Microvascular Function Affinity Group
The Cardiovascular Center has initiated AFFINITY GROUPS to stimulate and foster greater interaction and collaborations between CVC investigators and other investigators from MCW departments and outside institutions, such as Marquette University, the University of Wisconsin Milwaukee and the University of Georgia.
The microvascular function affinity group is formed by the laboratories of David Gutterman, MD, Michael Widlansky, MD, MPH, David Zhang, PhD, and Andreas Beyer, PhD. The research conducted in this affinity group focuses on the regulation of microvascular reactivity in health and disease states. In particular, the group is interested in understanding how vasodilation occurs in response to chemical and mechanical stimuli in isolated human microvessels, and how the dilatory response is altered by underlying vascular such as atherosclerosis, hypertension, and diabetes. Following are the three main projects currently being carried out by this group.
Dr. Gutterman’s laboratory is studying the mechanism of hydrogen peroxide–induced dilation in human coronary arterioles. Dilation resulting from shear stress, a mechanical force generated by blood flow, is one of the most important physiological mechanisms of dilation, and it occurs in virtually every vascular bed. Although flow-induced dilation has been examined extensively in animals, few studies have been performed with human vessels. Dr. Gutterman’s lab has recently identified a novel mechanism whereby reactive oxygen species (ROS), specifically hydrogen peroxide (H2O2) from endothelial mitochondria, mediate flow-induced dilation in human coronary microvessels from patients with coronary artery disease. How H2O2 dilates coronary arterioles remains unclear. This project is designed to test the hypothesis that protein kinase G1 alpha (PKG1α) activation via protein dimerization is an important mechanism responsible for H2O2-induced dilation. These studies should provide novel insights into vascular redox signaling related to coronary blood flow regulation in health and disease.
Dr. Zhang’s laboratory is studying endothelial TRPV4 channels in flow-mediated dilation. The lab’s current focus is to study the signaling mechanisms by which shear stress activates endothelial cells, a thin layer of cells lining the lumen of all blood vessels, to induce the release of vasodilator factors leading to flow-induced dilation. Specifically, the study examines whether a calcium ion channel (TRPV4) located on the cell surface membrane of vascular endothelial cells serves an essential and conserved signaling component for shear-induced dilation in mice and humans. The findings of these studies will importantly contribute to our understanding of endothelial shear transduction and signaling, and may help identify new therapeutic targets for the treatment of vascular disorders.
Dr. Widlansky’s laboratory is looking at the role of disturbances in mitochondrial homeostasis in the development of endothelial dysfunction in humans with type 2 diabetes. Endothelial dysfunction has been shown to precede the development of atherosclerosis and portend cardiovascular events in both those with and without clinically evident cardiovascular disease. This project characterizes vasodilatory responses in human subcutaneous microvessels from subjects with or without type 2 diabetes, and examines whether and how disturbances in the function of endothelial mitochondria contribute to altered vascular responses in type 2 diabetes. This translational research will substantially increase our understanding with regard to pathophysiological mechanisms underlying the development of endothelial dysfunction in humans with a variety of disease states, including coronary artery disease and diabetes.
Dr. Beyer's lab is using existing pharmacological and genetic tools to study the importance of telomerase in the maintenance of vascular tone in human and rodent microvessels. The long-term goal is to determine the mechanism by which telomerase activity contributes to cellular and vascular health and to understand the mechanism involved in the change from health to disease leading to further systemic cardiovascular defects. Further, the role of telomerase in the response to external stressors such as obesity, increased salt load, or the existence of other cardiovascular risk factors is being investigated.
Cardiovascular Annual Report 2010
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