Daniel Greif, MD
Research & Publications
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Research Summary
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. In addition, we study the role of alveolar myofibroblasts in lung development and fibrotic 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 and pulmonary 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; Lung myofibroblasts; Lung fibrosis.
Extensive Research Description
Our laboratory investigates blood vessel development and disease as well as myofibroblasts in lung development and fibrotic disease. To this end, we utilize fundamental biochemical, genetic/genomic and developmental biological approaches. We recently uncovered novel smooth muscle cell progenitors that undergo clonal expansion during diverse vascular diseases, such as pulmonary hypertension and atherosclerosis.
Our ongoing and planned studies of vessel and lung development, maintenance and disease use similar fundamental approaches. Our initial investigations focused on pulmonary artery development, and 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. Little is known about the maintenance of blood vessels, and we are interested in evaluating 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. In addition, we have extended our studies to lung fibrosis which is an important cause of hypoxia and hence pulmonary hypertension. Furthermore, 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. Finally, we have a strong interest in expanding our studies into single cell analysis, computational biology and human genetics/genomics.
Current Research Projects:
- Excess smooth muscle in pulmonary hypertension: cell autonomous and non-cell autonomous regulation.
- 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 lung development and fibrotic disease
Coauthors
Research Interests
Aorta; Aortic Stenosis, Subvalvular; Cardiology; Cerebral Hemorrhage; Hypertension, Pulmonary; Pulmonary Fibrosis; Vascular Diseases; Developmental Biology; Atherosclerosis; Myofibroblasts
Selected Publications
- The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaquesKabir I, Zhang X, Dave J, Chakraborty R, Qu R, Chandran R, Ntokou A, Gallardo-Vara E, Aryal B, Rotllan N, Garcia-Milian R, Hwa J, Kluger Y, Martin K, Fernández-Hernando C, Greif D. The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques. Nature Aging 2023, 1-18. DOI: 10.1038/s43587-022-00342-5.
- The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaquesKabir I, Zhang X, Dave J, Chakraborty R, Qu R, Chandran R, Ntokou A, Gallardo-Vara E, Aryal B, Rotllan N, Garcia-Milian R, Hwa J, Kluger Y, Martin K, Fernández-Hernando C, Greif D. The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques. Nature Aging 2023, 3: 64-81. PMID: 36743663, PMCID: PMC9894379, DOI: 10.1038/s43587-022-00342-5.
- Vascular pathobiology of pulmonary hypertensionGallardo-Vara E, Ntokou A, Dave J, Jovin D, Saddouk F, Greif D. Vascular pathobiology of pulmonary hypertension. The Journal Of Heart And Lung Transplantation 2022, 42: 544-552. PMID: 36604291, PMCID: PMC10121751, DOI: 10.1016/j.healun.2022.12.012.
- Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle PlasticityChakraborty R, Ostriker AC, Xie Y, Dave JM, Gamez-Mendez A, Chatterjee P, Abu Y, Valentine J, Lezon-Geyda K, Greif DM, Schulz VP, Gallagher PG, Sessa WC, Hwa J, Martin KA. Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity. Circulation 2022, 145: 1720-1737. PMID: 35502657, DOI: 10.1161/circulationaha.121.057599.
- JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiencyDave JM, Chakraborty R, Ntokou A, Saito J, Saddouk FZ, Feng Z, Misra A, Tellides G, Riemer RK, Urban Z, Kinnear C, Ellis J, Mital S, Mecham R, Martin KA, Greif DM. JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency. Journal Of Clinical Investigation 2022, 132: e142338. PMID: 34990407, PMCID: PMC8884911, DOI: 10.1172/jci142338.
- Out to the tissues: the arterial side (arteries, arterioles – development, structure, functions, pathologies).Dave, JM, Saito, J, Mottola, G, Greif, DM. Invited chapter: Out to the tissues: the arterial side (arteries, arterioles – development, structure, functions, pathologies). In: Z. Gallis. The Vasculome: From Many to One. Philadelphia, PA: Elsevier Inc.; 2022, pp 89-98.
- Chapter 8 Out to the tissues the arterial side (arteries, arterioles—development, structure, functions, and pathologies)Dave J, Saito J, Mottola G, Greif D. Chapter 8 Out to the tissues the arterial side (arteries, arterioles—development, structure, functions, and pathologies). 2022, 89-98. DOI: 10.1016/b978-0-12-822546-2.00015-0.
- Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesisChandran RR, Xie Y, Gallardo-Vara E, Adams T, Garcia-Milian R, Kabir I, Sheikh AQ, Kaminski N, Martin KA, Herzog EL, Greif DM. Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis. Nature Communications 2021, 12: 7179. PMID: 34893592, PMCID: PMC8664937, DOI: 10.1038/s41467-021-27499-8.
