Aorta; Aortic Stenosis, Subvalvular; Cardiology; Cerebral Hemorrhage; Hypertension, Pulmonary; Pulmonary Fibrosis; Vascular Diseases; Developmental Biology; Atherosclerosis
Cardiovascular disease is the number one cause of death globally. My laboratory utilizes multi-disciplinary approaches to investigate how blood vessels initially form, are maintained and go awry in disease. Our research spans from cultured cells to mouse models to human samples. We aim to gain critical insights into the pathogenesis of diverse cardiovascular pathologies and leverage these insights into novel therapeutics for human disease.
Specialized Terms: Vascular biology; Vascular smooth muscle; Vessel wall; Developmental biology; Clonal analysis; Lineage analysis; Pulmonary artery hypertension; Aorta; Intracranial hemorrhage; Atherosclerosis.
Extensive Research Description
My laboratory investigates blood vessel morphogenesis, the maintenance of the adult blood vessel and diseases of the vasculature. To this end, we utilize fundamental biochemical, genetic and developmental biological approaches. We initially investigated the origins of the smooth muscle and adventitial cells of the pulmonary artery and have delineated with cellular resolution the patterns of cell differentiation, proliferation, recruitment and migration in the developing pulmonary arterial wall. Furthermore, we have initiated a genetic dissection of the molecular processes and signals that underlie blood vessel formation and have demonstrated a role of the platelet derived growth factor pathway in this process.
Our ongoing and planned studies of vessel development, maintenance and disease use similar fundamental approaches. For instance, we are studying the morphogenesis of the walls of other vessels, such as the aorta and cerebral vasculature, and comparing and contrasting their morphogenesis with that of the pulmonary artery. In addition, little is known about the maintenance of blood vessels, and we are embarking on a study to evaluate the patterns of cell turnover, proliferation and migration as well as the underlying mechanisms in the adult vessel wall. Moreover, diseases of the vasculature are thought to largely involve a recapitulation of developmental programs, and we are applying our approaches to study animal models of vascular diseases that involve ectopic and aberrant smooth muscle cells, such as atherosclerosis, supravalvular aortic stenosis, restenosis, intracranial hemorrhage and pulmonary hypertension. We have recently extended our studies to lung fibrosis which is an important cause of hypoxia and hence pulmonary hypertension. Finally, we are studying clinical samples obtained from patients with vascular and lung diseases and relating them to our findings in animal models and cultured cells.
Current Research Projects:
- Excess smooth muscle in pulmonary hypertension: cell origins and recruitment.
- Aortic wall development and disease (atherosclerosis, supravalvular aortic stenosis): progenitor cell specification, migration and differentiation.
- Mural cell signaling and blood brain barrier formation: implications for intracerebral hemorrhage.
- Alveolar myofibroblasts in development and disease
Isolated P-selectin glycoprotein ligand-1 dynamic adhesion to P- and E-selectin.
Goetz, DJ+, Greif, DM+, Ding, H, Camphausen, RT, Howes, S, Comess, KM, Snapp, KR, Kansas, GS, Luscinskas, FW. (1997). Journal of Cell Biology, 137:509. (+Co-first authors). PMC2139768
- Cell-cell adhesive interactions in an in vitro fluid flow assay. Goetz DJ, Greif DM, Shen J, Luscinskas FW. (1999). Methods in Molecular Biology, 96:137. doi:10.1385/1-59259-258-9:137
Regulation of eNOS dephosphorylation by protein phosphatase 2A: evidence for crosstalk between phosphorylation sites.
Greif DM, Kou R, Michel T. (2002). Biochemistry, 41:15845. doi:10.1021/bio26732g
Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A.
Kou R, Greif D, Michel, T. (2002). Journal of Biological Chemistry, 277:29669. doi: 10.1074/jbc.M204519200
Calmodulin phosphorylation and modulation of endothelial nitric oxide synthase catalysis.
Greif, DM, Sacks, DB, Michel, T. (2004). Proceedings of the National Academy of Sciences, 101: 1165.
