Denisa D. Wagner

Department of Pathology
Harvard Medical School
The CBR Institute for Biomedical Research
800 Huntington Avenue
Boston, MA 02115
Tel: 617-278-3344
Fax: 617-278-3368
email:wagner@cbr.med.harvard.edu
Website:The Wagner Lab
11 Postdoctoral Fellows, 1 Graduate Student

My laboratory is interested in the rapid response of leukocytes, platelets and endothelial cells to vascular injury. We have shown that endothelial cells store the adhesion proteins von Willebrand factor and P-selectin in storage granules called Weibel-Palade bodies. Inflammatory stimuli (such as histamine) and injury stimuli (such as thrombin and fibrin) cause rapid exocytosis of the storage granules. We have prepared mice that are deficient in P-selectin or von Willebrand factor by homologous recombination in embryonic stem cells. The P-selectin-deficient mice have a pronounced defect in leukocyte interaction with the endothelium of the vessel wall and with activated platelets. von Willebrand factor-deficient mice have defects in platelet adhesion and a prolonged bleeding time. Currently, we study these animals in experimental models of thrombosis, inflammation, atherosclerosis and blood brain barrier function.

Endothelial cells treated with inflammatory cytokines synthesize another selectin, E-selectin, and, similar to P-selectin, it also mediates binding to leukocytes. We prepared mice deficient in both P-and E-selectins. In contrast to the rather mild phenotypes observed in mice deficient in a single selectin gene, the doubly deficient mice present extreme leukocytosis, elevated cytokine levels and alterations in hematopoiesis. Virtual lack of leukocyte rolling and low extravasation at sites of inflammation make these animals susceptible to opportunistic bacterial infections to which they succumb. The phenotype of these mice shows that the absence of endothelial selectins severely affects leukocyte homeostasis and indicates that these two selectins are as important for normal leukocyte function as the leukocyte ß2 integrins.

Recently, we became interested in the molecules involved in angiogenesis and the maintenance of blood brain barrier (BBB) -- a specific function of brain endothelium. We study the role of leukocyte and platelets in these processes. We found that apoE, a protein linked to pathogenesis of Alzheimer’s disease, is crucial for the maintenance of the BBB especially after brain injury. Thus we began to investigate a possible link between leaky brain vessels and neurodegenerative disease.

Papers & Publications:

1. Andre P, Prasad KSS, Denis CV, He M, Papalia JM, Hynes RO, Phillips DR and Wagner DD. CD40L stabilizes arterial thrombi by a β3 integrin-dependent mechanism. Nature Med. 8:247-252, 2002.
2. Hrachovinova I, Cambien B, Hafezi-Moghadam A, Kappelmayer J, Camphausen RT, Widom A, Xia L, Kazazian HH Jr, Schaub RG, McEver RP and Wagner DD. P-selectin/PSGL-1 interaction generates microparticles that correct hemostasis in a murine model of hemophilia A. Nat Med 9:1020-1025, 2003.
3. Kisucka J, Butterfield CE, Duda DG, Eichenberger SC, Saffaripour S, Ware J, Ruggeri ZM, Jain RK, Folkman J and Wagner DD. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage.Proc Natl Acad Sci USA 103: 855-860, 2006.
4. Chauhan AK, Motto DG, Lamb CB, Bergmeier W, Dockal M, Plaimauer B, Scheiflinger F, Ginsburg D and Wagner DD. Systemic anti-thrombotic effects of ADAMTS13.J Exp Med. 203:767-776, 2006.