In my laboratory, we study the role of primary afferent neurons in the control of cardiovascular responses to exercise. We are interested in the basic mechanisms that drive the exercise pressor reflex (EPR) under normal, physiological conditions but we also have a great deal of interest in the control of the EPR in disease.
Previous studies have suggested that the exaggerated increases in blood pressure, sympathetic nerve activity, and vascular resistance to exercise in patients with cardiovascular disease are due, in part, to an over active EPR. However, the mechanisms controlling these cardiovascular responses are not easily studied as few disease models exist in cats and dogs (the major species being used to study the EPR) and mechanistic studies in humans have encountered feasibility problems.
The rodent is an attractive candidate for the study of the EPR as disease models (e.g. heart failure, hypertension, and diabetes) are readily available or easily produced. Additionally, more genomic information is currently known for rodents compared to larger mammals presenting the opportunity to study the mechanisms of this reflex at the level of cellular and molecular physiology.
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Current Lab Projects
Determining the role of TRPv1 dysregulation in cardiovascular responses to exercise in heart failure:
Exaggerations in the cardiovascular responses to exercise in heart failure patients are mediated, in part, by an over active exercise pressor reflex (EPR). The EPR is a mechanism where blood pressure and heart rate increase in response to contraction-induced activation of primary afferent neurons and reflexive changes in autonomic outflow. LHI--MGarry_img_tensionTransduc Importantly, exaggerations in the EPR correlate with morbidity and mortality in heart failure patients. We developed a novel animal model to study the EPR in rats with heart failure. With this model, we have determined that the EPR is overactive in rats in heart failure just as it is in humans. We have also identified several mechanisms which contribute to this overactivity. First, we have determined that the TRPv1 receptor (previously known as the capsaicin receptor) mediates, in part, the EPR in the rat. In spite of an exaggerated EPR, the group IV afferent neurons are less responsive to capsaicin in heart failure when compared to sham treated controls. We have also demonstrated that ablation of group IV afferent neurons (in non-cardiomyopathic animals) results in an overactive EPR similar LHI--MGarry_img_cellsGlowto that observed in heart failure. Additionally, we have determined that group III afferent neurons mediate the exaggerated EPR in the absence of group IV afferent responsiveness. Based on these collective findings, we hypothesize that reduced responsiveness in group IV afferent neurons leads to increased activation of group III afferent neurons and results in an overactive EPR in heart failure. We are currently engaged in studies that explore the role that the TRPv1 down regulation or desensitization plays in the abnormal EPR in heart failure.
Determining factors that dysregulate the TRPv1 in heart failure:
To date, the known activators of TRPv1 include a diverse set of chemical entities as well as physical stimuli such as heat. In addition to capsaicin, numerous other vanilloids as well as many non-vanilloids are TRPv1 agonists. Lipids, including several lipoxygenase products and the endogenous cannabinoid, anandamide can also activate TRPv1. In addition to heat and lipids, protons (i.e., acids) can also be considered endogenous modulators of TRPv1 as they can potentiate, directly activate, and at higher concentrations, even block TRPv1. In addition, recent evidence indicates that adenosine can directly activate the TRPv1. We have recently determined that TRPv1 activation mediates the EPR in rats. Ongoing studies in our lab currently address whether the TRPv1 contributes to the EPR abnormalities in the pathological states.
Determining factors that mark the group III afferent neuron:
Direct evaluation of the contribution of group III afferent neurons to the EPR in health and disease is essential for understanding the mechanisms that mediate abnormalities in the EPR. We are currently identifying factors that serve to mark this population of afferent neurons in the periphery.
A full list of publications is available at email@example.com.
- Li Q, Garry MG. A murine model of the exercise pressor reflex. J Physiol. 2020; Author Manuscript. doi:10.1113/JP277602
- Maeng G, Gong W, Das S, Yannopoulos D, Garry DJ, Garry MG. ETV2 null porcine embryos survive to post-implantation following incomplete enucleation. Reproduction. 2020; May;159(5):539-547. doi: 10.1530/REP-19-0382.
- Das S*, Koyano-Nakagawa N*, Gafni O, Maeng G, Singh BN, Rasmussen T, Pan X, Choi K, Mickelson D, Gong W, Pota P, Weaver C, Kren S, Hanna J, Yannopoulos D, Garry MG**, Garry DJ**. Human endothelium in pig embryos deficient in ETV2 as a platform for exogenic organ production. Nature Biotechnology, 2020; Mar;38(3):297-302. doi: 10.1038/s41587-019-0373-y. Epub 2020 Feb 24. **Denotes equal contribution
- Garry DJ, Caplan AL, Garry MG. Chimeric humanized vasculature and blood: The intersection of science and ethics. Stem Cell Reports. 2020; Apr 14;14(4):538-540. doi: 10.1016/j.stemcr.2020.03.016. Featured Cover Article.
- Garry DJ, Garry MG. Interspecies Chimeras and the Generation of Humanized Organs. Circulation Research 2019; Jan 4;124(1):23-25. doi: 10.1161/CIRCRESAHA.118.314189.
- Singh BN, Koyano-Nakagawa N, Gong W, Moskowitz IP, Weaver CV, Braunlin E, Das S, vanBerlo JH, Garry MG*, Garry DJ*. (equal contributors) A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human. Nature Comm. 2018; 9:4237 | DOI: 10.1038/s41467-018-06617-z.