- SNCs meet SMCs in the atherosclerotic plaqueKabir I, Greif D. SNCs meet SMCs in the atherosclerotic plaque. Nature Aging 2021, 1: 631-633. DOI: 10.1038/s43587-021-00096-6.
- SNCs meet SMCs in the atherosclerotic plaqueKabir I, Greif D. SNCs meet SMCs in the atherosclerotic plaque. Nature Aging 2021, 1: 631-633. PMID: 36540165, PMCID: PMC9762735, DOI: 10.1038/s43587-021-00096-6.
- Mogamulizumab-Associated Acute Myocarditis in a Patient With T-Cell LymphomaKwan JM, Odanovic N, Arbune A, Higgins A, Henry M, Greif D, Foss F, Baldassarre LA. Mogamulizumab-Associated Acute Myocarditis in a Patient With T-Cell Lymphoma. JACC Case Reports 2021, 3: 1018-1023. PMID: 34317676, PMCID: PMC8311348, DOI: 10.1016/j.jaccas.2021.04.001.
- Targeting smooth muscle cell phenotypic switching in vascular diseaseChakraborty R, Chatterjee P, Dave JM, Ostriker AC, Greif DM, Rzucidlo EM, Martin KA. Targeting smooth muscle cell phenotypic switching in vascular disease. JVS Vascular Science 2021, 2: 79-94. PMID: 34617061, PMCID: PMC8489222, DOI: 10.1016/j.jvssci.2021.04.001.
- Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertensionNtokou A, Dave JM, Kauffman AC, Sauler M, Ryu C, Hwa J, Herzog EL, Singh I, Saltzman WM, Greif DM. Macrophage-derived PDGF-B induces muscularization in murine and human pulmonary hypertension. JCI Insight 2021, 6: e139067. PMID: 33591958, PMCID: PMC8026182, DOI: 10.1172/jci.insight.139067.
- Macrophage-derived netrin-1 drives adrenergic nerve–associated lung fibrosisGao R, Peng X, Perry C, Sun H, Ntokou A, Ryu C, Gomez JL, Reeves BC, Walia A, Kaminski N, Neumark N, Ishikawa G, Black KE, Hariri LP, Moore MW, Gulati M, Homer RJ, Greif DM, Eltzschig HK, Herzog EL. Macrophage-derived netrin-1 drives adrenergic nerve–associated lung fibrosis. Journal Of Clinical Investigation 2021, 131: e136542. PMID: 33393489, PMCID: PMC7773383, DOI: 10.1172/jci136542.
- Adrenergic Nerve-Associated Lung Fibrosis Is Driven by Myeloid Netrin-1Perry C, Gao R, Peng X, Ntokou A, Ryu C, Gomez J, Reeves B, Walia A, Sun H, Black K, Hariri L, Moore M, Gulati M, Homer R, Greif D, Eltzschig H, Herzog E. Adrenergic Nerve-Associated Lung Fibrosis Is Driven by Myeloid Netrin-1. 2020, a2410-a2410. DOI: 10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a2410.
- Macrophage Platelet-Derived Growth Factor B Induces Smooth Muscle Cell Proliferation and Migration in Murine and Human Pulmonary HypertensionNtokou A, Dave J, Kauffman A, Hwa J, Herzog E, Singh I, Saltzman M, Greif D. Macrophage Platelet-Derived Growth Factor B Induces Smooth Muscle Cell Proliferation and Migration in Murine and Human Pulmonary Hypertension. 2020, a2677-a2677. DOI: 10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a2677.
- Specialized Smooth Muscle Cell Progenitors in Pulmonary HypertensionSaddouk F, Ntokou A, Greif D. Specialized Smooth Muscle Cell Progenitors in Pulmonary Hypertension. 2020, 25-30. DOI: 10.1007/978-981-15-1185-1_4.
- Specialized smooth muscle cell progenitors in pulmonary hypertensionSaddouk, FZ, Ntokou, A, Greif, DM. Invited chapter: Specialized smooth muscle cell progenitors in pulmonary hypertension. In: T. Naknishi, H. Baldwin, J. Fineman, and H. Yamagishi, editors. Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension. Springer Nature, 2020, pp 25-30.
- Promoters to Study Vascular Smooth MuscleChakraborty R, Saddouk FZ, Carrao AC, Krause DS, Greif DM, Martin KA. Promoters to Study Vascular Smooth Muscle. Arteriosclerosis Thrombosis And Vascular Biology 2019, 39: 603-612. PMID: 30727757, PMCID: PMC6527360, DOI: 10.1161/atvbaha.119.312449.
- Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing BrainDave JM, Mirabella T, Weatherbee SD, Greif DM. Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain. Developmental Cell 2018, 47: 388-389. PMID: 30399337, PMCID: PMC6286435, DOI: 10.1016/j.devcel.2018.10.019.
- Vagal Nerve Stimulation for Pulmonary Hypertension Some Promise, Some Skepticism ∗Ntokou A, Greif DM. Vagal Nerve Stimulation for Pulmonary Hypertension Some Promise, Some Skepticism ∗. JACC Basic To Translational Science 2018, 3: 672-674. PMID: 30456338, PMCID: PMC6234512, DOI: 10.1016/j.jacbts.2018.09.002.
- NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathyDubrac A, Künzel SE, Künzel SH, Li J, Chandran RR, Martin K, Greif DM, Adams RH, Eichmann A. NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy. Nature Communications 2018, 9: 3463. PMID: 30150707, PMCID: PMC6110853, DOI: 10.1038/s41467-018-05926-7.
- Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cellsMisra A, Feng Z, Chandran RR, Kabir I, Rotllan N, Aryal B, Sheikh AQ, Ding L, Qin L, Fernández-Hernando C, Tellides G, Greif DM. Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells. Nature Communications 2018, 9: 2073. PMID: 29802249, PMCID: PMC5970166, DOI: 10.1038/s41467-018-04447-7.
- Cell Autonomous and Non-cell Autonomous Regulation of SMC Progenitors in Pulmonary HypertensionSheikh AQ, Saddouk FZ, Ntokou A, Mazurek R, Greif DM. Cell Autonomous and Non-cell Autonomous Regulation of SMC Progenitors in Pulmonary Hypertension. Cell Reports 2018, 23: 1152-1165. PMID: 29694892, PMCID: PMC5959296, DOI: 10.1016/j.celrep.2018.03.043.
- Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing BrainDave JM, Mirabella T, Weatherbee SD, Greif DM. Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain. Developmental Cell 2018, 44: 665-678.e6. PMID: 29456135, PMCID: PMC5871595, DOI: 10.1016/j.devcel.2018.01.018.
- Vascular embryology and angiogenesisNtokou, 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.
- Using In Vivo and Tissue and Cell Explant Approaches to Study the Morphogenesis and Pathogenesis of the Embryonic and Perinatal Aorta.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. Journal Of Visualized Experiments 2017 PMID: 28930997, PMCID: PMC5752224, DOI: 10.3791/56039.
- Where do new endothelial cells come from in the injured heart?Greif DM, Eichmann A. Where do new endothelial cells come from in the injured heart? Nature Reviews Cardiology 2017, 14: 507-508. PMID: 28770866, DOI: 10.1038/nrcardio.2017.121.
- mTOR (Mechanistic Target of Rapamycin) Inhibition Decreases Mechanosignaling, Collagen Accumulation, and Stiffening of the Thoracic Aorta in Elastin-Deficient MiceJiao 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. Arteriosclerosis Thrombosis And Vascular Biology 2017, 37: 1657-1666. PMID: 28751568, PMCID: PMC5574180, DOI: 10.1161/atvbaha.117.309653.
- Chapter Eight Vascular Cells in Blood Vessel Wall Development and DiseaseMazurek R, Dave JM, Chandran RR, Misra A, Sheikh AQ, Greif DM. Chapter Eight Vascular Cells in Blood Vessel Wall Development and Disease. 2016, 78: 323-350. PMID: 28212800, PMCID: PMC5559712, DOI: 10.1016/bs.apha.2016.08.001.
- Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosisMisra A, Sheikh A, Kumar A, Luo J, Zhang J, Hinton R, Smoot L, Kaplan P, Urban Z, Qyang Y, Tellides G, Greif D. Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis. The Journal Of General Physiology 2016, 147: 1473oia18. DOI: 10.1085/jgp.1473oia18.
- Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosisMisra 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. Journal Of Experimental Medicine 2016, 213: 451-463. PMID: 26858344, PMCID: PMC4813675, DOI: 10.1084/jem.20150688.
- Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertensionSheikh AQ, Misra A, Rosas IO, Adams RH, Greif DM. Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension. Science Translational Medicine 2015, 7: 308ra159. PMID: 26446956, PMCID: PMC4629985, DOI: 10.1126/scitranslmed.aaa9712.
- Brain vessels squeezed to deathGreif DM, Eichmann A. Brain vessels squeezed to death. Nature 2014, 508: 50-51. PMID: 24670635, DOI: 10.1038/nature13217.
- Recapitulation of Developing Artery Muscularization in Pulmonary HypertensionSheikh AQ, Lighthouse JK, Greif DM. Recapitulation of Developing Artery Muscularization in Pulmonary Hypertension. Cell Reports 2014, 6: 809-817. PMID: 24582963, PMCID: PMC4015349, DOI: 10.1016/j.celrep.2014.01.042.
