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Mechanisms mediating the exaggerated exercise pressor reflex in a murine model of hindlimb ischemia

Award Number: R01HL186278
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Mechanisms mediating the exaggerated exercise pressor reflex in a murine model of hindlimb ischemia - Peripheral Artery Disease (PAD) is a prevalent disease resulting in lower limb ischemia and is the leading cause of amputations. PAD is associated with high cardiovascular mortality and is estimated to occur in 20-25% of the octogenarian population. While a multifaceted approach, including lipid lowering agents, antiplatelet and anticoagulation therapies, is used for the treatment of this disease, one major therapeutic focus is exercise. Exercise is believed to be beneficial in improving functional capacity in patients with PAD yet exercise has also been demonstrated to evoke an abnormal and exaggerated cardiovascular response in patients with PAD. These abnormalities are highly correlated with morbidity and mortality, however, the mechanism(s) that mediates these abnormalities is unclear. The exercise pressor reflex (EPR) is evoked by muscle contraction and propagated via group III (predominately mechanically-sensitive) and group IV (predominately metabolically- sensitive) afferent fibers resulting in a rise in mean arterial pressure (MAP) and heart rate (HR). These reflexive cardiovascular functions serve to maintain adequate blood flow to exercising muscle and abnormalities in the EPR are correlated with significantly increased cardiovascular risk. We have developed a novel murine mouse model for the study of the EPR. With our mouse model, we have made mechanistic discoveries demonstrating that the EPR is exaggerated in mice with hindlimb ischemia and, further, that these mice display reduced tolerance for exercise. We have determined that the exaggerated EPR is mediated by mechanosensitive afferent neurons and that these responses are mediated, in part, by activation of the PIEZO2 ion channel. In the proposed studies, we will use Piezo2 reporter mice as well as mice in which we have conditionally deleted Piezo2 from dorsal root ganglia (DRG) to fully characterize the mechanisms that mediate the exaggerated EPR in hindlimb ischemia. In this proposal, we will use morphological, histological, physiological, molecular, and whole cell patch clamp technologies to define the pathological mechanism(s) that drive the exaggerated EPR as well as reduced exercise tolerance in hindlimb ischemia. Our hypothesis is that PIEZO2 expressing mechanosensitive afferent neurons mediate the exaggerated EPR in mice with hindlimb ischemia. We will rigorously test this hypothesis and interrogate the downstream pathways of PIEZO2 to identify potential therapies in normalizing the EPR in ischemia to allow for the safe prescription of exercise in PAD patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $765,131 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cardiovascular Diseases Research	000	1	9/2/2026	NEW	$765,131
														Subtotal = $765,131

Grand Total All Awards = $765,131

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Mechanisms mediating the exaggerated exercise pressor reflex in a murine model of hindlimb ischemia

Award Number: R01HL186278

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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