The two principle research themes in the lab are the mechanisms of arterial formation and angiogenic growth factor signaling. These process are investigated at all levels, including in vitro signaling studies, in vivo mouse transgenic and knock-out models and translational studies in larger animal models and early phase clinical trials.
Extensive Research Description
There are 3 major areas of research in my lab:
- Regulation of arterial development and branching morphogenesis The purpose of these studies is to elucidate molecular pathways leading to arterial specification of the endothelium and formation of arterial vasculature. We have recently demonstrated that knockout of synectin, a PDZ protein involved in endosomal trafficking of a number of TK receptor complexes leads to selective reduction in arterial morphogenesis and vascular branching (Chittenden et al Dev Cell, 2006). We have now demonstrated that synectin controls retrograde trafficking of VEGF-R2 containing endosomes via its binding to myosin-VI. Interestingly, myosin-VI knockout in mice or knockdown in zebrafish leads to the same arteriopenic phenotype. This abnormal receptor trafficking results in impaired activation of one of VEGF-R2 signaling pathways that appears to be crucial for arterial specification. Rescue of this aspect of VEGF signaling fully restores arterial morphogenesis not only in synectin null or myosin-VI null mice but in other models of poor arterial development. Thus, this may be the critical pathways specifying arterial formation. Funding: NHLBI (2007-2012)
- Regulation of vascular maintenance. It has not been realized until recently that maintenance of vascular integrity is an active process requiring an ongoing signaling. We have been able to demonstrate that suppression of basal FGF signaling in endothelial cells results in loss of cell-cell contacts and loss of endothelium from the vascular wall (Murakami et al. JCI 2008). The molecular events involved include FGF regulation of VE-cadherin phosphorylation and suppression of local Src activation. Current efforts are focused on characterization of the FGF signaling-VE-cadherin link and elucidation of other pathways regulating VE-cadherin maintenance t the plasma cell membrane Funding: NHLBI (2008-2013).
- Syndecan-4 signaling. Over the years my lab has demonstrated that syndecan-4 plays a critical role in regulation of FGF signaling (Horowitz, JCB ’02 and many others) and that this involves regulation of its trafficking to the plasma membrane rafts and endocytosis among other events (Tkachenko JBC ’02, JCS ’04, Circ Res ’06). Recently we discovered that in addition to its role in FGF signaling syndecan-4 controls formation of mTOR complex 2 and activation of the Akt pathway (Partovian et a l Mol Cell ’08). Among many interesting phenotypes in syndecan-4 null is mice is arterial hypertension (lack of Akt activation leads to suppressed NO production) and defective tumor but not ischemic angiogenesis. We are currently examining molecular events involved in syndecan-4 dependent regulation of mTORC2 formation that apparently include activation of RhoG via a novel mechanism involving sequestration of Rho-GDI (JCB, '09) Funding: NHLBI (2008-2013)
- Role of Raf1 and MAPK signaling in regulation of arterial specification: We find that PI3K has the ability to inhibit MAPK signaling by phosphorylating Raf1 and that activation of RAf1 leads to profound stimulation of arterial growth and arterial specification. The molecular details of this pathways are being examined in a variety of transgenic mice models
- Activation of arteriogenesis in arteriogenesis-resistant states: abnormal VEGF and other angiogenic growth factor signaling may be at the core of many events associated with advanced atherosclerosis, diabetes and other angiogenic signaling-resistant states. We are testing the concept that activation of arteriogenic signaling downstream of VEGF-R2 may promore arteriogenesis and become an effective therapeutic approach.
