Home LiteratureArticle Details
PMID: 22253564 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

TGFβ signaling and cardiovascular diseases.

International journal of biological sciences ·Vol. 8 ·No. 2 ·2012-00-00 ·Pages 195-213

Pardali E, Ten Dijke P

Abstract

Transforming growth factor β (TGFβ) family members are involved in a wide range of diverse functions and play key roles in embryogenesis, development and tissue homeostasis. Perturbation of TGFβ signaling may lead to vascular and other diseases. In vitro studies have provided evidence that TGFβ family members have a wide range of diverse effects on vascular cells, which are highly dependent on cellular context. Consistent with these observations genetic studies in mice and humans showed that TGFβ family members have ambiguous effects on the function of the cardiovascular system. In this review we discuss the recent advances on TGFβ signaling in (cardio)vascular diseases, and describe the value of TGFβ signaling as both a disease marker and therapeutic target for (cardio)vascular diseases.

Keywords
BMP Smad TGFβ atherosclerosis hypertension vessel calcification.
MeSH Terms
Animals Atherosclerosis/genetics,metabolism Calcinosis/genetics,metabolism Cardiovascular Diseases/metabolism Humans Ligands Mice Models, Biological Signal Transduction/genetics Transforming Growth Factor beta/genetics,metabolism,physiology
Chemicals
Ligands Transforming Growth Factor beta
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Pardali Evangelia
Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany. evangelia.pardali@ukmuenster.de
Ten Dijke Peter
References (234)
234 references, click to expand
  1. Pulmonary hypertension in adult Alk1 heterozygous mice due to oxidative stress.
    Cardiovasc Res. 2011 Dec 1;92(3):375-84 PMID: 21859819
  2. Aneurysm syndromes caused by mutations in the TGF-beta receptor.
    N Engl J Med. 2006 Aug 24;355(8):788-98 PMID: 16928994
  3. Transforming growth factor-beta1-induced expression of smooth muscle marker genes involves activation of PKN and p38 MAPK.
    J Biol Chem. 2005 Sep 2;280(35):31172-81 PMID: 15980430
  4. TGF-beta receptor kinase inhibitor enhances growth and integrity of embryonic stem cell-derived endothelial cells.
    J Cell Biol. 2003 Dec 22;163(6):1303-11 PMID: 14676305
  5. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia.
    Nat Med. 2010 Apr;16(4):420-8 PMID: 20364125
  6. Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects.
    Development. 1999 Apr;126(8):1631-42 PMID: 10079226
  7. The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives.
    Am J Physiol Regul Integr Comp Physiol. 2011 Jun;300(6):R1288-95 PMID: 21368267
  8. BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo.
    J Cell Sci. 2010 May 15;123(Pt 10):1684-92 PMID: 20406889
  9. Differential proinflammatory and prooxidant effects of bone morphogenetic protein-4 in coronary and pulmonary arterial endothelial cells.
    Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H569-77 PMID: 18539760
  10. Transforming growth factor-beta-induced differentiation of smooth muscle from a neural crest stem cell line.
    Circ Res. 2004 May 14;94(9):1195-202 PMID: 15059931
  11. Pulmonary arterial hypertension.
    N Engl J Med. 2004 Oct 14;351(16):1655-65 PMID: 15483284
  12. Extracellular control of TGFbeta signalling in vascular development and disease.
    Nat Rev Mol Cell Biol. 2007 Nov;8(11):857-69 PMID: 17895899
  13. Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-beta receptor inhibitor on extravasation of nanoparticles from neovasculature.
    Cancer Sci. 2009 Jan;100(1):173-80 PMID: 19037999
  14. Upregulatory expression of furin and transforming growth factor-beta by fluid shear stress in vascular endothelial cells.
    Arterioscler Thromb Vasc Biol. 2001 May;21(5):785-90 PMID: 11348875
  15. Endothelial progenitor cells give rise to pro-angiogenic smooth muscle-like progeny.
    Cardiovasc Res. 2010 Jun 1;86(3):506-15 PMID: 20083576
  16. Conversion of vascular endothelial cells into multipotent stem-like cells.
    Nat Med. 2010 Dec;16(12):1400-6 PMID: 21102460
  17. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase.
    Circ Res. 2004 Oct 15;95(8):773-9 PMID: 15388638
  18. Development of the aorta in the chick embryo: structural and ultrastructural study.
    Atherosclerosis. 1989 Apr;76(2-3):219-35 PMID: 2730719
  19. Endoglin regulates cyclooxygenase-2 expression and activity.
