Cardiology; Endothelium; Immune System; Inflammation; Macrophages; T-Lymphocytes; RNA Stability
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 β2 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 β2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis. The Journal Of Experimental Medicine 2014, 211:1957-68.
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. The American Journal Of Pathology 2014, 184:1562-76.
Endothelial estrogen receptor isoforms and cardiovascular disease.
Kim KH, Young BD, Bender JR. Endothelial estrogen receptor isoforms and cardiovascular disease. Molecular And Cellular Endocrinology 2014, 389:65-70.
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. Journal Of Cell Science 2014, 127:4381-95.
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, 128:327-32.
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. The Journal Of Clinical Investigation 2013, 123:5082-97.
Macrophage β2 integrin-mediated, HuR-dependent stabilization of angiogenic factor-encoding mRNAs in inflammatory angiogenesis.
Zhang J, Modi Y, Yarovinsky T, Yu J, Collinge M, Kyriakides T, Zhu Y, Sessa WC, Pardi R, Bender JR. Macrophage β2 integrin-mediated, HuR-dependent stabilization of angiogenic factor-encoding mRNAs in inflammatory angiogenesis. The American Journal Of Pathology 2012, 180:1751-60.
Splice isoform estrogen receptors as integral transmembrane proteins.
Kim KH, Toomre D, Bender JR. Splice isoform estrogen receptors as integral transmembrane proteins. Molecular Biology Of The Cell 2011, 22:4415-23.
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. Arteriosclerosis, Thrombosis, And Vascular Biology 2012, 32:1849-55.
T cell LFA-1 engagement induces HuR-dependent cytokine mRNA stabilization through a Vav-1, Rac1/2, p38MAPK and MKK3 signaling cascade.
Ramgolam VS, DeGregorio SD, Rao GK, Collinge M, Subaran SS, Markovic-Plese S, Pardi R, Bender JR. T cell LFA-1 engagement induces HuR-dependent cytokine mRNA stabilization through a Vav-1, Rac1/2, p38MAPK and MKK3 signaling cascade. PloS One 2010, 5:e14450.
- 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, Silva T, Yarovinsky T, Manes TD, Tavakoli S, Nie L, Tellides G, Pober JS, Bender JR, Sadeghi MM. VEGF blockade inhibits lymphocyte recruitment and ameliorates immune-mediated vascular remodeling. Circulation Research 2010, 107:408-17.
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 JR, Sadeghi MM. Endothelial and smooth muscle-derived neuropilin-like protein regulates platelet-derived growth factor signaling in human vascular smooth muscle cells by modulating receptor ubiquitination. The Journal Of Biological Chemistry 2009, 284:29376-82.
Membrane-initiated actions of estrogen on the endothelium.
Kim KH, Bender JR. Membrane-initiated actions of estrogen on the endothelium. Molecular And Cellular Endocrinology 2009, 308:3-8.
Targeted inactivation of the COP9 signalosome impairs multiple stages of T cell development.
Panattoni M, Sanvito F, Basso V, Doglioni C, Casorati G, Montini E, Bender JR, Mondino A, Pardi R. Targeted inactivation of the COP9 signalosome impairs multiple stages of T cell development. The Journal Of Experimental Medicine 2008, 205:465-77.
Rac, PAK, and eNOS ACTion.
Rao GK, Bender JR. Rac, PAK, and eNOS ACTion. Circulation Research 2008, 103:328-30.
Variant estrogen receptor-c-Src molecular interdependence and c-Src structural requirements for endothelial NO synthase activation.
Li L, Hisamoto K, Kim KH, Haynes MP, Bauer PM, Sanjay A, Collinge M, Baron R, Sessa WC, Bender JR. Variant estrogen receptor-c-Src molecular interdependence and c-Src structural requirements for endothelial NO synthase activation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104:16468-73.
Activated alphavbeta3 integrin targeting in injury-induced vascular remodeling.
Sadeghi MM, Bender JR. Activated alphavbeta3 integrin targeting in injury-induced vascular remodeling. Trends In Cardiovascular Medicine 2007, 17:5-10.
LFA-1-dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation.
Wang JG, Collinge M, Ramgolam V, Ayalon O, Fan XC, Pardi R, Bender JR. LFA-1-dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation. Journal Of Immunology (Baltimore, Md. : 1950) 2006, 176:2105-13.
Rapid, estrogen receptor-mediated signaling: why is the endothelium so special?
Kim KH, Bender JR. Rapid, estrogen receptor-mediated signaling: why is the endothelium so special? Science's STKE : Signal Transduction Knowledge Environment 2005, 2005:pe28.