Cardiovascular disease is the leading cause of death among women in the United States. Cardiovascular disease develops in women on average 10 years later than in men. This lag has been attributed, at least in part, to the protective effects of ovarian hormones, particularly estrogens (E2), before menopause. Studies of the vascular effects of E2 have yielded paradoxical findings: observational and animal studies carried out in young subjects have shown anti-inflammatory and vasoprotective effects of E2, while results of randomized controlled trials of menopausal hormones, such as the Women's Health Initiative, have shown no benefit and even harm of E2 treatment in elderly postmenopausal women, calling into question the concept of estrogenic vasoprotection. The leading explanation for these discrepant findings is the """"""""timing hypothesis"""""""", which proposes that E2 signaling pathways are altered in older women who have been deprived of endogenous E2 for many years such that anti-inflammatory/vasoprotective effects seen in pre-menopausal women are converted to proinflammatory/vasotoxic effects. C-reactive protein (CRP) is a widely accepted blood marker for risk of cardiovascular disease in women. We have utilized a unique transgenic mouse model (CRPtg) that expresses human CRP in the same manner as human subjects to demonstrate that CRP is a pathogenic mediator of cardiovascular disease and amplifies the inflammatory response to acute vascular injury. An intact complement system is required for the pro-inflammatory effect of CRP, which is mediated via its interaction with the immunoglobulin G Fc receptors (Fc?Rs) on monocytes/macrophages. CRP binds to Fc?RI on the surface of resident/recruited peri-adventitial macrophages, stimulating them to increase expression of C3, which accumulates and is available for activation by CRP. E2 administration to young ovariectomized CRPtg abolishes this CRP-mediated exacerbation of injury. Our exciting preliminary data reveal that E2, via ER?, inhibits CRP driven expression of inflammatory mediators, including C3, via regulation of Fc?Rs in macrophages in young ovariectomized mice. This response is lost and may be reversed with aging. This novel finding may help explain why E2 is vasoprotective in young animal models of cardiovascular disease and in young peri-menopausal women but carries increased risk of cardiovascular disease in older post-menopausal women who have been deprived from E2 for an extended period of time. The current study will test the novel hypothesis that E2 regulates CRP-induced inflammation in resident/recruited macrophages in the vessel wall in a bimodal manner that is dependent on age and hormonal status: E2 inhibits inflammation in younger women and mice in the presence of physiologic levels of circulating E2 in vivo but not in post-menopausal women and aged mice that had been subjected to extended periods of E2 deprivation.
Specific Aims are: 1) To test the hypothesis that E2, in an ER dependent manner, inhibits the vascular injury response in young female CRPtg mice via effects on monocytes/macrophages in vivo;2) To test the hypothesis that modulatory effects of E2 on human CRP-induced vascular inflammation/remodeling in CRPtg mice in vivo are dependent on age and E2 status;3) To test the hypothesis that modulatory effects of E2 on CRP-induced inflammation in human macrophages in vitro are dependent on the age and E2 status of the donor. Upon the successful completion of this research, cellular and molecular mechanisms responsible for the differential responsiveness to E2 of aged compared to young arteries will be elucidated. These fundamental mechanistic studies will enhance our understanding of the pathobiology of vascular disease in aging women and may provide the basis for development of novel therapeutic strategies.

Public Health Relevance

There are currently ~1.7 million veterans who are women, and women constitute ~14% of the armed forces. With the rising numbers of women in the military, it is expected that the number of aging women veterans will continue to rise. Cardiovascular disease (CVD) causes approximately 1 death per minute in women, contributing to more deaths than it does in men. Studies in young laboratory animals and in women in the early menopausal years suggest that estrogen can protect against vascular injury and CVD. In contrast, clinical trials that enrolled older women late after menopause demonstrated harmful cardiovascular effects of estrogen. Thus, clinical studies have raised many important questions about the effects of estrogen on vascular inflammation that cannot easily be answered in clinical trials. Insights from fundamental mechanistic studies such as those proposed here are needed to better understand how estrogen affects vascular inflammation in older women and pave the way to novel strategies for prevention and treatment of CVD in this population.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001431-02
Application #
8600842
Study Section
Cardiovascular Studies A (CARA)
Project Start
2012-10-01
Project End
2016-09-30
Budget Start
2013-10-01
Budget End
2014-09-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Birmingham VA Medical Center
Department
Type
DUNS #
082140880
City
Birmingham
State
AL
Country
United States
Zip Code
35233
Giordano, Samantha; Zhao, Xiangmin; Chen, Yiu-Fai et al. (2017) Induced Pluripotent Stem Cell-Derived Endothelial Cells Overexpressing Interleukin-8 Receptors A/B and/or C-C Chemokine Receptors 2/5 Inhibit Vascular Injury Response. Stem Cells Transl Med 6:1168-1177
Giordano, Samantha; Hage, Fadi G; Xing, Dongqi et al. (2015) Estrogen and Cardiovascular Disease: Is Timing Everything? Am J Med Sci 350:27-35
Fu, Jinyan; Chen, Yiu-Fai; Zhao, Xiangmin et al. (2014) Targeted delivery of pulmonary arterial endothelial cells overexpressing interleukin-8 receptors attenuates monocrotaline-induced pulmonary vascular remodeling. Arterioscler Thromb Vasc Biol 34:1539-47
Bowling, Meaghan R; Xing, Dongqi; Kapadia, Akash et al. (2014) Estrogen effects on vascular inflammation are age dependent: role of estrogen receptors. Arterioscler Thromb Vasc Biol 34:1477-1485
Pacurari, Maricica; Xing, Dongqi; Hilgers, Rob H P et al. (2013) Endothelial cell transfusion ameliorates endothelial dysfunction in 5/6 nephrectomized rats. Am J Physiol Heart Circ Physiol 305:H1256-64