Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Development 130 (2): 411-423


DEVELOPMENT AND DISEASE

A critical role for elastin signaling in vascular morphogenesis and disease

Satyajit K. Karnik1,2,*, Benjamin S. Brooke1,2,*, Antonio Bayes-Genis3,*, Lise Sorensen1, Joshua D. Wythe1,2, Robert S. Schwartz4, Mark T. Keating5, and Dean Y. Li1,2,{dagger}

1 Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT, USA
2 Department of Medicine and Oncological Science, University of Utah, Salt Lake City, UT, USA
3 Hospital Sant Pau, Barcelona, Spain
4 Minnesota Cardiovascular Research Institute, Minneapolis, MN, USA
5 Howard Hughes Medical Institute, Department of Cell Biology, Harvard Medical School, Department of Cardiology, Children's Hospital, Boston, MA, USA

{dagger} Author for correspondence (e-mail: dean.li{at}hmbg.utah.edu)

Accepted for publication 19 October 2002.

Abstract: Vascular proliferative diseases such as atherosclerosis and coronary restenosis are leading causes of morbidity and mortality in developed nations. Common features associated with these heterogeneous disorders involve phenotypic modulation and subsequent abnormal proliferation and migration of vascular smooth muscle cells into the arterial lumen, leading to neointimal formation and vascular stenosis. This fibrocellular response has largely been attributed to the release of multiple cytokines and growth factors by inflammatory cells. Previously, we demonstrated that the disruption of the elastin matrix leads to defective arterial morphogenesis. Here, we propose that elastin is a potent autocrine regulator of vascular smooth muscle cell activity and that this regulation is important for preventing fibrocellular pathology. Using vascular smooth muscle cells from mice lacking elastin (Eln-/-), we show that elastin induces actin stress fiber organization, inhibits proliferation, regulates migration and signals via a non-integrin, heterotrimeric G-protein-coupled pathway. In a porcine coronary model of restenosis, the therapeutic delivery of exogenous elastin to injured vessels in vivo significantly reduces neointimal formation. These findings indicate that elastin stabilizes the arterial structure by inducing a quiescent contractile state in vascular smooth muscle cells. Together, this work demonstrates that signaling pathways crucial for arterial morphogenesis can play an important role in the pathogenesis and treatment of vascular disease.

Key Words: Elastin matrix • Vascular smooth muscle • Morphogenesis • G-protein signaling • Vascular proliferative diseases


