Role of the Adaptive Immune System in Angiotensin II Induced Vascular Remodeling and Stiffening
AdvisorLarson, Douglas F.
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PublisherThe University of Arizona.
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AbstractElevation of blood pressure leads to structural and functional alterations in vasculature, resulting in increased arterial stiffness, which in turn is a predictor of future hypertension and cardiovascular risks. Angiotensin II (Ang II) plays a crucial role in blood pressure regulation. In addition to its hemodynamic effects, Ang II activates both innate and adaptive immunity. The objective of this study is to define the roles of CD4⁺ T lymphocyte subsets in the progression of vascular remodeling and stiffening induced by Ang II. A mouse model of Ang II infusion was used to induce hypertension and vascular diseases. In the WT mice, Ang II infusion led to an increased aortic stiffness within 7 days of the treatment as well as an increase in aortic remodeling within 14 days of the treatment. Interestingly, RAG1(-/-) mice, lacking functional T and B lymphocytes were prevented from the vascular stiffening and remodeling caused by Ang II. Characterization of T cell subsets in the perivascular aortic infiltrates showed that there was a sequential activation of peri-arotic Th1 and Th17 during the time course of Ang II treatment, which was associated with the initial increased aortic stiffness and the subsequent remodeling, respectively. To extend the concept, roles of suppressive regulatory T cells (Tregs) were further examined. Proliferation of Tregs was successfully induced in vivo using a cytokine complex of IL-2 and anti-IL-2 mAb clone JES6-1. Ang II-infused mice that received the IL-2/anti-IL-2 complex exhibited a reduced vascular remodeling and stiffening caused by Ang II. Stimulation of Tregs with the IL-2/anti-IL-2 complex also suppressed the Th1 and Th17 responses and reduced immune cells infiltrates in the aortas. Since hypertension is closely related to the kidney and renal homeostasis is also tightly regulated by Ang II, the kidney function was determined in this Ang II-hypertensive model. In the wild type mice, two weeks infusion of Ang II resulted in an increased glomerular filtration rate (GFR) whereas immunodeficient RAG1(-/-) mice exhibited a marked decrease in GFR. Subsequent experiments showed that Th17 was crucial in renal hemodynamic response to Ang II, partly by regulating secretion of vasodilatory prostaglandin E₂.
Degree ProgramGraduate College