KLF2 Is a novel transcriptional regulator of endothelial proinflammatory activation.
Banerjee, SS, Lin, Z, Atkins, GB, Greif, DM, Rao, RM, Feinberg, MW, Chen, Z, Simon, DI, Luscinskas, FW, Michel, TM, Garcia-Cardena, G, Gimbrone, MA, Jain, MK. (2004). Journal of Experimental Medicine, 199:1305. PMC2211816
The regulation and pharmacology of endothelial nitric oxide synthase.
Dudzinski, DM, Igarashi, J, Greif, D, Michel, T. (2006). Annual Review of Pharmacology and Toxicology, 46:235.
Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza.
London NR, Zhu W, Bozza FA, Smith MC, Greif DM, Sorensen LK, Chen L, Kaminoh Y, Chan AC, Passi SF, Day CW, Barnard DL, Zimmerman GA, Krasnow MA, Li DY. (2010). Science Translational Medicine, 23ra19. PMC2875996.
- Vascular embryology and angiogenesis. Greif, DM. (2012). Invited chapter in: Vascular Medicine, A Companion to Braunwald’s Heart Disease, 2nd edition, editors M.A. Creager, J.A. Beckman, and J. Loscalzo, Elsevier Inc., Philadelphia, PA.
Radial construction of an arterial wall.
Greif, DM*, Kumar, M, Lighthouse, JK, Hum, J, An, A, Ding, L, Red-horse, K, Espinoza, FH, Olson, L, Offermanns, S, Krasnow, MA*. (2012). Developmental Cell, 23:482. (*Co-corresponding authors).
An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension
Kim, J, Kang, Y, Kojima, Y, Lighthouse, JK, Hu, X, Aldred, MA, McLean, DL, Park, H, Comhair, SA, Greif, DM, Erzurum, SC, Chun, HJ. (2013). Nature Medicine, 19:74. PMC3540168
- Development and pathologies of the arterial wall. Seidelman, S, Lighthouse, JK, Greif, DM. (2014). Cellular and Molecular Life Sciences, 71:1977.
Recapitulation of developing artery muscularization in pulmonary hypertension.
Sheikh, AQ, Lighthouse, JK, Greif, DM. (2014). Cell Reports, 6:809.
Vascular biology: Brain vessels squeezed to death.
Greif, DM*, Eichmann A*. (2014). Nature, 508:50. (*Co-corresponding authors).
Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension.
Sheikh AQ, Misra A, Rosas IO, Adams RH, Greif DM. (2015). Science Translational Medicine, 7:308ra159. doi:10.1126/scitranslmed.aaa9712
Integrin beta3 inhibition is a therapeutic strategy for supravalvular aortic stenosis.
Misra, A, Sheikh, AQ, Kumar, A, Luo, J, Hinton, RB, Smoot, L, Kaplan, P, Urban, Z, Qyang, Y, Tellides, G, Greif, DM. (2016). Journal of Experimental Medicine, 3:451.
Vascular cells in blood vessel wall development and disease.
Mazurek, R, Dave, JM, Chandran, RR, Misra, A, Sheikh, AQ, Greif, DM. Invited chapter. In: Raouf A. Khalil, editor. Vascular Pharmacology, Vol 78, APHA, UK: Academic Press, 2017, pp. 323-350.
- Using in vivo and tissue and cell explant approaches to study morphogenesis and pathogenesis of the embryonic and perinatal aorta. Misra, A, Feng, Z, Zhang, J, Lou, Z, Greif, DM. (2017). Journal of Visualized Experiments, (127), e56039.
- Where do new endothelial cells come from in the injured heart? Greif, DM*, Eichmann, A*. (2017). Nature Reviews. Cardiology, 14:507. (*Co-corresponding authors).
- mTOR inhibition decreases mechanosignaling, collagen accumulation, and stiffening of the aorta in elastin-deficient mice. Jiao, Y, Li, G, Qin, L, Bersi, MR, Zhou, J, Li, Q, Li, W, Qyang, Y, Greif, DM, Mecham, RP, Humphrey, JD and Tellides G. (2017). Arteriosclerosis, Thrombosis, and Vascular Biology, 37:157.
