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Updated: Apr 25, 2026
An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Microvascular lesions by estrogen-induced ID3: its implications in cerebral and cardiorenal vascular disease
1Department of Environmental and Occupational Health, Florida International University, 11200 SW 8th Street, AHC-2 Bldg. Rm 593, Miami, FL, USA.
Abstract:
Severe symptoms of cerebral and cardiorenal vascular diseases can be triggered when cerebral, coronary, or glomerular arterioles grow inappropriately as a result of abnormal cell proliferation. The risk factor(s) and molecular mechanisms responsible for microvascular lesion formation are largely unknown. Although controversial, both animal and epidemiological studies have shown that estrogen increases the risk of stroke which may be due to microvascular lesions. Since microvascular diseases are characterized by excessive vessel growth, it is plausible that estrogen-induced neovascularization contributes to the growth of microvascular lesions. We present evidence for how ID3 overexpression in endothelial cells contributes to the development of an estrogen-induced neovascular phenotype with an additional focus on Pyk2 kinase. Our data showed that ID3 overexpression increased neovascularization, cell migration, and spheroid growth of human cerebral microvascular endothelial cells, hCMEC/D3. ID3-overexpressing cells showed significant estrogen-induced G2/M phase transition. Estrogen treatment increased both ID3 phosphorylation; total protein that was inhibited by tamoxifen, and Pyk2-mediated estrogen-induced ID3 mRNA expression. These findings suggest that Pyk2 signals ID3 expression and ID3 is necessary for estrogen-induced neovascularization in hCMEC/D3 cells. A better understanding of how microvascular lesions depend on ID3 may open new avenues for prevention and treatment of neurological diseases.
Insights
Estrogen may increase stroke risk by promoting abnormal blood vessel growth. This study shows Inhibitor of differentiation 3 (ID3) and Pyk2 kinase are key to estrogen-induced neovascularization in brain cells.
Area of Science:
- Vascular biology
- Molecular mechanisms of disease
- Endothelial cell function
Background:
- Cerebral and cardiorenal vascular diseases stem from abnormal arteriole growth.
- Estrogen's role in stroke risk is linked to microvascular lesions, but mechanisms are unclear.
- Neovascularization is a hallmark of microvascular disease, suggesting a role for estrogen-induced vessel growth.
Purpose of the Study:
- To investigate the role of Inhibitor of differentiation 3 (ID3) in estrogen-induced neovascularization.
- To explore the involvement of Pyk2 kinase in this process.
- To understand molecular mechanisms underlying estrogen's effect on cerebral microvascular endothelial cells.
Main Methods:
- Overexpression of ID3 in human cerebral microvascular endothelial cells (hCMEC/D3).
- Assessment of neovascularization, cell migration, and spheroid growth.
- Analysis of estrogen-induced cell cycle changes (G2/M phase transition).
- Investigation of ID3 phosphorylation and mRNA expression, and the role of Pyk2 and tamoxifen.
Main Results:
- ID3 overexpression enhanced neovascularization, migration, and spheroid growth in hCMEC/D3 cells.
- Estrogen induced G2/M phase transition in ID3-overexpressing cells.
- Estrogen increased ID3 phosphorylation and mRNA expression, mediated by Pyk2 kinase.
- Tamoxifen inhibited estrogen-induced ID3 phosphorylation.
Conclusions:
- Pyk2 kinase signaling is crucial for regulating ID3 expression.
- ID3 is essential for estrogen-induced neovascularization in hCMEC/D3 cells.
- Targeting ID3 may offer new therapeutic strategies for estrogen-related neurological diseases.
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