    Circ Res. 2006 Aug 4;99(3):248-56 PMID: 16840721
  20. Overexpression of transforming growth factor beta1 in arterial endothelium causes hyperplasia, apoptosis, and cartilaginous metaplasia.
    Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6983-8 PMID: 9618525
  21. Circulating transforming growth factor beta 1 and coronary artery disease.
    Cardiovasc Res. 1997 May;34(2):404-10 PMID: 9205555
  22. Effects of transforming growth factor-beta 1 on human arterial smooth muscle cells in vitro.
    Arterioscler Thromb. 1991 Jul-Aug;11(4):892-902 PMID: 2065041
  23. VEGF and inhibitors of TGFbeta type-I receptor kinase synergistically promote blood-vessel formation by inducing alpha5-integrin expression.
    J Cell Sci. 2009 Sep 15;122(Pt 18):3294-302 PMID: 19706683
  24. A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension.
    J Med Genet. 2009 May;46(5):331-7 PMID: 19211612
  25. Defective angiogenesis in mice lacking endoglin.
    Science. 1999 May 28;284(5419):1534-7 PMID: 10348742
  26. Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo.
    Circ Res. 2010 Jul 23;107(2):252-62 PMID: 20522807
  27. Production of transforming growth factor beta 1 during repair of arterial injury.
    J Clin Invest. 1991 Sep;88(3):904-10 PMID: 1832175
  28. Paracrine osteogenic signals via bone morphogenetic protein-2 accelerate the atherosclerotic intimal calcification in vivo.
    Arterioscler Thromb Vasc Biol. 2010 Oct;30(10):1908-15 PMID: 20651281
  29. Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle.
    Circ Res. 2004 Apr 30;94(8):1109-14 PMID: 15031260
  30. Bone morphogenic protein-4 induces hypertension in mice: role of noggin, vascular NADPH oxidases, and impaired vasorelaxation.
    Circulation. 2006 Jun 20;113(24):2818-25 PMID: 16769910
  31. BMP activity controlled by BMPER regulates the proinflammatory phenotype of endothelium.
    Blood. 2011 Nov 3;118(18):5040-9 PMID: 21900199
  32. Transforming growth factor beta in hypertensives with cardiorenal damage.
    Hypertension. 2000 Oct;36(4):517-22 PMID: 11040229
  33. Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice.
    Science. 2011 Apr 15;332(6027):358-61 PMID: 21493862
  34. Endoglin, a TGF-beta receptor-associated protein, is expressed by smooth muscle cells in human atherosclerotic plaques.
    Atherosclerosis. 2000 Dec;153(2):323-35 PMID: 11164421
  35. BMP-dependent activation of caspase-9 and caspase-8 mediates apoptosis in pulmonary artery smooth muscle cells.
    Am J Physiol Lung Cell Mol Physiol. 2006 Nov;291(5):L1059-67 PMID: 17030903
  36. Altered bone morphogenetic protein and transforming growth factor-beta signaling in rat models of pulmonary hypertension: potential for activin receptor-like kinase-5 inhibition in prevention and progression of disease.
    Circulation. 2009 Feb 3;119(4):566-76 PMID: 19153267
  37. Increased plasma soluble endoglin levels as an indicator of cardiovascular alterations in hypertensive and diabetic patients.
    BMC Med. 2010 Dec 20;8:86 PMID: 21171985
  38. Bevacizumab in hereditary hemorrhagic telangiectasia.
    N Engl J Med. 2009 May 14;360(20):2143-4 PMID: 19439755
  39. Bone morphogenetic protein-7 (osteogenic protein-1) inhibits smooth muscle cell proliferation and stimulates the expression of markers that are characteristic of SMC phenotype in vitro.
    J Cell Physiol. 2000 Jul;184(1):37-45 PMID: 10825232
  40. Regulation of bone morphogenetic protein-2 expression in endothelial cells: role of nuclear factor-kappaB activation by tumor necrosis factor-alpha, H2O2, and high intravascular pressure.
    Circulation. 2005 May 10;111(18):2364-72 PMID: 15851600
  41. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins.
    Circulation. 2001 Aug 14;104(7):790-5 PMID: 11502704
  42. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension.
    Hum Mutat. 2006 Feb;27(2):121-32 PMID: 16429395
  43. Signaling by members of the TGF-beta family in vascular morphogenesis and disease.
    Trends Cell Biol. 2010 Sep;20(9):556-67 PMID: 20656490
  44. Transforming growth factor beta and atherosclerosis: so far, so good for the protective cytokine hypothesis.
    Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):399-404 PMID: 14699019
  45. BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia.
    Am J Physiol Lung Cell Mol Physiol. 2004 Dec;287(6):L1241-7 PMID: 15286002
  46. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease.
    Nature. 1992 Oct 22;359(6397):693-9 PMID: 1436033
