Circulation Research. 2002;90:1189-1196
Published online before print May 9, 2002, doi: 10.1161/01.RES.0000021432.70309.28
Published online before print May 9, 2002, doi: 10.1161/01.RES.0000021432.70309.28
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2002 American Heart Association, Inc.
Cellular Biology |
Mature Vascular Endothelium Can Give Rise to Smooth Muscle Cells via Endothelial-Mesenchymal Transdifferentiation
In Vitro Analysis
From the Developmental Lung Biology Research Laboratory, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colo.
Correspondence to Maria Frid, Developmental Lung Biology Research Laboratory, Dept of Pediatrics, University of Colorado Health Sciences Center, 4200 E 9th Ave, Denver, CO 80262. E-mail Maria.Frid{at}UCHSC.edu
Abstract— Though in the past believed to be a rare phenomenon, endothelial-mesenchymal transdifferentiation has been described with increasing frequency in recent years. It is believed to be important in embryonic vascular development, yet less is known regarding its role in the adult vasculature. Using FACS and immunomagnetic (Dynabeads) purification techniques (based on uptake of DiI-acetylated low-density lipoproteins and/or PECAM-1 expression) and double-label indirect immunostaining (for endothelial and smooth muscle [SM] markers), we demonstrate that mature bovine vascular endothelium contains cells of an endothelial phenotype (defined by VE-cadherin, von Willebrand factor, PECAM-1, and elevated uptake of acetylated low-density lipoproteins) that can undergo endothelial-mesenchymal transdifferentiation and further differentiate into SM cells (as defined by expression of 
-SM-actin, SM22, calponin, and SM-myosin). "Transitional" cells, coexpressing both endothelial markers and -SM-actin, were consistently observed. The percentage of cells capable of endothelial-mesenchymal transdifferentiation within primary endothelial cultures was estimated as 0.01% to 0.03%. Acquisition of a SM phenotype occurred even in the absence of proliferation, in 
-irradiated (30 Gy) and/or mitomycin C–treated primary cell cultures. Initiation of transdifferentiation correlated with disruption of cell-cell contacts (marked by loss of VE-cadherin expression) within endothelial monolayers, as well as with the action of transforming growth factor-ß1. In conclusion, our in vitro data show that mature bovine systemic and pulmonary endothelium contains cells that can acquire a SM phenotype via a transdifferentiation process that is transforming growth factor-ß1– and cell-cell contact–dependent, but proliferation-independent.
Key Words: endothelial cell • transforming growth factor-&bgr • smooth muscle myosin • mesenchymal cell
This article has been cited by other articles:
 |
|
 |
|
  A. Kitao, Y. Sato, S. Sawada-Kitamura, K. Harada, M. Sasaki, H. Morikawa, S. Shiomi, M. Honda, O. Matsui, and Y. Nakanuma Endothelial to Mesenchymal Transition via Transforming Growth Factor-{beta}1/Smad Activation Is Associated with Portal Venous Stenosis in Idiopathic Portal Hypertension Am. J. Pathol., August 1, 2009; 175(2): 616 - 626. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Maurer Mitral Leaflet in Functional Regurgitation: Passive Bystander or Active Player? Circulation, July 28, 2009; 120(4): 275 - 277. [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Wagenseil and R. P. Mecham Vascular Extracellular Matrix and Arterial Mechanics Physiol Rev, July 1, 2009; 89(3): 957 - 989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. A. Dolgachev, M. R. Ullenbruch, N. W. Lukacs, and S. H. Phan Role of Stem Cell Factor and Bone Marrow-Derived Fibroblasts in Airway Remodeling Am. J. Pathol., February 1, 2009; 174(2): 390 - 400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Bouvier, J. P. Flinois, J. Gilleron, F.-L. Sauvage, C. Legendre, P. Beaune, E. Thervet, D. Anglicheau, and N. Pallet Cyclosporine triggers endoplasmic reticulum stress in endothelial cells: a role for endothelial phenotypic changes and death Am J Physiol Renal Physiol, January 1, 2009; 296(1): F160 - F169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Majka, M. Skokan, L. Wheeler, J. Harral, S. Gladson, E. Burnham, J. E. Loyd, K. R. Stenmark, M. Varella-Garcia, and J. West Evidence for cell fusion is absent in vascular lesions associated with pulmonary arterial hypertension Am J Physiol Lung Cell Mol Physiol, December 1, 2008; 295(6): L1028 - L1039. