Systemic vasculature remodeling in females: effects of the immune system and experience of pregnancy

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Heart disease is a significant killer of women in the United States. Heart disease is different in women as compared to men, and while hormonal milieu likely contributes to sex-specific cardiovascular physiology, the understanding of other mitigating factors is critical for the overall health. Epidemiologic data supports the idea that pregnancy is a driver of cardiovascular health risk. The physiologic stress of pregnancy reveals inherent cardiovascular strengths or deficiencies, enhances protective mechanisms, or has the potential to cause damage with cardiovascular consequences. Moreover, pregnancy-induced vascular adaptations continue postpartum (PP). The work proposed in this application stems from the basic idea that examination of cardiovascular biology soon after pregnancy is completed will give clues to the cardiovascular adaptations that persist long-term and therefore affect future cardiovascular disease risk. Study of these persistent adaptations is therefore expected to delineate mechanisms of sex-specific differences in cardiovascular biology. T cells play a role in hypertension and cardiovascular disease. Although pregnancy is a state of significant changes in the T cell pool, the PP status of these changes has not been completely elucidated, nor has it been examined in the context of maternal cardiovascular parameters. The PIs of this application are experts in the maternal immune system and in vascular biology and have partnered to provide preliminary evidence in a mouse model that immune deficiency in recombinase 1 deficient mice (Rag1-/-) modifies PP resistance vasculature physiology. The working model is that pregnancy generates T cells that are enhanced in their ability accumulate in perivascular tissues, that pregnancy increases the ability of vascular cells to interact with and respond to signals generated by T cells, and that this acquired state underlies the differences observed PP in vessels from normal and immune deficient animals. This R01 application proposes the following aims to test a specific model: Aim 1) Delineate the molecular mechanisms underlying PP perivascular tissue accumulation of T cells and macrophages and determine their role in PP vascular remodeling and function Aim 2) Determine the molecular basis relating CD8 T cell function to structural changes observed in PP systemic vasculature Aim 3) Define mechanisms underlying decreased PP vascular responses to Acetylcholine in CD8-reconstituted Rag1-/- as compared to un-manipulated Rag1-/- mice When examined in the context of existing human data, the information obtained will aid in designing relevant longitudinal studies in women, understanding the mechanisms linking T cell biology to PP vascular homeostasis, and in developing unique tools to delineate future cardiovascular disease risk in women. The proposed research addresses NHLBI strategic priorities, including Critical Challenges and Compelling questions related to sex differences in cardiovascular disease and also elements of the overall mission of NICHD.