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.
Professor Garry Presents at Society for Muscle Biology’s Frontiers in Myogenesis Conference
December 15, 2021
Mary Garry, PhD, Professor of Medicine in the Cardiovascular Division, attended The Society for Muscle Biology’s Frontiers in Myogenesis Conference held November 15-19, 2021, in Costa Rica. The conference focused on “Skeletal Muscle: Development, Regeneration, and Disease.”
Garry presented a lecture titled “Humanized skeletal muscle: novel therapies and models” at the conference. The presentation highlighted the development of human:animal chimeras for the generation of transplantable organs for patients. In particular, the studies were the work of Drs. Geunho Maeng and Satya Das, both Assistant Professors in the Cardiovascular Division.
A full list of publications is available at firstname.lastname@example.org.
1. Garry, MG, Kren, S, Wenger, JB, Garry, DJ (2021) Biologically derived, 3-dimensional embryonic scaffolds for long-term cardiomyocyte culture. Stem Cells & Dev. 30(14):697-704. Cover feature article.
2. Garry, DJ and Garry, MG (2021) Interspecies chimeras as a platform for exogenic organ production and transplantation. Exp. Biol. Med. (Maywood) 246(16):1838-1844.
3. Maeng G, Das S, Greising SM, Gong W, Singh BN, Kren S, Mickelson D, Skie E, Gafni O, Sorensen JR, Weaver CV, Garry DJ, Garry MG. (2021) Humanized skeletal muscle in MYF5/MYOD/MYF6 null pig embryos as a platform for interspecies organ production and xenotransplantation. Epub ahead of print, March 29, 2021 Nature Biomedical Engineering. 5(8):805-814.
4. Maeng G, Gong W, Das S, Yannopoulos D, Garry DJ and Garry MG. (2020) ETV2-null porcine embryos survive to post-implantation following incomplete enucleation. Reproduction. May;159(5):539-547. doi:10.1530/REP-19-0382.
5. Garry DJ, Maeng G and Garry MG. (2020) Foxk1 regulates cancer progression. Annals of Translational Medicine. Sep;(17):1041. doi:10.21037/atm-2020-94.
6. Li Q and Garry MG. (2020) A Murine Model of the Exercise Pressor Reflex. The Journal of Physiology. Aug;598(15):3155–3171. doi.org/10.1113/JP277602.
7. Das S, Koyano-Nakagawa N, Gafni O, Maeng G, Singh BN, Rasmussen T, Pan X, Choi KD, Mickelson D, Gong W, Pota P, Weaver CV, Kren S, Hanna JH, Yannopoulos D, Garry MG and Garry DJ. (2020) Generation of human endothelium in pig embryos deficient in ETV2. Nature Biotechnology. 38(3):297-302. doi:10.1038/s41587-019-0373-y.
8. Garry DJ, Caplan AL, Garry MG. (2020) Chimeric humanized vasculature and blood: The intersection of science and ethics. Stem Cell Reports. Apr;14(4):538-540. doi: 10.1016/j.stemcr.2020.03.016. Featured Cover Article.
Cheryl Lancto, MS