- Molecular mechanisms of fibroblast growth factors (FGF)-dependent regulation of vascular integrity and arteriogenesis. These studies focus on molecular details of FGF-R signaling including receptor endocytosis and trafficking and on FGF-dependent maintenance of VE-cadherin presence in cell-cell junctions. Supported by NIH R01 HL53793
- Arterial branching morphogenesis. These studies are focused on the role of synectin (GIPC), a PDZ-domain containing scaffold molecule regulation of arteriogenesis and arterial branching in development and in adult tissues. Specific problems examined include molecular mechanism of synectin-dependent regulation of VEGF signaling and cell type-specificity of effect. The latter involves generation and analysis of tissue-specific synectin knockouts and synectin null ES cells. Supported by R01 HL84619
- Syndecan signaling in endothelial cells. The project focuses on syndecan-4 signaling, a long standing interest in the lab. Two principle pathways being examined are the regulation of mTOR complex 2 assembly and Akt activation and Rac1 activation and cell motility. Supported by R01 HL53793
- Role of angiogenic inhibitors in the development of pulmonary hypertension. In this collaborative project with Dr Fred Wigley’s laboratory at Johns Hopkins we are examining the. Prevalence of circulating angiogenic inhibitors in patients with scleroderma and their effect on the natural history of disease. Supported by NIH SCCOR P50 HL084946
- Modulation of arteriogenic and metabolic environment in ischemia. The goal of this multi-laboratory collaborative project si to examine therapeutic approaches to preservation of tissue function by modulation of its metabolic state and arterial blood supply. Collaborating laboratories include Peter Carmeliet (European Coordinator, Vesalius Research Center, University of Leuven, Belgium), Holger Gerhardt (Cancer Research UK, London, UK), Luisa Iruela-Arispe (UCLA), Frank Giordano (Yale University) and A. Eichmann (College de France, Paris). Supprted by Leducq Foundation ARTEMIS Network
- Elfenbein A, Lanahan AA, Zhou TX, Yamasaki A, Tkachenko E, Matsuda M, Simons M. Syndecan 4 regulates endothelial FGFR1 signaling by directing macropinocytosis. Science Signaling 2012; 5:ra36. doi: 10.1126/scisignal.2002495 PMID: 22569333
- Tirziu D, Jaba IM, Yu P, Larrivée B, Coon BG, Cristofaro B, Zhuang ZW, Lanahan AA, Schwartz MA, Eichmann A and Simons M. Endothelial NF?B -dependent regulation of arteriogenesis and branching. Circulation 2012; 126:2589-2600; PMID: 23091063 doi: 10.1161/
- Chen P-Y*, Qin L*, Barnes C, Charisse K, Yi T, Zhang X, Ali R, Medina PP, Yu J, Slack FJ, Anderson DG, Kotelianski V, Wang F, Tellides G, Simons M. FGF regulates TGFß signaling and endothelial-to-mesenchymal transition via control of let-7 miRNA exp
- Deng Y, Atri D, Eichmann A, Simons M. Endothelial ERK signaling controls lymphatic fate specification. J. Clin Invest 2013; 123:1202:1215; doi: 10.1172/JCI63034;
- Lanahan AA*, Zhang X*, Fantin A, Zhuang ZW, Rivera-Molina F, Speichinger KR, Prahst C, Zhang J, Wang, Y, Davis GE, Toomre D, Ruhrberg C, Simons M.. The Neuropilin-1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis. Developmental Cell
- Moraes F, Paye J, Mc Gabhann F, Zhuang ZW, Zhang J, Lanahan AA, Simons M. Endothelial cell-dependent regulation of arteriogenesis. Circ Res 2013; 113:1076-86; doi: 10.1161/113.301340 (10 most read Circ Res papers of 2013)
- Chen P-Y, Qin L, Zhuang ZW, Tellides G, Lax I, Schlessinger J, Simons M. The docking protein FRS2a is a critical regulator of VEGF receptors signaling. Proc Natl Acad Sci USA 2014; 111:5514-19. doi: 10.1073/pnas.1404545111;
- Lanahan AA, Lech D, Dubrac A, Zhang J, Zhang ZW, Eichmann E, Simons M. PTP1b is a physiologic regulator of VEGF signaling in endothelial cells. Circulation 2014; 130:902-909 doi: 10.1161/CIRCULATIONAHA.114.009683.
- Chen PY, Qin L, Tellides G, Simons M. Fibroblast growth factor receptor 1 is a key regulator of TGFbeta signaling in the endothelium. Science Signaling 2014; 7:ra90