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kokudo, Y. Suzuki, Y. Yoshimatsu, T. Yamazaki, T. Watabe, and K. Miyazono Snail is required for TGF{beta}-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells J. Cell Sci., October 15, 2008; 121(20): 3317 - 3324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Stevens, S. Phan, M. G. Frid, D. Alvarez, E. Herzog, and K. R. Stenmark Lung Vascular Cell Heterogeneity: Endothelium, Smooth Muscle, and Fibroblasts Proceedings of the ATS, September 15, 2008; 5(7): 783 - 791. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Shan, T.-p. Yao, H. T. Nguyen, Y. Zhuo, D. R. Levy, R. C. Klingsberg, H. Tao, M. L. Palmer, K. N. Holder, and J. A. Lasky Requirement of HDAC6 for Transforming Growth Factor-{beta}1-induced Epithelial-Mesenchymal Transition J. Biol. Chem., July 25, 2008; 283(30): 21065 - 21073. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Xu Stem Cells and Transplant Arteriosclerosis Circ. Res., May 9, 2008; 102(9): 1011 - 1024. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Nath, R. M. Brown, M. Michaud, M. R. Sierra-Honigmann, M. Snyder, and J. A. Madri Leptin affects endocardial cushion formation by modulating EMT and migration via Akt signaling cascades J. Cell Biol., April 21, 2008; 181(2): 367 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Phan Biology of Fibroblasts and Myofibroblasts Proceedings of the ATS, April 15, 2008; 5(3): 334 - 337. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Burghoff, Z. Ding, S. Godecke, A. Assmann, A. Wirrwar, D. Buchholz, O. Sergeeva, C. Leurs, H. Hanenberg, H.-W. Muller, et al. Horizontal gene transfer from human endothelial cells to rat cardiomyocytes after intracoronary transplantation Cardiovasc Res, February 1, 2008; 77(3): 534 - 543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Diez, J. A. Barbera, E. Ferrer, R. Fernandez-Lloris, S. Pizarro, J. Roca, and V. I. Peinado Plasticity of CD133+ cells: Role in pulmonary vascular remodeling Cardiovasc Res, December 1, 2007; 76(3): 517 - 527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Arciniegas, M. G. Frid, I. S. Douglas, and K. R. Stenmark Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L1 - L8. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Hinz, S. H. Phan, V. J. Thannickal, A. Galli, M.-L. Bochaton-Piallat, and G. Gabbiani The Myofibroblast: One Function, Multiple Origins Am. J. Pathol., June 1, 2007; 170(6): 1807 - 1816. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Yana, H. Sagara, S. Takaki, K. Takatsu, K. Nakamura, K. Nakao, M. Katsuki, S.-i. Taniguchi, T. Aoki, H. Sato, et al. Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells J. Cell Sci., May 1, 2007; 120(9): 1607 - 1614. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. LaFramboise, D. Scalise, P. Stoodley, S. R. Graner, R. D. Guthrie, J. A. Magovern, and M. J. Becich Cardiac fibroblasts influence cardiomyocyte phenotype in vitro Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1799 - C1808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. O'Riordan, N. Mendelev, S. Patschan, D. Patschan, J. Eskander, L. Cohen-Gould, P. Chander, and M. S. Goligorsky Chronic NOS inhibition actuates endothelial-mesenchymal transformation Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H285 - H294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Paruchuri, J.-H. Yang, E. Aikawa, J. M. Melero-Martin, Z. A. Khan, S. Loukogeorgakis, F. J. Schoen, and J. Bischoff Human Pulmonary Valve Progenitor Cells Exhibit Endothelial/Mesenchymal Plasticity in Response to Vascular Endothelial Growth Factor-A and Transforming Growth Factor-{beta}2 Circ. Res., October 13, 2006; 99(8): 861 - 869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mayr, J. Zhang, A. S. Greene, D. Gutterman, J. Perloff, and P. Ping Proteomics-based Development of Biomarkers in Cardiovascular Disease: Mechanistic, Clinical, and Therapeutic Insights Mol. Cell. Proteomics, October 1, 2006; 5(10): 1853 - 1864. [Full Text] [PDF]
