Mack H. Wu, M.D.
Associate Professor
Division of Research
Department of Surgery
UC Davis Medical Center

I am interested in the signal transduction of growth factors in regulating microvascular function.  My laboratory is conducting research projects investigating: 1) the signaling mechanism of microvascular vasomotor and permeability responses to vascular endothelial growth factors (VEGFs) and fibroblast growth factor (FGFs); 2) the molecular control of endothelial cell-cell and cell-matrix interactions; and 3) VEGF regulation of angiogenesis and tumor metastasis. We study these problems using an integrative approach that combines the intact perfused microvessel model with cellular and molecular analyses. Experimental techniques that are currently employed in the lab include intravital microscopy, fluorescence confocal microscopy, atomic force microscopy, DNA/protein transfection, real-time RT-PCR, and microarray profiling of genes and proteins.

The wall of exchange microvessels consists of endothelial cells that connect to each other with closely opposed intercellular junctions.  This endothelial lining is tethered to a network of extracellular matrices via integrin-composed focal adhesion complexes.  Adhesive interactions at the cell-cell and cell-matrix contacts play an essential role in the maintenance of endothelial barrier integrity. Biochemical reactions or conformational changes in these adhesive structures lead to endothelial hyperpermeability and microvascular leakage. The molecular mechanisms that control the junction and focal adhesion responses are poorly understood. Limited information is available regarding how barrier structure and function are regulated by VEGF, an important cytokine that has been implicated in a wide range of physiological and pathological processes, including angiogenesis, wound healing, ischemia-reperfusion injury, diabetic complications, and tumor growth and metastasis.

Our earlier studies have revealed that VEGF induces endothelial hyperpermeability by activating an intracellular signaling cascade involving phospholipase C, calcium, nitric oxide, protein kinase C, and cGMP-dependent protein kinase.  Subsequent studies have extended this cascade to MAP kinases, with MEK1/2 identified as an important downstream signal that serves as a common pathway in the response to VEGF and various inflammatory mediators. Currently, our research effort is directed toward the identification of end-point cellular processes in the induction of microvascular leakage. The interactions between the endothelial contractile cytoskeleton and adherens junctions as well as focal adhesions are being closely examined with an emphasis on their biochemical and structural modifications during stimulation by VEGF.  In parallel, the impact of VEGF-induced endothelial barrier opening on tumor cell invasion and metastasis and its mechanisms of action are under investigation.

Sun H, Breslin J, Zhu J, Yuan SY, Wu MH. Involvement of the Rho GTPase in VEGF-induced microvasular  hyperpermeability.  Microcirculation  13: 1-11, 2006

Wu MH. Focal adhesion kinases and endothelial barrier function. J Physiol (London) 569: 359-366, 2005 (invited review)

Wu MH, Yuan SY and Granger HJ. The protein kinase MEK1/2 mediate VEGF- and histamine-induced porcine coronary venular hyperpermeability. J Physiol (London) 563 95-104, 2005

Wu MH, Guo M, Yuan SY, and Granger HJ.  Focal adhesion kinase mediates porcine venular hyperpermeability elicited by vascular endothelial growth factor. J Physiol (London) 552: 691-699, 2003

Wu MH, E Ustinova E and HJ Granger HJ. Integrins binding to fibronectin and vitronectin maintains the barrier function of isolated porcine coronary venules. J Physiol 532:785-791, 2001

Wu MH, Yuan Y, Zawieja DC, Tinsley JH and Granger HJ. Role of phospholipase C, protein kinase C and calcium in VEGF-induced venular hyperpermeability. Am J Physiol 276: H535-H542, 1999

Wu MH, Huang Q, Yuan Y, Granger HJ. VEGF induces NO-dependent hyperpermeability in coronary venules. Am J Physiol 271: H2735-H2739, 1996