Atherosclerosis is the leading cause of morbidity and mortality in the US. In this grant, we will examine the role of metabolite sensitive receptors on muscle afferent neurons in the responses of sympathetic nerve activity after limiting blood flow to hindlimb muscle, as seen in peripheral arterial occlusive disease due to atherosclerosis. A rat model of femoral artery occlusion will be used to restrict hindlimb blood flow.
The specific aim 1 is to examine expression of transient receptor potential vanilloid type 1 (TRPV1), purinergic P2X receptors, and acid sensing ion channels (ASICs) and responsiveness to activation of those receptors. Based on our published work and pilot data collected for this proposal, we hypothesize that femoral artery occlusion augments the reflex sympathetic response due to increases in those receptors' expression and responsiveness in dorsal root ganglion (DRG) neurons innervating muscles.
The specific aim 2 is to examine the role of nerve growth factor (NGF) in responses of TRPV1, P2X and ASICs. We hypothesize that NGF in the DRG neurons is a key factor for development of abnormality in reflex sympathetic response after artery occlusion. Our pilot data have shown that levels of NGF are increased in DRG neurons of rats with artery occlusion. We anticipate that NGF infused in the muscle of healthy rats using an osmotic minipump will induce an increase in sympathetic response to activation of those receptors or muscle contraction;and neutralization of NGF will improve the reflex sympathetic response in rats with femoral artery occlusion.
The specific aim 3 is to examine the role of by-products in responses of TRPV1, P2X and ASICs. We hypothesize that accumulated metabolites in the muscle have an important contribution to abnormal sympathetic response after femoral artery occlusion. We anticipate that artery occlusion will elevate muscle by-products such as ATP, acid, etc. to a greater degree as compared with control. We further anticipate that chronic infusion of by-products in the muscle of healthy rats will augment the reflex responses as seen in rats with arterial occlusion via respective receptors. Finally, we anticipate that attenuating those receptors will improve the sympathetic responses.

Public Health Relevance

Chronic muscle ischemia commonly appears in some cardiovascular diseases such as peripheral arterial disease. The proposed studies in this grant are to examine the role of primary muscle afferents'receptors in mediating abnormal sympathetic nerve responses using a rat model of femoral artery occlusion.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Pennsylvania State University
United States
Zip Code
Muller, Matthew D; Li, Zhijun; Sica, Christopher T et al. (2016) Muscle oxygenation during dynamic plantar flexion exercise: combining BOLD MRI with traditional physiological measurements. Physiol Rep 4:
Cui, Jian; Blaha, Cheryl; Sinoway, Lawrence I (2016) Whole body heat stress attenuates the pressure response to muscle metaboreceptor stimulation in humans. J Appl Physiol (1985) 121:1178-1186
Li, Zhijun; Muller, Matthew D; Wang, Jianli et al. (2016) Dynamic characteristics of T2*-weighted signal in calf muscles of peripheral artery disease during low-intensity exercise. J Magn Reson Imaging :
Ross, Amanda J; Gao, Zhaohui; Luck, Jonathan Carter et al. (2016) Coronary Exercise Hyperemia Is Impaired in Patients with Peripheral Arterial Disease. Ann Vasc Surg :
Copp, Steven W; Kim, Joyce S; Ruiz-Velasco, Victor et al. (2016) The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in decerebrate rats. J Physiol 594:641-55
Clark, Christine M; Monahan, Kevin D; Drew, Rachel C (2016) Omega-3 polyunsaturated fatty acid supplementation attenuates blood pressure increase at onset of isometric handgrip exercise in healthy young and older humans. Physiol Rep 4:
Stone, Audrey J; Kaufman, Marc P (2015) The exercise pressor reflex and peripheral artery disease. Auton Neurosci 188:69-73
Clark, Christine M; Monahan, Kevin D; Drew, Rachel C (2015) Aging augments renal vasoconstrictor response to orthostatic stress in humans. Am J Physiol Regul Integr Comp Physiol 309:R1474-8
Copp, Steven W; Stone, Audrey J; Li, Jianhua et al. (2015) Role played by interleukin-6 in evoking the exercise pressor reflex in decerebrate rats: effect of femoral artery ligation. Am J Physiol Heart Circ Physiol 309:H166-73
Muller, Matthew D; Drew, Rachel C; Ross, Amanda J et al. (2015) Inhibition of cyclooxygenase attenuates the blood pressure response to plantar flexion exercise in peripheral arterial disease. Am J Physiol Heart Circ Physiol 309:H523-8

Showing the most recent 10 out of 64 publications