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Variation of mechanical properties and quantitative proteomics of VSMC along the arterial tree.
C. L. Dinardo, G. Venturini, E. H. Zhou, I. S. Watanabe, L. C. G. Campos, R. Dariolli, J. M. da Motta-Leal-Filho, V. M. Carvalho, K. H. M. Cardozo, J. E. Krieger, et al. (2014)
Am J Physiol Heart Circ Physiol 306, H505-H516
   Abstract »    Full Text »    PDF »
A Novel Cell Adhesion Region in Tropoelastin Mediates Attachment to Integrin {alpha}V{beta}5.
P. Lee, D. V. Bax, M. M. M. Bilek, and A. S. Weiss (2014)
J. Biol. Chem. 289, 1467-1477
   Abstract »    Full Text »    PDF »
Cardiovascular Disease in Williams Syndrome.
R. T. Collins II (2013)
Circulation 127, 2125-2134
   Full Text »    PDF »
A higher maternal choline intake among third-trimester pregnant women lowers placental and circulating concentrations of the antiangiogenic factor fms-like tyrosine kinase-1 (sFLT1).
X. Jiang, H. Y. Bar, J. Yan, S. Jones, P. M. Brannon, A. A. West, C. A. Perry, A. Ganti, E. Pressman, S. Devapatla, et al. (2013)
FASEB J 27, 1245-1253
   Abstract »    Full Text »    PDF »
Derivation and maturation of synthetic and contractile vascular smooth muscle cells from human pluripotent stem cells.
M. Wanjare, F. Kuo, and S. Gerecht (2013)
Cardiovasc Res 97, 321-330
   Abstract »    Full Text »    PDF »
Vascular Disease in a Dish: All the Right Ingredients?.
S. Sinha (2012)
Circulation 126, 1676-1677
   Full Text »    PDF »
Modeling Supravalvular Aortic Stenosis Syndrome With Human Induced Pluripotent Stem Cells.
X. Ge, Y. Ren, O. Bartulos, M. Y. Lee, Z. Yue, K.-Y. Kim, W. Li, P. J. Amos, E. C. Bozkulak, A. Iyer, et al. (2012)
Circulation 126, 1695-1704
   Abstract »    Full Text »    PDF »
Matrix metalloproteinases and their inhibitors in pulmonary hypertension.
P. Chelladurai, W. Seeger, and S. S. Pullamsetti (2012)
Eur. Respir. J. 40, 766-782
   Abstract »    Full Text »    PDF »
Structural and cellular characterization of electrospun recombinant human tropoelastin biomaterials.
K. A. McKenna, K. W. Gregory, R. C. Sarao, C. L. Maslen, R. W. Glanville, and M. T. Hinds (2012)
J Biomater Appl 27, 219-230
   Abstract »    PDF »
Mechanical assessment of elastin integrity in fibrillin-1-deficient carotid arteries: implications for Marfan syndrome.
J. Ferruzzi, M. J. Collins, A. T. Yeh, and J. D. Humphrey (2011)
Cardiovasc Res 92, 287-295
   Abstract »    Full Text »    PDF »
Retinoblastoma Protein Modulates the Inverse Relationship between Cellular Proliferation and Elastogenesis.
S. Sen, S. Bunda, J. Shi, A. Wang, T. F. Mitts, and A. Hinek (2011)
J. Biol. Chem. 286, 36580-36591
   Abstract »    Full Text »    PDF »
Aortic Aneurysm Generation in Mice With Targeted Deletion of Integrin-Linked Kinase in Vascular Smooth Muscle Cells.
D. Shen, J. Li, J. J. Lepore, T. J. T. Anderson, S. Sinha, A. Y. Lin, L. Cheng, E. D. Cohen, J. D. Roberts Jr, S. Dedhar, et al. (2011)
Circ. Res. 109, 616-628
   Abstract »    Full Text »    PDF »
Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish.
J. D. Wythe, M. J. Jurynec, L. D. Urness, C. A. Jones, M. K. Sabeh, A. A. Werdich, M. Sato, H. J. Yost, D. J. Grunwald, C. A. MacRae, et al. (2011)
Dis. Model. Mech. 4, 607-621
   Abstract »    Full Text »    PDF »
Molecular Imaging Insights Into Early Inflammatory Stages of Arterial and Aortic Valve Calcification.
S. E. P. New and E. Aikawa (2011)
Circ. Res. 108, 1381-1391
   Abstract »    Full Text »    PDF »
Oxidative Modifications of the C-terminal Domain of Tropoelastin Prevent Cell Binding.
K. Akhtar, T. J. Broekelmann, H. Song, J. Turk, T. J. Brett, R. P. Mecham, and T. L. Adair-Kirk (2011)
J. Biol. Chem. 286, 13574-13582
   Abstract »    Full Text »    PDF »
The importance of elastin to aortic development in mice.
J. E. Wagenseil, C. H. Ciliberto, R. H. Knutsen, M. A. Levy, A. Kovacs, and R. P. Mecham (2010)
Am J Physiol Heart Circ Physiol 299, H257-H264
   Abstract »    Full Text »    PDF »
Thoracic aortic disease in tuberous sclerosis complex: molecular pathogenesis and potential therapies in Tsc2+/- mice.
J. Cao, L. Gong, D. c. Guo, U. Mietzsch, S. Q. Kuang, C. S. Kwartler, H. Safi, A. Estrera, M. J. Gambello, and D. M. Milewicz (2010)