- Development and pathologies of the arterial wallSeidelmann SB, Lighthouse JK, Greif DM. Development and pathologies of the arterial wall. Cellular And Molecular Life Sciences 2013, 71: 1977-1999. PMID: 24071897, DOI: 10.1007/s00018-013-1478-y.
- Chapter 1 Vascular Embryology and AngiogenesisGreif D. Chapter 1 Vascular Embryology and Angiogenesis. 2013, 1-13. DOI: 10.1016/b978-1-4377-2930-6.00001-x.
- An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertensionKim 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. Nature Medicine 2012, 19: 74-82. PMID: 23263626, PMCID: PMC3540168, DOI: 10.1038/nm.3040.
- Radial Construction of an Arterial WallGreif 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. Developmental Cell 2012, 23: 482-493. PMID: 22975322, PMCID: PMC3500096, DOI: 10.1016/j.devcel.2012.07.009.
- 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.
- Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and InfluenzaLondon 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. Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza. Science Translational Medicine 2010, 2: 23ra19. PMID: 20375003, PMCID: PMC2875996, DOI: 10.1126/scitranslmed.3000678.
- THE REGULATION AND PHARMACOLOGY OF ENDOTHELIAL NITRIC OXIDE SYNTHASEDudzinski DM, Igarashi J, Greif D, Michel T. THE REGULATION AND PHARMACOLOGY OF ENDOTHELIAL NITRIC OXIDE SYNTHASE. The Annual Review Of Pharmacology And Toxicology 2006, 46: 235-276. PMID: 16402905, DOI: 10.1146/annurev.pharmtox.44.101802.121844.
- KLF2 Is a Novel Transcriptional Regulator of Endothelial Proinflammatory ActivationSenBanerjee S, Lin Z, Atkins GB, Greif DM, Rao RM, Kumar A, Feinberg MW, Chen Z, Simon DI, Luscinskas FW, Michel TM, Gimbrone MA, García-Cardeña G, Jain MK. KLF2 Is a Novel Transcriptional Regulator of Endothelial Proinflammatory Activation. Journal Of Experimental Medicine 2004, 199: 1305-1315. PMID: 15136591, PMCID: PMC2211816, DOI: 10.1084/jem.20031132.
- Calmodulin phosphorylation and modulation of endothelial nitric oxide synthase catalysisGreif DM, Sacks DB, Michel T. Calmodulin phosphorylation and modulation of endothelial nitric oxide synthase catalysis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2004, 101: 1165-1170. PMID: 14736917, PMCID: PMC337024, DOI: 10.1073/pnas.0306377101.
- Site-Specific Dephosphorylation of Endothelial Nitric Oxide Synthase by Protein Phosphatase 2A: Evidence for Crosstalk between Phosphorylation Sites †Greif DM, Kou R, Michel T. Site-Specific Dephosphorylation of Endothelial Nitric Oxide Synthase by Protein Phosphatase 2A: Evidence for Crosstalk between Phosphorylation Sites †. Biochemistry 2002, 41: 15845-15853. PMID: 12501214, DOI: 10.1021/bi026732g.
- 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. Dephosphorylation of Endothelial Nitric-oxide Synthase by Vascular Endothelial Growth Factor IMPLICATIONS FOR THE VASCULAR RESPONSES TO CYCLOSPORIN A*. Journal Of Biological Chemistry 2002, 277: 29669-29673. PMID: 12050171, DOI: 10.1074/jbc.m204519200.
- Cell-Cell Adhesive Interactions in an In Vitro Flow ChamberGoetz D, Greif D, Shen J, Luscinskas F. Cell-Cell Adhesive Interactions in an In Vitro Flow Chamber. 1999, 96: 137-145. DOI: 10.1385/1-59259-258-9:137.
- Cell-Cell Adhesive Interactions in an In Vitro Flow ChamberGoetz D, Greif D, Shen J, Luscinskas F. Cell-Cell Adhesive Interactions in an In Vitro Flow Chamber. 1999, 96: 137-145. PMID: 10098131, DOI: 10.1385/1-59259-258-9:137.
- Isolated P-selectin Glycoprotein Ligand-1 Dynamic Adhesion to P- and E-selectinGoetz D, Greif D, Ding H, Camphausen R, Howes S, Comess K, Snapp K, Kansas G, Luscinskas F. Isolated P-selectin Glycoprotein Ligand-1 Dynamic Adhesion to P- and E-selectin. Journal Of Cell Biology 1997, 137: 509-519. PMID: 9128259, PMCID: PMC2139768, DOI: 10.1083/jcb.137.2.509.