Natural Regulatory T Cells Control Coronary Arteriolar Endothelial Dysfunction in Hypertensive Mice

Abstract

Coronary artery disease in patients with hypertension is increasing worldwide and leads to severe cardiovascular complications. The cellular and molecular mechanisms that underlie this pathologic condition are not well understood. Experimental and clinical research indicates that immune cells and inflammation play a central role in the pathogenesis of cardiovascular diseases. Recently, it has been reported that CD4(+)CD25(+) regulatory T cells (Tregs) regulate heart fibrosis in hypertension. In this study, we determined the role of Tregs in coronary arteriolar endothelial dysfunction in angiotensin II-dependent hypertensive mice. Mice infused with angiotensin II had significantly increased blood pressure, as determined using telemetry, and apoptotic Treg numbers, as measured using flow cytometry. The mice displayed inflammation, assessed by macrophage activation/infiltration into coronary arterioles and the heart, and increased local tumor necrosis factor-α release, which participates in reduced coronary arteriolar endothelial-dependent relaxation in response to acetylcholine using an arteriograph. Hypertensive mice injected with Tregs isolated from control mice had significantly reduced macrophage activation and infiltration, reduced tumor necrosis factor-α release, and improved coronary arteriolar endothelium-dependent relaxation. Our novel data indicate that Tregs are important in the development of coronary arteriolar endothelial dysfunction in hypertension. These results suggest a new direction in the investigation of vascular disease in hypertension and could lead to a therapeutic strategy that involves immune system modulation using Tregs.

Immune Mechanisms in Arterial Hypertension

“…Several groups have shown that adoptive transfer of Tregs lowers BP and ameliorates cardiac and renal injury in different models of hypertension. [65][66][67][68] Mice deficient in IL-10, an important product of Tregs, develop similar degrees of hypertension in response to angiotensin II, but have severe endothelial dysfunction and vessels from these mice show an increased superoxide production when incubated with angiotensin II. 69 These and other data suggest that Treg-derived IL-10 mediates the beneficial effects of Tregs in hypertension.…”

Impact of Immune Deficiency on Remodeling of Maternal Resistance Vasculature 4 Weeks Postpartum in Mice

“…The CD4 TREGs 46,52 and B cells 63 have been observed to mediate vascular physiology and pathology. To begin to determine the potential role played by the interaction between CD8 T cells and B cells in the absence of CD4 T cells in PP vascular physiology, and to address the relatively low systemic levels of CD8 T cells in the adoptive transfer experiments, we began the analysis of vessels from PP CD4-deficient mice 57 ( Figure 8).…”

“…[46][47][48][49] Because of these characteristics, we examined the effects of CD8 T-cell reconstitution in Rag1 ÀÀ mice. In light of the potential role played by CD4 TREGs in the immune homeostasis of pregnancy 18,50 and in the modification of cardiovascular disease, 46,[51][52][53][54] we also examined mice with genetic deficiency in CD4 T cells. 55 We chose mesenteric vessels because of their role in the regulation of systemic blood pressure.…”

Hypertension exacerbates liver injury and hepatic fibrosis induced by a choline-deficient L-amino acid-defined diet in rats

“…By contrast, hypertension inhibited IL-10 and HO-1 expression, with a resultant increase in ALT to a level higher than that caused by the CDAA diet alone. In addition, indirect evidence indicates that IL-10 exerts a protective effect on endothelial function in diabetes and hypertension (17,30). IL-10 has also been shown to inhibit the activation of hepatic stellate cells and decrease hepatic fibrosis and apoptosis in a CCl4-induced rat liver fibrosis model (31,28).…”