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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL096570-04
Application #
8502531
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$354,145
Indirect Cost
$125,018
Name
Pennsylvania State University
Department
Type
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Li, Zhijun; Muller, Matthew D; Wang, Jianli et al. (2017) Dynamic characteristics of T2*-weighted signal in calf muscles of peripheral artery disease during low-intensity exercise. J Magn Reson Imaging 46:40-48
Luck, J Carter; Miller, Amanda J; Aziz, Faisal et al. (2017) Blood pressure and calf muscle oxygen extraction during plantar flexion exercise in peripheral artery disease. J Appl Physiol (1985) 123:2-10
Drew, Rachel C; Blaha, Cheryl A; Herr, Michael D et al. (2017) Muscle mechanoreflex activation via passive calf stretch causes renal vasoconstriction in healthy humans. Am J Physiol Regul Integr Comp Physiol 312:R956-R964
Xing, Jihong; Li, Jianhua (2017) Proteinase-Activated Receptor-2 Sensitivity of Amplified TRPA1 Activity in Skeletal Muscle Afferent Nerves and Exercise Pressor Reflex in Rats with Femoral Artery Occlusion. Cell Physiol Biochem 44:163-171
Drew, Rachel C (2017) Baroreflex and neurovascular responses to skeletal muscle mechanoreflex activation in humans: an exercise in integrative physiology. Am J Physiol Regul Integr Comp Physiol 313:R654-R659
Cui, Jian; Boehmer, John; Blaha, Cheryl et al. (2017) Muscle sympathetic nerve activity response to heat stress is attenuated in chronic heart failure patients. Am J Physiol Regul Integr Comp Physiol 312:R873-R882
Xing, Jihong; Li, Jianhua (2017) TRPA1 Function in Skeletal Muscle Sensory Neurons Following Femoral Artery Occlusion. Cell Physiol Biochem 42:2307-2317
Ross, Amanda J; Gao, Zhaohui; Luck, Jonathan Carter et al. (2017) Coronary Exercise Hyperemia Is Impaired in Patients with Peripheral Arterial Disease. Ann Vasc Surg 38:260-267
Xing, Jihong; Li, Jianhua (2016) The Role Played by Adenosine in Modulating Reflex Sympathetic and Pressor Responses Evoked by Stimulation of TRPV1 in Muscle Afferents. Cell Physiol Biochem 40:39-48
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:

Showing the most recent 10 out of 70 publications