Tuesday, April 1, 2025
4/1/2025
Nrf2 and the exaggerated Exercise Pressor Reflex in Peripheral Arterial Disease - Peripheral arterial disease (PAD) affects 8 to 12 million people in the United States. Intermittent claudication (exercise-induced leg pain and severe walking limitation) is a hallmark of PAD which severely limits exercise capacity and deceases quality of life. Clinical studies demonstrate that the exercise pressor reflex (EPR), a neural reflex originating in skeletal muscle which contributes to the regulation of cardiovascular function during physical activity, is exaggerated in patients with PAD. Furthermore, the exaggerated EPR during exercise in PAD patients is seen before the onset of claudication. We hypothesize that in PAD, exercise-induced activation of muscle afferents (i.e. the EPR), which is initially below the threshold for pain , initiates an exaggerated vasoconstriction and worsens the ischemia of the exercising PAD muscle, which may further activate muscle afferents above the nociceptive threshold level and produce the familiar exertional pain symptoms of claudication. In Aim 1, We will examine the time-course of EPR function including heart rate, blood pressure and local muscle blood flow during static and dynamic exercise in a rat model of chronic PAD and in sham animals. We will determine the potential correlation between EPR function, muscle ischemia and pain behavior scores in both sham and PAD rats. Finally, we will determine if selective ablation of the EPR with the potent TRPV1 receptor agonist, resiniferatoxin (RTX), improves muscle perfusion during exercise and pain indices in PAD rats. Assessment of RTX efficacy will be carried out using a novel tissue clearing method in a TRPV1-tdTomato reporter mouse model. Furthermore, our pilot study found that neural inflammation indicated by macrophage infiltration occurs in lumbar DRGs post PAD. In parallel, we observed upregulated protein expression of nuclear factor erythroid 2-related factor (Nrf2, a transcription factor that mediates the cellular response to oxidative stress/inflammation) in lumbar DRGs post PAD. We believe that the purpose of upregulated Nrf2 protein is to counteract the influence of neural inflammation in DRG neurons post PAD. However, this self-limited compensatory response by an intrinsic DRG system may not be potent enough in DRG neurons to antagonize exogenous neural inflammation evoked by PAD. Therefore, in Aim 2, We hypothesize that selective upregulation of muscle afferent Nrf2 via Keap1-Knock-out (KO) will mitigate enhanced muscle afferent neuronal excitability and pain sensation in a mouse model of chronic PAD. We also hypothesize that local epidural delivery of hydrogel-based drug system with encapsulation of Nrf2 activator (i.e., Curcumin) will mitigate the exaggerated EPR and pain sensation in a rat model of chronic PAD. Finally, we propose to examine the potential influence of Nrf2 signaling onto DRG ion channel function such as potassium channels in muscle afferent neurons in PAD. To date, the underlying molecular/cellular mechanisms of the exaggerated EPR in chronic PAD has not been examined in any chronic PAD animal model. The long-term goal of this application is to discover the neural mechanisms operating in the exaggerated EPR and claudication and to provide a novel treatment for PAD.
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