Cardiology; Endothelium; Immune System; Inflammation; Macrophages; T-Lymphocytes; RNA Stability
Stem Cell Center, Yale: Tissue Specific Stem Cells
Defining cellular, molecular and immunological mechanisms governing leukocyte-endothelial cell (EC) interactions and endothelial dysfunction, and testing these molecular discoveries in animal vascular pathology models, include studies of:
- molecular mechanisms of intercellular adhesion;
- leukocyte-mediated vascular injury;
- influence of ovarian steroid hormones on endothelial activation; and
- effects of lipid abnormalities associated with the metabolic syndrome on angiogenesis.
Studying the integrin LFA-1 as a transmembrane signaling molecule in T lymphocytes and macrophages, evaluating nuclear targets and stabilization of activation mRNAs encoding cytokines and chemokines involved in atherogenesis, plaque instability, allograft rejection and angiogenesis; also using recently generated mice with leukocyte-specific, integrin-induced, mRNA regulatory gene deletions. Studying the effects of 17b-estradiol on rapid, novel membrane estrogen receptor-mediated signaling in EC, leading to nitric oxide synthase activation. Newest interest is “molecular imaging”, merging in vivo imaging methods with basic biologic principles to evaluate disease mechanisms and progression.
Specialized Terms: Inflammatory, Immune, Metabolic and Hormonal Effects on the Endothelium
Extensive Research Description
My laboratory has had a longstanding interest in inflammation and immunity, as they relate to vascular physiology and pathology. The interactions between mononuclear leukocytes and endothelial cells play major roles in atherogenesis, acute and chronic manifestations of atherosclerosis, angiogenesis and allograft rejection. We have extended these studies to evaluating effects of ovarian steroid hormones on endothelial function. The work is performed at the cellular, molecular, and pre-clinical animal model levels. Our major efforts are directed at:
(1) Integrin-dependent leukocyte adhesion and T cell/macrophage gene expression.
We have discovered that when β2 integrins are engaged in T lymphocytes, labile mRNAs that are normally rapidly degraded are markedly stabilized. This includes transcripts encoding many immune and pro-inflammatory cytokines, such as TNF, IFN-γ, IL-1, and IL-17. We have defined the signal transduction cascade, which involves Rho family GTPases, and modulation of select RNA-binding proteins, most notably HuR. Through proteomics approaches, we have recently defined integrin-induced nuclear protein-protein interactions, which we believe will be important targets for molecular therapeutics. In addition to our studies on cells of the adaptive immune system, we have recently extended our work to innate immune cells, namely monocyte/macrophages. Many of the aforementioned signaling events occur in these cells as well. Relevant integrin-stabilized mRNAs in macrophages include those encoding angiogenic molecules, such as VEGF, MMPs and angiopoietins, and many of the pro-inflammatory molecules mentioned above. To determine the role of this adhesion-induced mRNA stabilization mechanism in vivo, we have recently targeted the HuR gene, and are using tissue-specific knockout mice for pre-clinical studies.
Macrophage-specific HuR knockouts indeed have prominent angiogenic defects in response to inflammation or ischemia. Vascular remodeling, atherosclerosis and allograft rejection models are being developed with these genetically modified animals.
(2) Influence of ovarian steroid hormones on endothelial activation and endothelial progenitor cell function.
The effects of estrogen on the endothelium remains a major question, despite clinical controversies regarding hormone replacement therapy in postmenopausal women, We have defined a splice form of estrogen receptor (ER)α, ER46, that is plasma membrane-targeted in endothelial cells and which initiates rapid signaling responses, leading to eNOS activation, nitric oxide release and vasodilation in vivo. Most recently, we have used a variety of cell imaging techniques, including FRET and TIRF microscopy, to demonstrate that ER46 has transmembrane spanning and ectodomains, and multiple membrane pools. This has never been described for a steroid hormone receptor, and provides a tremendous opportunity for differential therapeutic targeting.
(3) Effects of metabolic syndrome-associated lipids on endothelial function.
We have recently defined a series of endothelial cell signaling defects imparted by free fatty acids, leading to a state of "VEGF resistance", and greatly impaired responses to angiogenic growth factors. We have documented a mechanistic role of ceramide generation, in vitro, and demonstrated that such lipids cause impaired angiogenic responses to hindlimb ischemia in murine models. Current studies include mapping the cellular and molecular defects, those which occur both at the plasma membrane and Golgi.
- Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β Production. Ceneri N, Zhao L, Young BD, Healy A, Coskun S, Vasavada H, Yarovinsky TO, Ike K, Pardi R, Qin L, Qin L, Tellides G, Hirschi K, Meadows J, Soufer R, Chun HJ, Sadeghi MM, Bender JR, Morrison AR. Arterioscler Thromb Vasc Biol. 2017 Feb;37(2):328-340. doi: 10.1161/ATVBAHA.116.308507.
