Jeffrey R. Bender, M.D. Robert I. Levy Professor of Preventive Cardiology Professor of Medicine (Cardiovascular Medicine) and Immunobiology Associate Chief, Cardiovascular Medicine Member, Vascular Biology and Therapeutics Program

B.A., Brandeis University, 1975; M.D., University of California, San Francisco, 1979; Residency Training, Yale-New Haven Hospital and Yale University School of Medicine, 1983; Postdoctoral Fellowship Training, Stanford University School of Medicine, 1988; Joined Yale Faculty, 1988. 

Inflammatory, Immune, Metabolic and Hormonal Effects on the Endothelium

Leukocyte-endothelial cell (EC) interactions are thought to play a role in a variety of pathological processes including inflammation, allograft rejection, and atherosclerosis.  As the contiguous barrier to circulating immunocompetent cells in vascularized allografts, donor endothelium is a major stimulator and target of alloimmune responses by recipient lymphocytes, resulting in graft rejection, one form of which is transplant coronary arteriosclerosis.  Furthermore, non-transplant atherosclerosis is now recognized as a multifactorial complex process that bears many similarities to chronic inflammatory conditions as demonstrated by the focal accumulation of leukocytes.  The gender/hormonal influences on the development of atherosclerosis may be manifested in alterations in these inflammatory components.  The systemic abnormalities associated with the metabolic syndrome have profound influences on the endothelium, creating an inflammatory, dysfunctional endothelial environment.  The efforts of my laboratory are directed at defining cellular and molecular mechanisms that govern leukocyte-EC interactions and endothelial dysfunction, and to test these molecular discoveries in animal vascular pathology models.  More specifically, there are four major areas of investigation:  (1)  molecular mechanisms of cell-cell adhesion;  (2) leukocyte-mediated vascular activation and injury; (3) influence of ovarian steroid hormones of endothelial activation; and (4) the effects of lipid abnormalities associated with the metabolic syndrome on angiogenesis.

With regard to the first area, our adhesion studies have focused on the heterodimeric integrin complex LFA-1 as a transmembrane signaling molecule in T lymphocytes and macrophages,  evaluating nuclear targets and stabilization of activating mRNAs encoding cytokines and chemokines involved in atherogenesis,  plaque instability and allograft rejection.  These studies include the development of leukocyte-specific  knockouts of  integrin-induced, regulatory genes and assessment in atherosclerosis, vascular rejection and ischemia-angiogenesis models.  The second area of investigation is most recently directed at novel subsets of innate immune cells that have the potential to modulate (promote or retard) atherosclerosis.  In vitro, ex vivo and animal model experiments address the localization and function of these cells in vascular pathology.  Thirdly, in our studies of hormonal effects on endothelial activation, we have recently focused on the effects of 17β-estradidiol on rapid, estrogen receptor (ER)-mediated signaling in EC, leading to nitric oxide synthase activation through a sequential kinase cascade.  Attempts to define novel, membrane-associated EC ERs, which mediate these responses, are ongoing.  This work includes vasoreactivity studies on aortas obtained from genetically modified mice, and membrane protein purification for ER structural analysis.  Recently, we have evaluated estrogen receptor isoforms in endothelial progenitor cells (EPCs), and how estrogen affects EPC contributions to angiogenic responses.  The fourth area involves assessing the effects of free fatty acids on endothelial responses to VEGF, and on angiogenic responses to ischemia in vivo.

My newest interest involves the broad area of "molecular imaging."  This represents a union of nuclear imaging with the basic principles of molecular and cellular biology to fashion a new means of evaluating basic disease processes and mechanisms of disease. These studies are being performed in collaboration with Mehran Sadeghi.



Li, L., Haynes, M.P., Bender, J.R. Plasma Membrane Localization and Function of the Estrogen Receptor α Variant (ER46) in Human Endothelial Cells.  Proc. Natl. Acad. Sci, USA., 100:4807-4812, 2003.

