Cardio-and Cerebro-Vascular (CCVR) Research Laboratory
Research Interests
•Chronic Stress & Vascular Contributions to Cognitive Impairment & Dementia (VCID)
•Electronic cigarettes and vascular dysfunction
•Obesity & Exercise and their role in vascular biology
Description of Research
Research in my laboratory is focused on vascular biology and how certain disease states (obesity, and aging) or conditions (chronic stress, E-cig, or exercise) mediates vascular biology. My lab operates with both human and animal models; this dual approach allows us to further explore the mechanisms underlying the vascular consequences of disease progression. We have shown that the fat around the aorta plays a significant role on vascular health and disease progression. Recently, we have focused on the microvessels in the brain, and how vascular damage here contributes to cognitive impairment and VCID. Indeed, we have shown that chronic stress is involved in accelerating VCID due to a pro-oxidative microenvironment impacting the cerebrovascular network, resulting in impaired vascular function, structure, and a loss of vessels. This project is currently funded by NIH for the next 4 years (2021-2025).
Another area of focus is the role of E-cig exposure on vascular function. In collaboration with Dr. Olfert, we started off and examined the chronic (8-months) effects of e-cig exposure on aortic function and stiffness in adult mice. We report that E-cig exposure for the equivalent of ~25 yr of exposure in humans increased arterial stiffness and impaired aortic reactivity, similar to other risk factors, including cigarette smoking, which contribute to the development of cardiovascular disease. We have also shown that rats exposed to e-cig while pregnant causes severely impaired cerebrovascular dysfunction and aortic stiffness. This project is currently funded by NIH and AHA.
As a member of the Center for Inhalation Toxicology and the Center for Basic and Translational Stroke Research, and my strong collaborations outside of my lab (Phys Pharm, neuroscience, immunology etc) ensures that the lab is positioned in a fertile and collaborative environment conducive to ensure successful attainment of the research goals.
I am extremely grateful to the various funding agencies (NIH, AHA, Benedum) and the internal WVU programs for supporting this research
NIH funded projects
We currently have two funded projects:
Vascular contributions to cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzheimer's disease (AD), and is a frequent comorbidity with AD. Furthermore, the deleterious effect of vascular pathologies combined with AD pathology leads to increased likelihood of dementia. Despite the importance of VCID, little is known about its molecular mechanisms underlying vascular and cognitive dysfunction. Chronic psychosocial stress is a risk factor of VCID. Our preliminary data showing that chronic stress leads to considerable cerebrovascular and neuroinflammatory changes that have similar fundamental changes evident in the progression of AD has led us to focus on this process. Endothelial dysfunction is a critical determinant of vascular disease and predictor of clinical events. The overall goal of this study is to determine the etiology of the stress-related XOR and pro-inflammatory changes in mediating VCID, and its progression to AD pathology. The studies will fill gaps identified by the NIH regarding the need for understanding of vascular contributions to cognitive impairment and dementia.
Funded by NIH
We have also established that the obese rats and mice expresses underlying depressive symptoms, and when the obese rodents are exposed to chronic mild stress they develop significant vascular pathologies that are mechanistically drive by adipose tissue oxidative stress and inflammation. Further, chronic exposure to mild stress in a health lean animal results in vascular pathologies similar to that in a non-stressed obese rodents, and the lean adipose tissue phenotype becomes pro-inflammatory with increased oxidative stress. Importantly, exercise performed during the chronic mild stress ameliorates the vascular pathologies. We have also identified sex-differences with regard to how the vasculature is affected by chronic stress. In addition, we have examined how the adipose tissue surrounding the vasculature playas a direct role in modulating vascular function, and that with chronic stress the adipose tissue phenotype is modulated to a “bad” phenotype which has negative actions on vascular function.
3. In collaboration with Dr. Olfert, we are determining the effects of e-cig exposure on vascular health. Initially, we started off and examined the chronic (8-months) effects of e- cig exposure on aortic function and stiffness in adult mice. We report that E-cig exposure for the equivalent of ~25 yr of exposure in humans increased arterial stiffness and impaired aortic reactivity, similar to other risk factors, including cigarette smoking, which contribute to the development of cardiovascular disease. For this application, we have shown that rats exposed to e-cig while pregnant causes severely impaired cerebrovascular dysfunction and aortic stiffness in the offspring.
This work was recently funded by NIH (R21) to further explore the mechanisms behind the vascular dysfunction.
Vaping has surpassed all other forms of tobacco use in middle- and high-schoolers. New research led by Mark Olfert, and Paul Chantler, associate professors in the West Virginia University School of Medicine, suggests if teenagers continue to vape into adulthood, the cardiovascular effects may, by some measures, be as dire as if they’d smoked cigarettes. https://wvutoday.wvu.edu/stories/2018/10/09/wvu-researcher-delves-into-cardiovascular-effects-of-vaping
West Virginia University’s new Inhalation Facility will be the home for research and collaborations that measure, identify and discover how the particles we breathe affect our health. Timothy Nurkiewicz, a microvascular physiologist in the School of Medicine’s Department of Physiology, Pharmacology and Neuroscience, is the director of the new lab. It will also enable upcoming research into how nanomaterials and other inhalable particles from things like e-cigarettes, auto emissions and the aerosols released during 3-D printing may impact our health.
Human clinical studies reflect how exercise interventions or pharmacological supplementation can impact cardiovascular health. We then use our pre-clinical models to explore the mechanisms by which exercise mediated the beneficial actions.
Undergraduate student Brianna Skaff performing PWA as part of her undergraduate research project.
