Gary P. Van Guilder
Ph.D.: University of Colorado at Boulder
Postdoctoral Training: Vanderbilt University Medical Center, University of Colorado Medical Center
Integrative Vascular Cytoprotection Laboratory
Department of Health & Nutritional Sciences
Wagner Hall Room 401/138
Vascular endothelial biology and function, endogenous cytoprotection, exercise physiology, ischemic conditioning, lactate metabolism, menstrual cycle
The overall focus of the Van Guilder Laboratory is to determine the biological mediators that affect vascular endothelial stress resistance and resilience in the context of increased cardiovascular disease risk in humans. A major focus is to develop new therapeutic strategies to improve cell protection from ischemia-reperfusion injury, which today remains clinically untreatable with existing cardioprotective interventions. Therapeutic strategies span mechanical (remote ischemic preconditioning), pharmacological (lactate infusions) and lifestyle (diet and exercise) approaches to bolster cell protection. In particular, we are currently investigating how alterations in lactate, a preferred energy substance for the body, influences vascular protection. The old train-of-thought was that lactate was simply a metabolic waste product. The vision today recognizes lactate as having many diverse roles related to gene expression, cell signaling, blood flow regulation and cell repair. This suggests that lactate has promising therapeutic value aimed at reducing cell injury. For example, as shown in the drawing below, a cell that has been preconditioned, particularly the endothelial cell or a cardiac muscle cell, tends to shift lactate towards metabolic energy production compared with a cell that has not been preconditioned. By enabling a better use of lactate inside the cell, less lactate is 'wasted' and can stimulate cytoprotective responses that reduce damage from ischemia/reperfusion injury.
Another focus of my lab is to better understand how the menstrual cycle in women affects vascular endothelial cytoprotection. We know that serious consequences associated with ischemia/reperfusion injury are becoming more frequent in younger groups of premenopausal women. Despite successful coronary revascularization, women develop more severe bleeding, more in-hospital mortality and more widespread postoperative myocardial infarctions and non-cardiac organ injury compared with men of similar age. Invoking cell protection could be more challenging depending on the phase of the menstrual cycle.
Vascular Endothelial Function Experiments and Research Approach
To address these research questions, we employ a variety of integrative methodological approaches exclusively in humans. Experimental techniques involve measuring vascular function in vivo in response to reactive hyperemia, vasoactive drug infusions and with acute bouts of exercise. We utilize randomized crossover designs, cross-sectional approaches or interventions to address our research questions.
In the image below, we use are using strain-gauge venous occlusion plethysmography to quantify changes in brachial artery reactive hyperemia in response endothelial ischemia/reperfusion injury. This technique can also be used to also draw samples of blood from the vein and artery to quantify whole blood lactate turnover. Together with measures of forearm blood flow, provides a great way to demonstrate how well the vascular system is working under stress and with health and disease.
In the experimental set-up below, the subject is placed on a bed with two blood pressure cuffs placed on their upper arms. Inflation of these cuffs can be manipulated to occlude the brachial artery or veins. Remote ischemic preconditioning can be invoked by inflating the blood pressure cuff on the person’s right arm to occlude blood flow through the brachial artery three times for a period of 5 min per cycle. In our experiments, we cause transient endothelial ischemia/reperfusion injury in the left arm. To do this, we inflate the blood pressure cuff for 20 min. This technique can be used to determine if cell protection by remote ischemic preconditioning is working properly, or if it is influenced by disease and related factors.