Thursday, December 26, 2024
12/26/2024
Abstract . Vascular complications associated with lifestyle-related diseases, such as diabetes, contribute to an increased risk of hypertension, coronary artery disease, and heart failure associated with preserved ejection fraction (HFpEF). These vascular complications may involve, at least in part, vascular smooth muscle (VSM) dysfunction leading to impaired vasomotor function, but mechanisms remain poorly understood. We recently identified a novel AKAP5/P2Y11/AC5/PKA/CaV1.2 nanocomplex that is activated by the release of extracellular nucleotides, such as ATP. This complex controls VSM contractility, vasoconstriction, and altered blood flow (BF) and blood pressure (BP) in response to elevated extracellular glucose (e.g. hyperglycemia; HG – a major metabolic abnormality in diabetes). Yet, whether HG stimulates cellular nucleotide release, the precise molecular entity underlying this process, and its potential role in diabetes and other diseases (e.g. HFpEF) are unknown. The overarching goal of this MPI proposal is to provide insight into these issues. Our preliminary data offers a unique window into these queries and uncover an essential role for the large-pore channel pannexin 1 (Panx1) as a key member and upstream protein activating the nanocomplex and thus contributing to altered vascular reactivity during diabetes and perhaps other diseases such as HFpEF. We will address the novel central hypothesis that Panx1 is upstream and part of the AKAP5/P2Y11/AC5/PKA/CaV1.2 signaling axis that promotes VSM contractility and altered BF/BP in response to diabetic hyperglycemia. The proposal has high significance as it defines Panx1 as 1) a key upstream pathway triggering pathological signaling resulting in VSM hypercontractility during diabetic hyperglycemia and 2) a potential therapeutic target to treat vascular complications in diabetes (and perhaps HFpEF). The influence of Panx1 in contributing to the ATP release in response to HG, and in strengthening/weakening the formation of nanocomplexes to mediate functional responses, which may have broader implications in any Panx1-dependent signaling process, is an emerging and innovative concept. Our innovative multi-scale approach using state-of-the-art approaches will be implemented to explore the following aims. Aim 1 is to elucidate the role of Panx1 on HG signaling in VSM. Aim 2 is to determine the impact of Panx1 on VSM dysfunction during diabetes and HFpEF. The impact of the proposal is in establishing Panx1 as a key contributor to defective VSM function and vascular complications in diabetes and HFpEF.
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