Sadeghi, M.M., Krassilnikova, S., Zhang, J., Gharaei, A.A., Luo, G., Kooshkabadi, A., Edwards, S., Yalamanchili, P., Harris, T.D., Sinusas, A.J., Zaret, B.L., Bender, J.R.:  Detection of injury-induced proliferative process by targeting activated αvβ3 integrin in vivo.  Circulation, 110:84-90, 2004.

Fabbri, M., Di Meglio, S., Gagliani, M.C., Consonni, E., Molteni, R., Bender, J.R. Tacchetti, C., Pardi, R.:  Dynamic partitioning into lipid rafts controls the endo-exocytic cycle of the l/2 integrin (LFA-1) during leukocyte chemotaxis. Mol Biol Cell.  116:5793-5803, 2005.

Kim, K-H., Bender, J.R.:  Rapid, Estrogen Receptor-mediated Signaling in Vascular Cells:  Why is the Endothelium So Special? Science (STKE).  pe28, 1-4, 2005.

Zhang, J., Krassilnikova, S., Gharaei, A.A., Fassaie, H.R., Esmailzadeh, L., Asadi, A., Edwards, D.S., Harris, T.D., Azure, M., Tellides, G., Sinusas, A., Zaret, B., Bender, J.R., Sadeghi, M.:  αvβ3- targeted detection of arteriopathy in transplanted human coronary arteries:  an autoradiographic study.  FASEB J.  19:1857-1859, 2005.

Mehra, V., Ramgolam, V., Bender, J.R.:  Inflammatory Mechanisms in Vascular Disease.  Drug Discovery Today:  Molecular Mechanisms, 2:77-84, 2005.

Wang, J.,   Collinge, M., Ramgolam, V.  Ayalon, A., Xinhao, C.F., Pardi, R., Bender, J.R.:  LFA-1-Dependent HuR Nuclear Export and Cytokine mRNA Stabilization in T Cell Activation..  J. Immunol. 176(4):2105-2113, 2006.

Moriarty, K., Bender, J.R.:  Rapid, Non-genomically Mediated Effects of Estradiol, Endocrinology, 147:5557 – 5563, 2006.

Sadgehi, M.M., Bender, J.R.:   Targeting αvβ3 in vascular remodeling.  Trends in Cardiovascular Medicine.  17:5-10, 2007

Smith, D., Sadeghi, M.M., Bender, J.R.:  Imaging Targets in Atherosclerosis. In:  Textbook of Cardiovascular Molecular Imaging. Informa Healthcare Publishing.  Ed.  Sinusas A, Gropler R, Glover D, Taegtmeyer H.  Ch. 18, p. 189-202, 2007.

Li, L., Hisamoto, K., Haynes, P.,  Bauer, P., Sanjay, A., Baron,R., Sessa, W.C., Bender, J.R. Variant Estrogen Receptor -c-Src Molecular Interdepen Proc. Natl. Acad. Sci, USA, 104(42):16468-16473, 2007.

Panattoni, M., Sanvito, F., Basso, V., Bender, J.R., Doglioni, C., Casorati, G., Mondino, A., Pardi, R.:  Targeted Inactivation Of the COP9 Signalsome Impairs Multiple Stages Of T Cell Development. J. Exp. Med.,  doi:10/1084/jem/20070725, 2008.

Kim, KH, Moriarty K, Bender, JR:  Vascular cell signaling by membrane estrogen receptors.  Steroids, in press.

Ramgolam, V., DeGregorio, S., Subaran, S., Pardi, R., Collinge, M., Bender, J.R.: LFA-1 Engagement Induces HuR-dependent Cytokine mRNA Stabilization Through a Phosphadylinositol 3-Kinase, Vav-1, Rac Cascade.  J. Immunol., submitted.

Copyright © 2000, Yale University, New Haven, Connecticut, USA.
All rights reserved. Comments or suggestions to site editor.
Certifying authority:

Last modified:Thursday, 03-Apr-2008 14:29:11 EDT (PL).