Sarah Y. Yuan, M.D., Ph.D.
Pearl Stamps Stewart Professor
Director, Division of Research
Department of Surgery
UC Davis Medical Center

The overall goal of our research program is to elucidate the cellular and molecular mechanisms that regulate cardiovascular function in health and disease. Our current projects investigate the signal transduction in blood and vascular cell-cell and cell-matrix interactions that control microcirculation during trauma and inflammation, as well as the molecular pathogenesis of diabetic cardiovascular complications. We employ a multidisciplinary research approach using in vivo, in situ, and in vitro models that integrate cell molecular biology with system pathophysiology. Techniques utilized in our experiments include 3D fluorescence imaging, FRET, AFM, ECIS, isometric tension, and various molecular analyses with genetic mutation and gene knockout. Our lab has been recognized for developing unique experimental models, such as the isolated microvessel preparation for quantification of permeability, and protein/peptide transfection to intact tissues for targeted delivery. These models provide powerful tools for identification and characterization of specific structural and signaling molecules in the regulation of cardiovascular function.

Microvascular hyperpermeability is a hallmark of inflammatory response seen in trauma, sepsis, diabetes, and tumor metastasis. Our research in this area is directed to the signaling mechanisms of leukocyte-endothelium interactions in regulating microvascular barrier function. We examine various injurious conditions ranging from systemic inflammation resulting from burn, sepsis and blast injury to cell models of infection and tumor transmigration. We find that shear stress, growth factors, and chemical mediators are capable of activating PLC, PKC, NOS, PKG, MAPK, FAK, Src, and MLCK. Theses signaling cascades trigger cellular responses characterized by cytoskeletal contraction, adherens junction dissociation, tight junction internalization, and focal adhesion redistribution. Moreover, neutrophils play a central role in this process by coordinating the signaling and structural changes leading to widened paracellular pathways for plasma leakage or cell transmigration. Our ongoing studies continue to characterize the molecular basis and biophysical properties of the contractile cytoskeleton and cell-cell or cell-matrix adhesive structures with a practical view toward future development of therapies targeting the end-point cellular process of barrier injury.

Cardiovascular complications are a major cause of morbidity and mortality in patients with diabetes, obesity, and atherosclerosis. The end-organ diseases stem from microcirculatory disturbance, of which the underlying mechanism remains poorly understood. Our initial efforts in this area have led to the development of a clinically relevant animal model of diabetes. Subsequent genomic and functional characterization in theses animals demonstrate that hyperglycemia and dyslipidemia are associated with abnormal expression of PKC genes coupled with arteriolar vasomotor dysfunction and venular hyperpermeability. Further molecular assays indicate differential regulation of multiple PKC isozymes at both the transcriptional and posttranslational levels, where PKCβ plays a dominant role in vascular barrier dysfunction. More recently, we have developed a FRET-based 3D imaging analysis to further characterize the kinase subcellular dynamics and activity. Through these studies we hope to identify new therapeutic targets for better treatment and prevention of diabetic complications.

Tinsley JH, Wu MH, Ma W, Taulman AC, and Yuan SY. Activated neutrophils induce hyperpermeability and phosphorylation of adherence junction proteins in coronary venular endothelial cells. J Biol Chem 274: 24930-24934, 1999

Yuan SY, Ustinova EE, Wu MH, Tinsley JH, Korompai FL, Xu W, and Taulman AC. PKC activation contributes to microvascular barrier dysfunction in the heart at early stages of diabetes. Circ Res 87: 412-417, 2000

Yuan SY, Wu MH, Ustinova EE, Tinsley JH, and Xu W. Myosin light chain phosphorylation in neutrophil-stimulated coronary microvascular leakage. Circ Res 90: 1214-1221, 2002.

Yuan SY. Protein kinase signaling in the modulation of microvascular permeability. Vascular Pharmacology 39: 213-223, 2003.

Gaudreault N, Perrin RM, Guo M, Clanton CP, Wu MH, and Yuan SY.  Counter-regulatory effects of PKCβ and PKCβ on coronary endothelial permeability.  Arterioscler Thromb Vasc Biol.  28: 1527-1533, 2008.