Hum. Mol. Genet. 19, 1908-1920
   Abstract »    Full Text »    PDF »
Fibulin-4 Deficiency Results in Ascending Aortic Aneurysms: A Potential Link Between Abnormal Smooth Muscle Cell Phenotype and Aneurysm Progression.
J. Huang, E. C. Davis, S. L. Chapman, M. Budatha, L. Y. Marmorstein, R. A. Word, and H. Yanagisawa (2010)
Circ. Res. 106, 583-592
   Abstract »    Full Text »    PDF »
Site Specificity of Aneurysmal Disease.
P. E. Norman and J. T. Powell (2010)
Circulation 121, 560-568
   Full Text »    PDF »
Williams-Beuren syndrome--stretching to learn big lessons from small patients.
C. Gimpel and F. Schaefer (2010)
Nephrol. Dial. Transplant. 25, 339-341
   Full Text »    PDF »
Matrix metalloproteinase-2 and -9 exacerbate arterial stiffening and angiogenesis in diabetes and chronic kidney disease.
A. W.Y. Chung, H.H. C. Yang, M. K. Sigrist, G. Brin, E. Chum, W. A. Gourlay, and A. Levin (2009)
Cardiovasc Res 84, 494-504
   Abstract »    Full Text »    PDF »
Cell Adhesion to Tropoelastin Is Mediated via the C-terminal GRKRK Motif and Integrin {alpha}V{beta}3.
D. V. Bax, U. R. Rodgers, M. M. M. Bilek, and A. S. Weiss (2009)
J. Biol. Chem. 284, 28616-28623
   Abstract »    Full Text »    PDF »
Vascular Extracellular Matrix and Arterial Mechanics.
J. E. Wagenseil and R. P. Mecham (2009)
Physiol Rev 89, 957-989
   Abstract »    Full Text »    PDF »
Reduced Vessel Elasticity Alters Cardiovascular Structure and Function in Newborn Mice.
J. E. Wagenseil, C. H. Ciliberto, R. H. Knutsen, M. A. Levy, A. Kovacs, and R. P. Mecham (2009)
Circ. Res. 104, 1217-1224
   Abstract »    Full Text »    PDF »
Arterial and Aortic Valve Calcification Abolished by Elastolytic Cathepsin S Deficiency in Chronic Renal Disease.
E. Aikawa, M. Aikawa, P. Libby, J.-L. Figueiredo, G. Rusanescu, Y. Iwamoto, D. Fukuda, R. H. Kohler, G.-P. Shi, F. A. Jaffer, et al. (2009)
Circulation 119, 1785-1794
   Abstract »    Full Text »    PDF »
Neoarteries grown in vivo using a tissue-engineered hyaluronan-based scaffold.
B. Zavan, V. Vindigni, S. Lepidi, I. Iacopetti, G. Avruscio, G. Abatangelo, and R. Cortivo (2008)
FASEB J 22, 2853-2861
   Abstract »    Full Text »    PDF »
Discoidin Domain Receptor 1 (Ddr1) Deletion Decreases Atherosclerosis by Accelerating Matrix Accumulation and Reducing Inflammation in Low-Density Lipoprotein Receptor-Deficient Mice.
C. Franco, G. Hou, P. J. Ahmad, E. Y.K. Fu, L. Koh, W. F. Vogel, and M. P. Bendeck (2008)
Circ. Res. 102, 1202-1211
   Abstract »    Full Text »    PDF »
Elastin Gene Polymorphisms in Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy.
N. Kondo, S. Honda, K. Ishibashi, Y. Tsukahara, and A. Negi (2008)
Invest. Ophthalmol. Vis. Sci. 49, 1101-1105
   Abstract »    Full Text »    PDF »
Osteogenesis Associates With Inflammation in Early-Stage Atherosclerosis Evaluated by Molecular Imaging In Vivo.
E. Aikawa, M. Nahrendorf, J.-L. Figueiredo, F. K. Swirski, T. Shtatland, R. H. Kohler, F. A. Jaffer, M. Aikawa, and R. Weissleder (2007)
Circulation 116, 2841-2850
   Abstract »    Full Text »    PDF »
Gelatinase expression and proteolytic activity in giant-cell arteritis.
M. Segarra, A. Garcia-Martinez, M. Sanchez, J. Hernandez-Rodriguez, E. Lozano, J. M Grau, and M. C Cid (2007)
Ann Rheum Dis 66, 1429-1435
   Abstract »    Full Text »    PDF »
Bouncing Back From Elastin Deficiency.
P. J. Ahmad, L. R. Osborne, and M. P. Bendeck (2007)
Circ. Res. 101, 439-440
   Full Text »    PDF »
Loss of Elastic Fiber Integrity and Reduction of Vascular Smooth Muscle Contraction Resulting From the Upregulated Activities of Matrix Metalloproteinase-2 and -9 in the Thoracic Aortic Aneurysm in Marfan Syndrome.
A. W.Y. Chung, K. Au Yeung, G. G.S. Sandor, D. P. Judge, H. C. Dietz, and C. van Breemen (2007)
Circ. Res. 101, 512-522
   Abstract »    Full Text »    PDF »
Abnormal deposition of collagen/elastic vascular fibres and prognostic significance in idiopathic interstitial pneumonias.
E. Roger Parra, R. Adib Kairalla, C. R. R. de Carvalho, and V. L. Capelozzi (2007)
Thorax 62, 428-437
   Abstract »    Full Text »    PDF »
Nutrient Restriction In Utero Induces Remodeling of the Vascular Extracellular Matrix in Rat Offspring.
O. Khorram, M. Momeni, M. Desai, and M. G. Ross (2007)
