-nuclear ER signaling in physiological and pathological processes remains an active area of investigation.
Purpose Of The Study
- To investigate the role of non-nuclear estrogen receptor signaling in endothelial cells.
- To determine if an estrogen-dendrimer conjugate (EDC), excluded from the nucleus, can selectively target non-nuclear ER pathways.
- To evaluate the therapeutic potential of non-nuclear ER activation for cardiovascular protection without promoting cancer.
Main Methods
- Utilized an estrogen-dendrimer conjugate (EDC) designed to exclude from the nucleus.
- Assessed endothelial cell proliferation, migration, and endothelial nitric oxide synthase (eNOS) activation.
- Employed mouse models with reporter genes, analyzed uterine ER-regulated gene expression, and evaluated carotid artery reendothelialization and neointimal hyperplasia.
- Compared the effects of estradiol and EDC on cancer cell growth in vitro and xenograft growth in vivo.
Main Results
- EDC stimulated endothelial cell proliferation and migration via ERalpha, G protein interaction, and eNOS activation, independent of nuclear entry.
- In vivo studies confirmed EDC targeted non-nuclear processes, promoting carotid artery reendothelialization and attenuating neointimal hyperplasia.
- Estradiol stimulated endometrial and breast cancer cell growth, whereas EDC did not, establishing EDC as a non-nuclear selective ER modulator (SERM).
Conclusions
- Non-nuclear estrogen receptor signaling, activated by EDC, promotes cardiovascular protection in mice.
- Non-nuclear selective ER modulation offers a potential strategy for vascular benefit without the oncogenic risks associated with traditional estrogen therapy.
- These findings highlight the distinct roles of nuclear and non-nuclear ER signaling pathways and their therapeutic implications.
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