A significant focus on the lab is the role of obesity on CVD risk. In pre-clinical models of obesity we have shown that the perivascular adipose tissue mediates some of the aortic dysfunction noted with obesity via a TNF-a/NOX2 pathway, and that exercise training can reverse the actions of perivascular adipose tissue on aortic function.
Abstract:
The aim of the study was to determine the effects of exercise training on improving the thoracic perivascular adipose tissue (tPVAT) phenotype (inflammation, oxidative stress, and proteasome function) in metabolic syndrome and its subsequent actions on aortic function.
Methods: Lean and obese (model of metabolic syndrome) Zucker rats (n=8/group) underwent 8-weeks of control conditions or treadmill exercise (70% of max speed, 1 h/day, 5 days/week). At the end of the intervention, the tPVAT was removed and conditioned media was made. The cleaned aorta was attached to a force transducer to assess endothelium-dependent and independent dilation in the presence or absence of tPVAT-conditioned media. tPVAT gene expression, inflammatory /oxidative phenotype, and proteasome function were assessed.
Results: The main findings were that Ex induced: (1) a beige-like, anti-inflammatory tPVAT phenotype; (2) a greater abundance of •NO in tPVAT; (3) a reduction in tPVAT oxidant production; and (4) an improved tPVAT proteasome function. Regarding aortic function, endothelium-dependent dilation was greater in exercised lean and obese groups vs. controls (p < 0.05). Lean control tPVAT improved aortic relaxation, whereas obese control tPVAT decreased aortic relaxation. In contrast, the obese Ex-tPVAT increased aortic dilation, whereas the lean Ex-tPVAT did not affect aortic dilation.
Conclusion: Overall, exercise had the most dramatic impact on the obese tPVAT reflecting a change towards an environment with less oxidant load, less inflammation and improved proteasome function. Such beneficial changes to the tPVAT micro-environment with exercise likely played a significant role in mediating the improvement in aortic function in metabolic syndrome following 8 weeks of exercise. https://pubmed.ncbi.nlm.nih.gov/31374361/
Research Support
Ongoing Research Support
NIH, NINDS, BINP R01 NS117754, Psychosocial Stress-Induced Vascular Contributions To Cognitive Impairment And Alzheimer's Disease: The Role of Xanthine Oxidase
Chronic psychosocial stress is a major risk factor that contributes to the vascular contributions to cognitive impairment and dementia. The purpose of this project is to determine the mechanisms by which chronic stress contributed to cerebrovascular dysfunction and cognitive decline, and the relationship with Alzheimer’s disease, with a focus on the mechanistic role of xanthine oxidase. 9/1/21-7/31/2025
Role: PI (Chantler)
20CSA35320107 Collaborative Sciences Award
Vascular Dysfunction in Offspring Exposed to Maternal Vaping
Role: CO-PI (Olfert, Chantler, Dakhlallah, Boyd)
Completed Research Support
NIH, BINP R56 NS117754-01, Psychosocial Stress-Induced Vascular Contributions To Cognitive Impairment And Alzheimer's Disease: The Role of Xanthine Oxidase
Chronic psychosocial stress is a major risk factor that contributes to the vascular contributions to cognitive impairment and dementia. The purpose of this project is to determine the mechanisms by which chronic stress contributed to cerebrovascular dysfunction and cognitive decline, and the relationship with Alzheimer’s disease, with a focus on the mechanistic role of xanthine oxidase. 9/15/20-8/31/2021
Role: PI (Chantler)
1R21 DA051745-01 (NINDA/NIEHS) 07/01/2020-06/30/22
Effects of electronic cigarette wattage setting on vascular harm
Role: CO-PI (Chantler and Olfert)
WV CTSI Pilot Project 10/05/17 – 09/31/18
West Virginia Clinical Translational Science Institute
Role: PI
P20 GM109098 Simpkins (Grant PI) West Virginia Stroke CoBRE 09/01/14 - 08/31/17
Chantler (Project PI): The Impact of Cardiovascular Function on Acute Ischemic Stroke Outcome
The purpose of this grant is to examine the effects of CVD on ischemic stroke severity. Focus will include autonomic control of blood pressure and immune dysfunction in both human and animal (lean and obese Zucker rats) models.
Role: Project PI
WV CTSI Pilot Project 07/01/14 – 06/31/15
West Virginia Clinical Translational Science Institute
Title: Multilifestyle intervention in Rural West Virginia
Role: PI
Benedum Foundation Chantler (PI) 01/01/14 – 12/31/14
Title: The Diabetic rHeART (The Rural Health: Accelerating Research Translation).
Role: PI
National Swimming Pool Foundation Chantler (PI) 09/01/12-08/31/14
The Effects of Aquatic Based Exercise Training on Arterial Stiffness in Patients with
the Metabolic Syndrome
Role: PI
11 CRP7370056 Chantler (PI) 07/01/11-06/30/14
American Heart Association
Cardiac and Arterial Responses to Exercise Study (CARES)
The purpose of this grant is to examine the effects of 8 weeks of resistance training on
arterial stiffness in patients with the metabolic syndrome.
Role: PI
WVU Program to Stimulate Competitive Research Chantler (PI) 01/01/12-12/31/12
The Effects of Resveratrol on Arterial Stiffness in Patients with the Metabolic Syndrome
Role: PI
Research Foundation Development Grant, West Virginia University Chantler (PI) 03/02/11-02/29/12
The purpose of this grant is to examine the effects of exercise training on cardiovascular
function in patients with the metabolic syndrome.
Role: PI