Reproductive Sciences 14, 73-80
   Abstract »    PDF »
Extensive Genetic Analysis of 10 Candidate Genes for Hypertension in Japanese.
N. Iwai, K. Kajimoto, Y. Kokubo, and H. Tomoike (2006)
Hypertension 48, 901-907
   Abstract »    Full Text »    PDF »
Significant Decrease in Tropoelastin Gene Expression in Fibroblasts from a Japanese Costello Syndrome Patient with Impaired Elastogenesis and Enhanced Proliferation.
Y. Tatano, T. Takahashi, D. Tsuji, N. Takeuchi, K. Tsuta, G. Takada, M. Ohsawa, H. Sakuraba, and K. Itoh (2006)
J. Biochem. 140, 193-200
   Abstract »    Full Text »    PDF »
Postnatal alterations in elastic fiber organization precede resistance artery narrowing in SHR.
J. M. Gonzalez, A. M. Briones, B. Somoza, C. J. Daly, E. Vila, B. Starcher, J. C. McGrath, M. C. Gonzalez, and S. M. Arribas (2006)
Am J Physiol Heart Circ Physiol 291, H804-H812
   Abstract »    Full Text »    PDF »
Elastin biosynthesis: The missing link in tissue-engineered blood vessels.
A. Patel, B. Fine, M. Sandig, and K. Mequanint (2006)
Cardiovasc Res 71, 40-49
   Abstract »    Full Text »    PDF »
A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms.
H. Akagawa, A. Tajima, Y. Sakamoto, B. Krischek, T. Yoneyama, H. Kasuya, H. Onda, T. Hori, M. Kubota, T. Machida, et al. (2006)
Hum. Mol. Genet. 15, 1722-1734
   Abstract »    Full Text »    PDF »
Fibrillins 1 and 2 Perform Partially Overlapping Functions during Aortic Development.
L. Carta, L. Pereira, E. Arteaga-Solis, S. Y. Lee-Arteaga, B. Lenart, B. Starcher, C. A. Merkel, M. Sukoyan, A. Kerkis, N. Hazeki, et al. (2006)
J. Biol. Chem. 281, 8016-8023
   Abstract »    Full Text »    PDF »
Tropoelastin Interacts with Cell-surface Glycosaminoglycans via Its COOH-terminal Domain.
T. J. Broekelmann, B. A. Kozel, H. Ishibashi, C. C. Werneck, F. W. Keeley, L. Zhang, and R. P. Mecham (2005)
J. Biol. Chem. 280, 40939-40947
   Abstract »    Full Text »    PDF »
Negative Regulation of Monocyte Adhesion to Arterial Elastic Laminae by Signal Regulatory Protein {alpha} and Src Homology 2 Domain-containing Protein-Tyrosine Phosphatase-1.
S. Q. Liu, P. K. Alkema, C. Tieche, B. J. Tefft, D. Z. Liu, Y. C. Li, B. E. Sumpio, J. A. Caprini, and M. Paniagua (2005)
J. Biol. Chem. 280, 39294-39301
   Abstract »    Full Text »    PDF »
Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c.
S. K. Karnik, C. M. Hughes, X. Gu, O. Rozenblatt-Rosen, G. W. McLean, Y. Xiong, M. Meyerson, and S. K. Kim (2005)
PNAS 102, 14659-14664
   Abstract »    Full Text »    PDF »
Increased Fibulin-5 and Elastin in S100A4/Mts1 Mice With Pulmonary Hypertension.
S. L. Merklinger, R. A. Wagner, E. Spiekerkoetter, A. Hinek, R. H. Knutsen, M. G. Kabir, K. Desai, S. Hacker, L. Wang, G. M. Cann, et al. (2005)
Circ. Res. 97, 596-604
   Abstract »    Full Text »    PDF »
Impaired Revascularization in a Mouse Model of Type 2 Diabetes Is Associated With Dysregulation of a Complex Angiogenic-Regulatory Network.
S. Schiekofer, G. Galasso, K. Sato, B. J. Kraus, and K. Walsh (2005)
Arterioscler Thromb Vasc Biol 25, 1603-1609
   Abstract »    Full Text »    PDF »
Vascular Development, Pulse Pressure, and the Mechanisms of Hypertension.
M. E. Safar and H. S. Boudier (2005)
Hypertension 46, 205-209
   Abstract »    Full Text »    PDF »
Altered vascular remodeling in fibulin-5-deficient mice reveals a role of fibulin-5 in smooth muscle cell proliferation and migration.
J. A. Spencer, S. L. Hacker, E. C. Davis, R. P. Mecham, R. H. Knutsen, D. Y. Li, R. D. Gerard, J. A. Richardson, E. N. Olson, and H. Yanagisawa (2005)
PNAS 102, 2946-2951
   Abstract »    Full Text »    PDF »
The axonal attractant Netrin-1 is an angiogenic factor.
K. W. Park, D. Crouse, M. Lee, S. K. Karnik, L. K. Sorensen, K. J. Murphy, C. J. Kuo, and D. Y. Li (2004)
PNAS 101, 16210-16215
   Abstract »    Full Text »    PDF »
Lysosomal Cysteine Proteases in Atherosclerosis.
J. Liu, G. K. Sukhova, J.-S. Sun, W.-H. Xu, P. Libby, and G.-P. Shi (2004)
Arterioscler Thromb Vasc Biol 24, 1359-1366
   Abstract »    Full Text »    PDF »
Proteoglycans in Atherosclerosis and Restenosis: Key Roles for Versican.
T. N. Wight and M. J. Merrilees (2004)
Circ. Res. 94, 1158-1167
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882