Acid sensing ion channel 1 (ASIC1) is a voltage-insensitive cation channel that has been shown to be expressed in vascular smooth muscle and endothelial cells. However, little is known about the contribution of ASIC1 to vascular resistance. Our preliminary data demonstrates that ASIC1 contributes to agonist-induced vasodilation and endothelial cell Ca2+ influx in mesenteric arteries. Since the endothelium is a key regulator in cardiovascular homeostasis and endothelial dysfunction is associated with several cardiovascular diseases, the overall objective of this study is to identify the mechanisms by which ASIC1 contributes to endothelium- dependent vasodilation and systemic vascular resistance. Based on our preliminary studies, our central hypothesis is that ASIC1 contributes to cardiovascular homeostasis by mediating endothelium-dependent vasodilation in the systemic circulation. We will identify the mechanisms by which ASIC1 contributions to endothelial-dependent vasodilation and the role of ASIC1 to blood flow and blood pressure regulation with the following specific aims:
Specific Aim 1 : Determine the mechanism(s) involved in the activation of endothelial ASIC1. Hypothesis: Acetylcholine-induced release of arachidonic acid activates ASIC1 in the mesenteric endothelium.
Specific Aim 2 : Identify the mechanism by which ASIC1 mediates endothelium-dependent vasodilation. Hypothesis: ASIC1 Ca2+ influx leads to the activation of small or intermediate conductance Ca2+ activated potassium channels, thus mediating an endothelium-derived hyperpolarizing response.
Specific Aim 3 : Determine the contribution of ASIC1 to cardiovascular homeostasis and disease. Hypothesis: Endothelial ASIC1 contributes to both blood flow and blood pressure regulation, where a loss of endothelial ASIC1 will lead to endothelial dysfunction and the development of hypertension. To test these hypotheses, we will use various techniques such as whole cell patch clamp electrophysiology, sharp electrode membrane potential recording, and transient Ca2+ event recording upon activation of ASIC1. We will also look at in vivo blood flow and blood pressure measurements in order to understand the role of ASIC1 in cardiovascular homeostasis and blood pressure regulation. This project is innovative in its investigation of a novel-signaling pathway involving the contribution of ASIC1 in agonist-induced mesenteric vasodilation. These studies are significant because they are expected to virtually impact our understanding of a novel mechanism that contributes to cardiovascular homeostasis and blood pressure regulation. Ultimately, the training under this fellowship will facilitate the applicant?s next step into a postdoctoral fellowship and overall career goal of becoming an independent scientist in cardiovascular physiology.
The vascular endothelium is the inner lining of blood vessels and the primary regulator of vascular wall function including vascular relaxation and contraction, blood clotting, and immune function. Damage of the endothelial layer, or endothelial dysfunction, is recognized as the initial step leading to end-organ damage in many cardiovascular diseases. The proposed studies are relevant to the mission of the National Heart, Lung, and Blood Institute because they will mechanistically examine the contribution of the novel endothelial cell signaling pathway involved in cardiovascular homeostasis and blood pressure regulation.