Andreas Beyer Lab
Andreas M. Beyer, PhD
Associate Professor, Department of Medicine and Physiology
Curriculum Vitae (PDF)
Our collaborative team has established that the mechanisms of flow-mediated dilation (FMD) changes over the lifespan and shift with the onset of CAD. In healthy patients, FMD is regulated by the vasoprotective dilator nitric oxide (NO). In contrast, in CAD patients or in vessels exposed to acute stressors, NO bioavailability is reduced, and FMD is attributed to a compensatory rise in hydrogen peroxide (H2O2), a pro-inflammatory reactive oxygen species (ROS). These findings expanded our understanding of CAD, which was previously viewed as a disease limited to large conduit arteries, to reflect microvascular pathology to with significant prognostic implications. Our studies pioneered genetic manipulation techniques (siRNA, viral overexpression) in the human coronary circulation to answer mechanistic questions.
Work in my lab has long integrated animal studies with mechanistic evaluation of isolated human microvessels. Recent collaborative projects led us to expand our repertoire to study vascular function in vivo (e.g., brachial artery FMD, arterial tonometry, echocardiography, skin microdialysis/laser Doppler flowmetry). Our work fulfills a critical need to translate preclinical findings into human studies and thus serves as a bridge to clinical investigations. Understanding the molecular and physiological changes that contribute to CVD has clinical implications that, may lead to novel means to predict pathological changes and intervene before irreversible damage occurs.
Current work in understanding the pathological changes that occur with onset of CAD focuses on the role of TERT, the catalytic subunit of telomerase, in maintaining vasodilator function in the human microcirculation. Specifically, we study a noncanonical role of TERT in preserving mitochondrial homeostasis. We discovered previously unrecognized signaling between TERT and well-known regulators of vascular health, such as the renin angiotensin system and autophagy. Data from my lab and that of others implicate decreased levels of TERT with elevated mitochondrial DNA (mtDNA) damage as important regulators of mitochondrial integrity. This evidence led to a new collaborative work designed to understand the contribution of mitochondrial networks and their regulation to pathological changes in the human microcirculation. In specific, we aim to define how mitochondrial fission and fusion and its regulation, a fundamental process to maintain mitochondrial and cellular health, is critically linked as a regulator of FMD in the human microcirculation.
Fig. 1. Mitochondrial integrity and microvascular function.
Cardiovascular disease (CVD) and cancer are the number one and two causes of mortality and morbidity, and it is increasingly recognized that cancer and CVD share overlapping risk profiles. Long-term cancer survival is closely tied to CVD, while CVD conditions contribute to the progression of cancer and influence relevant treatment choices. With the use of systemic and targeted anti-cancer therapies (CTx), the number of annual deaths from cancer has been significantly reduced; however, most CTx agents have severe adverse consequences for the cardiovascular system. In fact, CVD related to CTx has emerged as the leading cause of non-cancer related deaths among breast cancer (BC) survivors. Given the magnitude of the clinical problem of cardiovascular-related mortality in cancer survivors, the novel clinical field of cardio-oncology has emerged with the aim of improving long-term, disease-free survival in cancer patients while addressing the underlying mechanism of cardiovascular comorbidity. While injury to the heart resulting from exposure to CTx is well established, little data exist on the contribution of CTx to endothelial cell dysfunction and the direct effect on mitochondria in the microcirculation. Microvascular endothelial dysfunction is the best predictor of future cardiovascular events, superior even to the degree of large vessel disease (i.e., CAD (coronary artery disease)) or ejection fraction in patients with or without coronary stenoses. This suggests that understanding the long-term consequences of CTx on microvascular function represents a novel, to date mostly unexplored, avenue to understanding and predicting the risk of cardiovascular complications in cancer patients.
We are using lessons learned from our ongoing investigations in understanding the changes in microvascular function in patients with CAD and expand them to investigate the vascular and mitochondrial changes and systemic consequences in cancer patients undergoing clinical necessary anti-cancer therapy. The objectives of this proposal are to 1) establish the contribution of microvascular dysfunction to CVD progression with an emphasis on cardio-oncology; 2) Establish the relevance of mitochondrial damage and secondary signaling in development and progression of CV events in cancer survivors; 3) define and predict risk for adverse CV events in cancer patients building on concepts of systems biology.
Fig. 3. CTx-induced mitochondrial damage and secondary signaling.
- Critical Role of Mitochondrial Fission/Fusion in Regulation of Microvascular Endothelial Function
- Understanding and Addressing Cancer Therapy Induced Systemic Inflammation and Associated Endothelial Dysfunction. Clinical Project Defining Differences in Endothelial Function and Response to CTx among a Diverse Population of Women with BC
- Pivotal Role of Mitochondrial Telomerase in Regulation of Vascular Tone and Redox Homeostasis
- Differentiation of mitochondrial vs. nuclear function of telomerase
Laura Norwood Toro
Research Scientist I
Laura Norwood Toro is a Research Scientist I in the Andreas Beyer Lab. Her primary responsibility is to explore the effect of chemotherapy on cardiovascular outcomes in coronary circulation and vascular endothelium. One focus of her studies is to investigate the functions of telomerase in the nucleus versus the mitochondria. Her background is in cell biology and molecular biology.