- Vascular embryology and angiogenesis Ntokou, A, Kabir, I, Saddouk, FZ, Greif, DM. (2018). Invited chapter in: Vascular Medicine, A Companion to Braunwald’s Heart Disease, 3rd edition, editors M.A. Creager, J.A. Beckman, and J. Loscalzo, Elsevier Inc., Philadelphia, PA.
- Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain. Dave, JM, Mirabella, T, Weatherbee, SD, Greif, DM. (2018). Developmental Cell, 44:665
- Cell autonomous and non-cell autonomous regulation of SMC progenitors in pulmonary hypertension Sheikh, AQ, Saddouk, FZ, Ntokou, A, Mazurek, R, Greif, DM. (2018). Cell reports, 23:1152
- Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells Misra, A, Feng, Z, Chandran, RR, Kabir, I, Rotllan, N, Aryal, B, Sheikh, AQ, Ding, L, Qin, L, Fernández-Hernando, C, Tellides, G, Greif, DM. (2018). Nature Communications, accepted for publication.
Full List of PubMed Publications
- Dave JM, Mirabella T, Weatherbee SD, Greif DM: Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain. Dev Cell. 2018 Mar 26; 2018 Feb 15. PMID: 29456135
- Misra A, Feng Z, Zhang J, Lou ZY, Greif DM: Using In Vivo and Tissue and Cell Explant Approaches to Study the Morphogenesis and Pathogenesis of the Embryonic and Perinatal Aorta. J Vis Exp. 2017 Sep 12; 2017 Sep 12. PMID: 28930997
- Jiao Y, Li G, Li Q, Ali R, Qin L, Li W, Qyang Y, Greif DM, Geirsson A, Humphrey JD, Tellides G: mTOR (Mechanistic Target of Rapamycin) Inhibition Decreases Mechanosignaling, Collagen Accumulation, and Stiffening of the Thoracic Aorta in Elastin-Deficient Mice. Arterioscler Thromb Vasc Biol. 2017 Sep; 2017 Jul 27. PMID: 28751568
- Greif DM, Eichmann A: Basic research: Where do new endothelial cells come from in the injured heart? Nat Rev Cardiol. 2017 Sep; 2017 Aug 3. PMID: 28770866
- Misra A, Sheikh AQ, Kumar A, Luo J, Zhang J, Hinton RB, Smoot L, Kaplan P, Urban Z, Qyang Y, Tellides G, Greif DM: Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis. J Exp Med. 2016 Mar 7; 2016 Feb 8. PMID: 26858344
- Sheikh AQ, Misra A, Rosas IO, Adams RH, Greif DM: Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension. Sci Transl Med. 2015 Oct 7. PMID: 26446956
- Seidelmann SB, Lighthouse JK, Greif DM: Development and pathologies of the arterial wall. Cell Mol Life Sci. 2014 Jun; 2013 Sep 27. PMID: 24071897
- Greif DM, Eichmann A: Vascular biology: Brain vessels squeezed to death. Nature. 2014 Apr 3; 2014 Mar 26. PMID: 24670635
- Sheikh AQ, Lighthouse JK, Greif DM: Recapitulation of developing artery muscularization in pulmonary hypertension. Cell Rep. 2014 Mar 13; 2014 Feb 27. PMID: 24582963
- Kim J, Kang Y, Kojima Y, Lighthouse JK, Hu X, Aldred MA, McLean DL, Park H, Comhair SA, Greif DM, Erzurum SC, Chun HJ: An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med. 2013 Jan; 2012 Dec 23. PMID: 23263626
- Greif DM, Kumar M, Lighthouse JK, Hum J, An A, Ding L, Red-Horse K, Espinoza FH, Olson L, Offermanns S, Krasnow MA: Radial construction of an arterial wall. Dev Cell. 2012 Sep 11. PMID: 22975322