|
|
|
|
|
|
S. Sakao, L. Taraseviciene-Stewart, K. Wood, C. D. Cool, and N. F. Voelkel Apoptosis of pulmonary microvascular endothelial cells stimulates vascular smooth muscle cell growth Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L362 - L368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Park, K. Lavine, Y. Mishina, C.-X. Deng, D. M. Ornitz, and K. Choi Bone morphogenetic protein receptor 1A signaling is dispensable for hematopoietic development but essential for vessel and atrioventricular endocardial cushion formation Development, September 1, 2006; 133(17): 3473 - 3484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. L. Sales, G. C. Engelmayr Jr, B. A. Mettler, J. A. Johnson Jr, M. S. Sacks, and J. E. Mayer Jr Transforming Growth Factor-{beta}1 Modulates Extracellular Matrix Production, Proliferation, and Apoptosis of Endothelial Progenitor Cells in Tissue-Engineering Scaffolds Circulation, July 4, 2006; 114(1_suppl): I-193 - I-199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Schafer, M. R. Schroeter, C. Dellas, M. Puls, M. Nitsche, E. Weiss, G. Hasenfuss, and S. V. Konstantinides Plasminogen Activator Inhibitor-1 From Bone Marrow-Derived Cells Suppresses Neointimal Formation After Vascular Injury in Mice Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1254 - 1259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kogata, Y. Arai, J. T. Pearson, K. Hashimoto, K. Hidaka, T. Koyama, S. Somekawa, Y. Nakaoka, M. Ogawa, R. H. Adams, et al. Cardiac Ischemia Activates Vascular Endothelial Cadherin Promoter in Both Preexisting Vascular Cells and Bone Marrow Cells Involved in Neovascularization Circ. Res., April 14, 2006; 98(7): 897 - 904. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Bertolino, M. Deckers, F. Lebrin, and P. ten Dijke Transforming Growth Factor-{beta} Signal Transduction in Angiogenesis and Vascular Disorders Chest, December 1, 2005; 128(6_suppl): 585S - 590S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Bertolino, M. Deckers, F. Lebrin, and P. ten Dijke Transforming Growth Factor-{beta} Signal Transduction in Angiogenesis and Vascular Disorders Chest, December 1, 2005; 128(6_suppl): 585S - 590S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Zaiman, I. Fijalkowska, P. M. Hassoun, and R. M. Tuder One Hundred Years of Research in the Pathogenesis of Pulmonary Hypertension Am. J. Respir. Cell Mol. Biol., November 1, 2005; 33(5): 425 - 431. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Richter, M. E. Yeager, A. Zaiman, C. D. Cool, N. F. Voelkel, and R. M. Tuder Impaired Transforming Growth Factor-{beta} Signaling in Idiopathic Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., December 15, 2004; 170(12): 1340 - 1348. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kipshidze, G. Dangas, M. Tsapenko, J. Moses, M. B. Leon, M. Kutryk, and P. Serruys Role of the endothelium in modulating neointimal formation: Vasculoprotective approaches to attenuate restenosis after percutaneous coronary interventions J. Am. Coll. Cardiol., August 18, 2004; 44(4): 733 - 739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Liebner, A. Cattelino, R. Gallini, N. Rudini, M. Iurlaro, S. Piccolo, and E. Dejana {beta}-Catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse J. Cell Biol., August 2, 2004; 166(3): 359 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. Owens, M. S. Kumar, and B. R. Wamhoff Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease Physiol Rev, July 1, 2004; 84(3): 767 - 801. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. C. Cooley Murine Model of Neointimal Formation and Stenosis in Vein Grafts Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1180 - 1185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. G. Pietra, F. Capron, S. Stewart, O. Leone, M. Humbert, I. M. Robbins, L. M. Reid, and R. M. Tuder Pathologic assessment of vasculopathies in pulmonary hypertension J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 25S - 32S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Vincent, K. Xiao, K. M. Buckley, and A. P. Kowalczyk VE-cadherin: adhesion at arm's length Am J Physiol Cell Physiol, May 1, 2004; 286(5): C987 - C997. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Noseda, G. McLean, K. Niessen, L. Chang, I. Pollet, R. Montpetit, R. Shahidi, K. Dorovini-Zis, L. Li, B. Beckstead, et al. Notch Activation Results in Phenotypic and Functional Changes Consistent With Endothelial-to-Mesenchymal Transformation Circ. Res., April 16, 2004; 94(7): 910 - 917. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Le Ricousse-Roussanne, V. Barateau, J.-o. Contreres, B. Boval, L. Kraus-Berthier, and G. Tobelem Ex vivo differentiated endothelial and smooth muscle cells from human cord blood progenitors home to the angiogenic tumor vasculature Cardiovasc Res, April 1, 2004; 62(1): 176 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Wang, N. Ciliberti, S.-H. Li, P. E. Szmitko, R. D. Weisel, P. W.M. Fedak, M. Al-Omran, W.-J. Cherng, R.-K. Li, W. L. Stanford, et al. Rosiglitazone Facilitates Angiogenic Progenitor Cell Differentiation Toward Endothelial Lineage: A New Paradigm in Glitazone Pleiotropy Circulation, March 23, 2004; 109(11): 1392 - 1400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. A. Ploplis, R. Balsara, M. J. Sandoval-Cooper, Z. J. Yin, J. Batten, N. Modi, D. Gadoua, D. Donahue, J. A. Martin, and F. J. Castellino Enhanced in Vitro Proliferation of Aortic Endothelial Cells from Plasminogen Activator Inhibitor-1-deficient Mice J. Biol. Chem., February 13, 2004; 279(7): 6143 - 6151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Greenway, R. J. van Suylen, G. Du Marchie Sarvaas, E. Kwan, N. Ambartsumian, E. Lukanidin, and M. Rabinovitch S100A4/Mts1 Produces Murine Pulmonary Artery Changes Resembling Plexogenic Arteriopathy and Is Increased in Human Plexogenic Arteriopathy Am. J. Pathol., January 1, 2004; 164(1): 253 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Gulati, D. Jevremovic, T. E. Peterson, T. A. Witt, L. S. Kleppe, C. S. Mueske, A. Lerman, R. G. Vile, and R. D. Simari Autologous Culture-Modified Mononuclear Cells Confer Vascular Protection After Arterial Injury Circulation, September 23, 2003; 108(12): 1520 - 1526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hao, G. Gabbiani, and M.-L. Bochaton-Piallat Arterial Smooth Muscle Cell Heterogeneity: Implications for Atherosclerosis and Restenosis Development Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1510 - 1520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Rookmaaker, A. M. Smits, H. Tolboom, K. van 't Wout, A. C. Martens, R. Goldschmeding, J. A. Joles, A. J. van Zonneveld, H.-J. Grone, T. J. Rabelink, et al. Bone-Marrow-Derived Cells Contribute to Glomerular Endothelial Repair in Experimental Glomerulonephritis Am. J. Pathol., August 1, 2003; 163(2): 553 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hristov, W. Erl, and P. C. Weber Endothelial Progenitor Cells: Mobilization, Differentiation, and Homing Arterioscler Thromb Vasc Biol, July 1, 2003; 23(7): 1185 - 1189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Xiao, D. F. Allison, M. D. Kottke, S. Summers, G. P. Sorescu, V. Faundez, and A. P. Kowalczyk Mechanisms of VE-cadherin Processing and Degradation in Microvascular Endothelial Cells J. Biol. Chem., May 23, 2003; 278(21): 19199 - 19208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Stenmark and S. A. Gebb Lung Vascular Development: Breathing New Life Into An Old Problem Am. J. Respir. Cell Mol. Biol., February 1, 2003; 28(2): 133 - 137. [Full Text] [PDF]
|
|
|
|
|
|
A. Ishisaki, H. Hayashi, A.-J. Li, and T. Imamura Human Umbilical Vein Endothelium-derived Cells Retain Potential to Differentiate into Smooth Muscle-like Cells J. Biol. Chem., January 3, 2003; 278(2): 1303 - 1309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nishimura, J. L. Faul, G. J. Berry, L. T. Vaszar, D. Qiu, R. G. Pearl, and P. N. Kao Simvastatin Attenuates Smooth Muscle Neointimal Proliferation and Pulmonary Hypertension in Rats Am. J. Respir. Crit. Care Med., November 15, 2002; 166(10): 1403 - 1408. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hu, M. Mayr, B. Metzler, M. Erdel, F. Davison, and Q. Xu Both Donor and Recipient Origins of Smooth Muscle Cells in Vein Graft Atherosclerotic Lesions Circ. Res., October 4, 2002; 91 (7): e13 - e20. [Abstract] [Full Text] [PDF]
|
|