Bill Hughes, PhD
Bill Hughes is a postdoctoral fellow in the Beyer/Gutterman Lab. Prior to starting at MCW he received his PhD from the University of Iowa. His research interests are human integrative cardiovascular physiology and vascular biology in health, aging, and chronic disease. In collaboration with Dr. Beyer and Dr. Gutterman, he is studying the cross-talk between autophagy, a basic cellular recycling process, and telomerase within the context of microvascular function in coronary artery disease (CAD). Flow-mediated dilation is predominately mediated by nitric oxide (NO) in healthy populations, but this mediator switches to hydrogen peroxide (H2O2) with CAD. Autophagy has recently been demonstrated to be sensitive to shear stress, and preliminary data from our lab indicates that inhibition of autophagy switches the mediator of FMD from NO to H2O2 in non-CAD vessels, while activation of autophagy in CAD vessels recapitulates a healthy phenotype (NO-mediated). Additionally, our lab has also demonstrated that upregulation of telomerase reduces mitochondrial release of H2O2 in vessels with CAD, restoring NO-mediated FMD. In this context, it is possible that there is significant crosstalk between pathways, with telomerase upstream of autophagy. Collectively, as numerous chronic diseases modulate both telomerase activity and autophagy it remains unknown how these two processes are inherently linked in the context of CAD.
Research Technologist II
Shelby Hader is a Research Technologist II in the Beyer/Gutterman Lab. Prior to starting at MCW she received her BA from the Lawrence University. Her primary goal is to analyze the vascular reactivity of human coronary arterioles and adipose micro vessels within different healthy and diseased patients. Some of her projects include: the cardiotoxicity of chemotherapy upon the microvasculature along with measuring the differences between fission and fusion of mitochondria in human arterioles. Additionally, Shelby provides research support for multiple projects in the lab via imaging, dissection of discarded tissue, and rat/mice colony maintenance.
Janée Terwoord is a postdoctoral fellow working with Drs Beyer and Gutterman to investigate human microvascular physiology. Prior to joining the team at MCW, Janée earned her PhD in a clinical laboratory focused on the integrative control of blood flow distribution in humans. Her research interests include the signaling mechanisms that regulate vascular tone. Currently, Janée is working to characterize the cellular mechanisms by which cancer therapeutic drugs damage the microvasculature. She is studying how mitochondrial damage induced by these drugs contributes to endothelial dysfunction, which will inform new approaches to mitigate the detrimental cardiovascular effects of anti-cancer therapy.
Research Technologist I
Erin Birch is a research technologist in Dr. Beyer and Dr. Zhang’s labs. Erin has experience researching autoimmune diseases, chronic kidney disease, and cardiovascular disease. She is working with Dr. Beyer’s lab to provide support with several projects. Erin also contributes to the analysis of microvascular function in patients with coronary artery disease, COVID-19, and healthy patients. In her free time, Erin enjoys traveling and adventuring in the Rocky Mountains.
Lukas Brandt is a graduate student in Dr. Beyer's lab. Prior to starting at MCW's physiology program, he received his bachelor's degree from the University of Applied Science Bingen, Germany with a major in biotechnology. He received additional training in a Molecular Biology master program at the Goethe University Frankfurt, Germany before pursuing his education in physiology at MCW. His research interests are whole organ physiology with a focus on cardiovascular pathology in response to clinical used anti-cancer therapy. Lukas aims to utilize rodent models to investigate physiological and molecular changes that lead to cardiovascular disease.
Cristhian Gutierrez Huerta
Cristhian Gutierrez Huerta is a graduate MSTP student in the Beyer/Gutterman Lab. He graduated with a BS in Applied Mathematics and Biological Sciences from the University of California, Merced in 2018. He then completed a 2-yr post-baccalaureate research fellowship at the National Heart, Lung, and Blood Institute. In the Beyer/Gutterman group, he will begin work on identifying the role of mitochondrial fission/fusion on microvascular endothelial function and its relationship to coronary artery disease progression.
Karen Clark, PhD
Karen Clark is a postdoctoral fellow working with Drs Beyer and Kriegel to investigate biological factors that lead to disparate chemotherapy treatment outcomes in breast cancer patients of color compared to Caucasian women. She is also studying the role of mitofusin 1 in the vascular endothelium and whether overexpression is a protective factor against certain stressors. Prior to joining the team, she earned her PhD in Genetics at the University of Iowa, investigating the genetic basis of susceptibility to complex diseases in a rat model of Metabolic Syndrome. Her research interests include Precision Medicine, cancer biology, and metabolism.
- Karima Ait-Aissa
- Daniela Didier
- Johnathan Ebben
- Alena Hanson
- Joe Hockenberry
- Andrew D. Kadlec, PhD
- Minhi Kang
- Todd Le
- Jasmine Linn
- Micaela Young
Nedd4-2 upregulation is associated with ACE2 ubiquitination in hypertension.
