? The central mechanisms involved in hypertension-induced vascular pathology, a public health crisis, remain unknown. There is still a significant rate of adverse events in hypertensive patients prescribed these therapeutic and 2/3 of hypertensive patients are still resistant to these therapies. Thus, the critical unmet need is to identify mechanism based-treatable targets to rescue vascular function and structure in established hypertension. The pilot data showed that transferring healthy Treg into a mouse with established hypertension-induced by angiotensin II (Ang II) infusion improved vascular endothelial function and structure. We showed an increase in stromal interaction molecule 1 (STIM1) expression in Treg that could be responsible for Treg apoptosis by Nox2 and endoplasmic reticulum (ER) stress- dependent mechanisms. The overexpression of STIM1 in Treg cell caused Treg cell apoptosis. The depletion of dendritic cells in hypertensive mice improved arterial function and reduced arterial fibrosis and calcification through a reduction in INF? and IL-1? release from dendritic cells and the inhibition of the ER stress in the endothelial cells. The central hypothesis is that STIM1 overexpression in Treg cells, through ROS and ER stress mechanism, cause Treg cells apoptosis and decrease IL-10 release, which increases dendritic cell activity leading to an increase in pro-inflammatory cytokines release (INF? and IL-1?) and a decrease in anti-inflammatory IL-10 release causing the induction of the ER stress in endothelial cells and vascular pathology. To advance the Translational Sciences, we will test the hypothesis in two-kidney one- clip (2K1C) hypertensive mice Ang II-dependent.
Specific Aim #1 : To determine that in established hypertension, STIM1 expression is increased in Treg cells causing Treg cells apoptosis, a decrease in IL-10 release, and vascular pathology. Thus disrupting STIM1 expression in Treg cells would restore Treg cells number, IL-10 levels, and improve vascular endothelial function and reduce fibrosis and calcification in established hypertension.
Specific Aim #2 : To delineate that the decrease in IL-10 release, because of apoptosis in Treg, increases dendritic cells activity to release IFN? and IL-1? and blunt IL-10 release, which causes vascular pathology via the induction of the ER stress mechanism in endothelial cells, and therefore depleting dendritic cells or manipulating the ER stress in endothelial cell improve vascular endothelial function and reduce fibrosis and calcification in established hypertension-induced by 2K1C. These studies are central to the mission of the NHLBI and address all Goals and multiple Strategies outlined in the NHLBI Strategic Plan. These studies will address 1) a need to further illuminate the biological mechanisms and pathological processes of the contribution of the immune cells, 2) The interaction between the immune system and the vascular system as a priority research topic and, 3) To advance the Translational Sciences, we will test the hypothesis in 2K1C mice model.
Vascular complication is a high risk for morbidity and mortality in hypertensive patients. Analysis of cellular and molecular mechanisms by which key molecules regulate vascular function and structure will significantly advance our understanding of the basic mechanisms of vascular complication in hypertension. This approach has the potential to contribute to novel therapies to treat the hypertension-induced vascular complication.
