Hypothesis: Our previous studies using elastase-perfusion and angiotensin II models of abdominal aortic aneurysms (AAA) have shown that female rodents have a decreased incidence and size of aneurysm formation. We have also recently shown that human placental mesenchymal stem cells (MSCs) are protective in a mouse model of AAA. In the current proposal, we will investigate the role of dietary phytoestrogen as a preventive therapy, and its synergistic effects with MSCs as a treatment strategy to protect against AAA. Methods: We will use an elastase-perfusion and angiotensin II murine model of AAA using male and female wild-type, estrogen receptor knockout mice (ER-?-/- and ER-b-/-) and ApoE-/- mice. Dietary phytoestrogen will be administered to male and female mice via estrogen-rich or estrogen-free chow. Various subsets of female MSCs (placenta-, bone marrow- or adipose-derived) primed with or without estrogen will be administered intravenously or by aortic implantation in mice models of AAA. Aortic diameter will be measured on day 3, 7 and 14 (elastase perfusion model) and day 28 (angiotensin II model). Aortic tissue will be harvested to analyze pro-inflammatory cytokine (IL-17, TNF-?, MCP-1, IL-1?, KC and RANTES) and HMGB1 (high mobility group box 1;a pro-inflammatory nuclear protein) production by ELISA, MMP2 and MMP9 activity by zymography, serine proteases (uPA, tPA and PAI-1) by western blots, paracrine factors (VEGF, HGF, PGE2) by ELISA, elastin and collagen degradation as well as aortic smooth muscle expression by histology, and immune cell (macrophages, CD4+ T cells, neutrophils) infiltration by flow cytometry. Results: Preliminary results demonstrate a significant upregulation of estrogen receptor (ER-a) expression in female mice on days 1, 3 and 14 after elastase-perfusion compared to males, as well as in aortic tissue from human females compared to males after AAA. Also, male mice fed a diet rich in estrogen display a significantly decreased aortic diameter, decreased cytokine production (IL-23, IL-1?, IL-6 and IL-27), decreased MMP2 and 9 expression and decreased macrophage and neutrophil infiltration compared to male mice fed an estrogen free diet. Furthermore, treatment with human female MSCs attenuates aortic diameter, pro-inflammatory cytokine production and cell infiltration after AAA. Female MSCs inhibit HMGB1 and IL-17 production more significantly than male MSCs. Also, estradiol-priming of female MSCs offer significantly increased protection from vascular inflammation in aortic tissue from male AAA patients. Conclusions: Dietary estrogen therapy and mesenchymal stem cells can attenuate aneurysm formation and inflammation in the elastase-perfusion murine model of AAA and in human aortic tissue from AAA patients. We propose to delineate the phytoestrogen mediated anti-inflammatory effects, and its crosstalk with various subsets of gender-specific MSCs, on aortic aneurysm formation in the murine (elastase-perfusion and angiotensin II) models as well aortic tissue and cells from AAA patients.

Public Health Relevance

Abdominal aortic aneurysms are a significant clinical problem with no known treatment and leads to increased mortality, especially in caucasian males. Our research proposal aims to identify specific cellular targets to help prevent aortic aneurysms with dietary estrogen therapy, and to treat them with human mesenchymal stem cells. This study involves experiments with mouse aneurysm models and aortic tissue from abdominal aortic aneurysm patients which will help us better understand the mechanisms of aneurysm formation and has high potential of being translated into a viable treatment strategy in patients of this deadly disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Tolunay, Eser
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University of Virginia
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Fashandi, Anna Z; Hawkins, Robert B; Salmon, Morgan D et al. (2018) A novel reproducible model of aortic aneurysm rupture. Surgery 163:397-403
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