(Mohammed M, Ogunlade B, Elgazzaz M, Berdasco C, Lakkappa N, Ghita I, Guidry JJ, Sriramula S, Xu J, Restivo L, Mendiola Plá MA, Bowles DE, Beyer AM, Yue X, Lazartigues E, Filipeanu CM.) Cardiovasc Res. 2023 May 10 PMID: 37161607 05/10/2023
Differential impacts of COVID-19 variants on human microvascular function.
(Nishijima Y, Hader SN, Beyer AM.) Cardiovasc Res. 2023 Mar 17;119(1):e115-e117 PMID: 36708228 SCOPUS ID: 2-s2.0-85150665595 01/29/2023
Lipid phosphate phosphatase 3 maintains NO-mediated flow-mediated dilatation in human adipose resistance arterioles.
(Chabowski DS, Hughes WE, Hockenberry JC, LoGiudice J, Beyer AM, Gutterman DD.) J Physiol. 2023 Feb;601(3):469-481 PMID: 36575638 SCOPUS ID: 2-s2.0-85145823691 12/29/2022
New developments in translational microcirculatory research.
(SenthilKumar G, Gutierrez-Huerta CA, Freed JK, Beyer AM, Fancher IS, LeBlanc AJ.) Am J Physiol Heart Circ Physiol. 2022 Dec 01;323(6):H1167-H1175 PMID: 36306213 PMCID: PMC9678417 SCOPUS ID: 2-s2.0-85142403599 10/29/2022
Adipose stromal vascular fraction reverses mitochondrial dysfunction and hyperfission in aging-induced coronary microvascular disease.
(Tracy EP, Nair R, Rowe G, Beare JE, Beyer A, LeBlanc AJ.) Am J Physiol Heart Circ Physiol. 2022 Oct 01;323(4):H749-H762 PMID: 36018760 PMCID: PMC9529257 SCOPUS ID: 2-s2.0-85139376250 08/27/2022
Emerging mitochondrial signaling mechanisms in cardio-oncology: beyond oxidative stress.
(Bikomeye JC, Terwoord JD, Santos JH, Beyer AM.) Am J Physiol Heart Circ Physiol. 2022 Oct 01;323(4):H702-H720 PMID: 35930448 PMCID: PMC9529263 SCOPUS ID: 2-s2.0-85139374997 08/06/2022
Endothelial dysfunction as a complication of anti-cancer therapy.
(Terwoord JD, Beyer AM, Gutterman DD.) Pharmacol Ther. 2022 Sep;237:108116 PMID: 35063569 PMCID: PMC9294076 SCOPUS ID: 2-s2.0-85123611979 01/23/2022
Greenspace, Inflammation, Cardiovascular Health, and Cancer: A Review and Conceptual Framework for Greenspace in Cardio-Oncology Research.
(Bikomeye JC, Beyer AM, Kwarteng JL, Beyer KMM.) Int J Environ Res Public Health. 2022 Feb 19;19(4) PMID: 35206610 PMCID: PMC8872601 SCOPUS ID: 2-s2.0-85124908145 02/26/2022
The impact of greenspace or nature-based interventions on cardiovascular health or cancer-related outcomes: A systematic review of experimental studies.
(Bikomeye JC, Balza JS, Kwarteng JL, Beyer AM, Beyer KMM.) PLoS One. 2022;17(11):e0276517 PMID: 36417344 PMCID: PMC9683573 SCOPUS ID: 2-s2.0-85142876878 11/24/2022
Noncanonical Role of Telomerase in Regulation of Microvascular Redox Environment With Implications for Coronary Artery Disease.
(Ait-Aissa K, Norwood-Toro LE, Terwoord J, Young M, Paniagua LA, Hader SN, Hughes WE, Hockenberry JC, Beare JE, Linn J, Kohmoto T, Kim J, Betts DH, LeBlanc AJ, Gutterman DD, Beyer AM.) Function (Oxf). 2022;3(5):zqac043 PMID: 36168588 PMCID: PMC9508843 09/29/2022
Lisinopril Mitigates Radiation-Induced Mitochondrial Defects in Rat Heart and Blood Cells.
(Ortiz de Choudens S, Sparapani R, Narayanan J, Lohr N, Gao F, Fish BL, Zielonka M, Gasperetti T, Veley D, Beyer A, Olson J, Jacobs ER, Medhora M.) Front Oncol. 2022;12:828177 PMID: 35311118 PMCID: PMC8924663 SCOPUS ID: 2-s2.0-85126780777 03/22/2022
Greenspace, Inflammation, Cardiovascular Health, and Cancer: A Review and Conceptual Framework for Greenspace in Cardio-Oncology Research
(Bikomeye JC, Beyer AM, Kwarteng JL, Beyer KMM.) International Journal of Environmental Research and Public Health. February-2 2022;19(4) SCOPUS ID: 2-s2.0-85124908145 02/01/2022