Chemokine-coupled ß2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis
Morrison AR, Yarovinsky TO, Young BD, Moraes F, Ross TD, Ceneri N, Zhang J, Zhuang ZW, Sinusas AJ, Pardi R, Schwartz MA, Simons M, Bender JR. Chemokine-coupled ß2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis. J Exp Med. 2014 Sep 22;211(10):1957-68. doi: 10.1084/jem.20132130. PMID:25180062
Ceramide-activated phosphatase mediates fatty acid-induced endothelial VEGF resistance and impaired angiogenesis
Mehra VC, Jackson E, Zhang XM, Jiang XC, Dobrucki LW, Yu J, Bernatchez P, Sinusas AJ, Shulman GI, Sessa WC, Yarovinsky TO, Bender JR. Ceramide-activated phosphatase mediates fatty acid-induced endothelial VEGF resistance and impaired angiogenesis. Am J Pathol. 2014 May;184(5):1562-76. PMID: 24606881
Endothelial estrogen receptor isoforms and cardiovascular disease
Kim KH, Young BD, Bender JR. Endothelial estrogen receptor isoforms and cardiovascular disease. Mol Cell Endocrinol. 2014 May 25;389(1-2):65-70. PMID: 24530925
The PAR complex controls the spatiotemporal dynamics of F-actin and the MTOC in directionally migrating leukocytes
Crespo CL, Vernieri C, Keller PJ, Garrè M, Bender JR, Wittbrodt J, Pardi R.The PAR complex controls the spatiotemporal dynamics of F-actin and the MTOC in directionally migrating leukocytes. J Cell Sci. 2014 Sep 1. pii: jcs.146217. [Epub ahead of print] PMID:25179599
Silver lining in the dark cloud of aneurysm disease
Chau KH, Bender JR, Elefteriades JA. Silver lining in the dark cloud of aneurysm disease. Cardiology. 2014;128(4):327-32. doi: 10.1159/000358123. Epub 2014 Jun 17. PMID: 24942201
Transmembrane protein ESDN promotes endothelial VEGF signaling and regulates angiogenesis
Nie L, Guo X, Esmailzadeh L, Zhang J, Asadi A, Collinge M, Li X, Kim JD, Woolls M, Jin SW, Dubrac A, Eichmann A, Simons M, Bender JR, Sadeghi MM. Transmembrane protein ESDN promotes endothelial VEGF signaling and regulates angiogenesis. J Clin Invest. 2013 ;123(12):5082-97.
Macrophage ß2 integrin-mediated, HuR-dependent stablization of angiogenic-factor encoding mRNAs in inflammatory angiogenesis
Zhang, J., Modi, Y., Yarovinsky, T., Yu, J., Collinge, M., Kyriakides, T., Zhu, Z., Sessa, W.C., Pardi, R., Bender, J.R.: Macrophage ß2 integrin-mediated, HuR-dependent stablization of angiogenic-factor encoding mRNAs in inflammatory angiogenesis. Am. J. Pathol. 180:1751-1760, 2012.
Splice isoform estrogen receptors as integral transmembrane proteins
Kim, K.H., Toomre, D., Bender, J.R.: Splice isoform estrogen receptors as integral transmembrane proteins. Mol. Biol. Cell. 22:4415-4423, 2011. PMID: 21937726
Molecular imaging of vascular endothelial growth factor receptors in graft arteriosclerosis
Zhang J, Razavian M, Tavakoli S, Nie L, Tellides G, Backer JM, Backer MV, Bender JR, Sadeghi MM. Molecular imaging of vascular endothelial growth factor receptors in graft arteriosclerosis. Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):1849-55. PMID:22723442
T cell LFA-1 engagement induces HuR-dependent cytokine mRNA stabilization through a Vav-1, Rac 1/2, p38MAPK and MKK3 signaling cascade
Ramgolam V.S., DeGregorio S.D., Rao G.K., Collinge M, Subaran S, Markovic-Plese S, Pardi R, Bender J.R.: T cell LFA-1 engagement induces HuR-dependent cytokine mRNA stabilization through a Vav-1, Rac 1/2, p38MAPK and MKK3 signaling cascade. PLoS ONE: 5(12):e14450, 2010. PMID: 21206905
- Menopause and the Heart Nkonde-Price, C., Bender, J.R.: Menopause and the Heart, in: H. Taylor, M.J. Minkin, ed., Menopause, Oxford Press, in press.
VEGF blockade inhibits lymphocyte recruitment and ameliorates immune-mediated vascular remodeling
Zhang, J., Yarovinsky, T., Manes, T., Silva, T., Tellides, G., Pober, J.S., Bender, J.R., Sadeghi, M.M.: VEGF blockade inhibits lymphocyte recruitment and ameliorates immune-mediated vascular remodeling. Circ. Res., 107(3):408-17, 2010. PMID: 20538685
Endothelial and smooth muscle-derived neuropilin-like protein regulates platelet-derived growth factor signaling in human vascular smooth muscle cells by modulating receptor ubiquitination
Guo, X., Nie, L, Esmailzadeh, L, Zhang, J, Bender, J.R., Sadeghi, M.M.: Endothelial and smooth muscle-derived neuropilin-like protein regulates platelet-derived growth factor signaling in human vascular smooth muscle cells by modulating receptor ubiquitination. J. Biol. Chem, 284(43):29376-82, 2009. PMID: 19696027
Membrane-initiated actions of estrogen on the endothelium
Kim, K.H., Bender, J.R.: Membrane-initiated actions of estrogen on the endothelium. Mol. Cell. Endoc., 308, 3-8, 2009. PMID: 19549586
Targeted Inactivation Of the COP9 Signalsome Impairs Multiple Stages Of T Cell Development
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., 205:465-477, 2008. PMID: 18268034
Rac, PAK and eNOS ACTion
Rao, G.K., Bender, J.R.: Rac, PAK and eNOS ACTion. Circ. Res., 103: 328-330, 2008. PMID: 18703782
Variant Estrogen Receptor -c-Src Molecular Interdepen Proc
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.
Targeting avß3 in vascular remodeling
Sadgehi, M.M., Bender, J.R.: Targeting avß3 in vascular remodeling. Trends in Cardiovascular Medicine. 17:5-10, 2007
LFA-1-Dependent HuR Nuclear Export and Cytokine mRNA Stabilization in T Cell Activation
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.
Rapid, Estrogen Receptor-mediated Signaling in Vascular Cells: Why is the Endothelium So Special? Science (STKE)
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.