  47. Altered MicroRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8.
    Am J Respir Crit Care Med. 2011 Dec 15;184(12):1400-8 PMID: 21920918
  48. Transforming growth factor-betas and CD105 expression in calcification and bone formation in human atherosclerotic lesions.
    Z Kardiol. 2001;90 Suppl 3:23-6 PMID: 11374028
  49. Targeted mutagenesis of Smad1 reveals an essential role in chorioallantoic fusion.
    Dev Biol. 2001 Dec 1;240(1):157-67 PMID: 11784053
  50. Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice.
    EMBO J. 2001 Apr 2;20(7):1663-73 PMID: 11285230
  51. Bone morphogenetic protein (BMP) and activin type II receptors balance BMP9 signals mediated by activin receptor-like kinase-1 in human pulmonary artery endothelial cells.
    J Biol Chem. 2009 Jun 5;284(23):15794-804 PMID: 19366699
  52. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database.
    Hum Mutat. 2003 Sep;22(3):199-208 PMID: 12938084
  53. Involvement of MAP kinases in TGF-beta-stimulated vascular endothelial growth factor synthesis in osteoblasts.
    Arch Biochem Biophys. 2003 Jul 1;415(1):117-25 PMID: 12801520
  54. Transforming growth factor-beta-dependent growth inhibition in primary vascular smooth muscle cells is p38-dependent.
    J Pharmacol Exp Ther. 2005 Dec;315(3):1005-12 PMID: 16120811
  55. A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia.
    Circ Res. 2005 Apr 1;96(6):684-92 PMID: 15718503
  56. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor.
    Circulation. 2002 Apr 9;105(14):1672-8 PMID: 11940546
  57. Negative regulation of TGF-beta receptor/Smad signal transduction.
    Curr Opin Cell Biol. 2007 Apr;19(2):176-84 PMID: 17317136
  58. Casein kinase 2beta as a novel enhancer of activin-like receptor-1 signaling.
    FASEB J. 2009 Nov;23(11):3712-21 PMID: 19592636
  59. Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development.
    Dev Biol. 2000 Jan 1;217(1):42-53 PMID: 10625534
  60. Defective paracrine signalling by TGFbeta in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia.
    Development. 2004 Dec;131(24):6237-47 PMID: 15548578
  61. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response.
    Nat Cell Biol. 1999 Sep;1(5):260-6 PMID: 10559937
  62. Essential role of endothelial Smad4 in vascular remodeling and integrity.
    Mol Cell Biol. 2007 Nov;27(21):7683-92 PMID: 17724086
  63. ERK signaling is a central regulator for BMP-4 dependent capillary sprouting.
    Cardiovasc Res. 2007 Dec 1;76(3):390-9 PMID: 17850776
  64. Inhibition of VEGF or TGF-{beta} signaling activates endothelium and increases leukocyte rolling.
    Arterioscler Thromb Vasc Biol. 2009 Aug;29(8):1185-92 PMID: 19461051
  65. Smad3 mutant mice develop metastatic colorectal cancer.
    Cell. 1998 Sep 18;94(6):703-14 PMID: 9753318
  66. Inhibition of rat vascular smooth muscle proliferation in vitro and in vivo by bone morphogenetic protein-2.
    J Clin Invest. 1997 Dec 1;100(11):2824-32 PMID: 9389748
  67. Role of bone morphogenetic protein receptors in the development of pulmonary arterial hypertension.
    Adv Exp Med Biol. 2010;661:251-64 PMID: 20204735
  68. BMPER is an endothelial cell regulator and controls bone morphogenetic protein-4-dependent angiogenesis.
    Circ Res. 2008 Oct 10;103(8):804-12 PMID: 18787191
  69. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta.
    EMBO J. 1999 Mar 1;18(5):1280-91 PMID: 10064594
  70. The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis.
    Nat Med. 1995 Jan;1(1):74-9 PMID: 7584958
  71. Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis.
    J Exp Med. 2010 Jan 18;207(1):85-100 PMID: 20065063
  72. A murine model of hereditary hemorrhagic telangiectasia.
    J Clin Invest. 1999 Nov;104(10):1343-51 PMID: 10562296
  73. Ligand-specific function of transforming growth factor beta in epithelial-mesenchymal transition in heart development.
    Dev Dyn. 2009 Feb;238(2):431-42 PMID: 19161227
  74. Retinal expression, regulation, and functional bioactivity of prostacyclin-stimulating factor.
    J Clin Invest. 2000 Aug;106(4):541-50 PMID: 10953029
  75. Emilin1 links TGF-beta maturation to blood pressure homeostasis.
    Cell. 2006 Mar 10;124(5):929-42 PMID: 16530041
  76. Soluble endoglin contributes to the pathogenesis of preeclampsia.
    Nat Med. 2006 Jun;12(6):642-9 PMID: 16751767
  77. Recent progress in genetics of Marfan syndrome and Marfan-associated disorders.
    J Hum Genet. 2007;52(1):1-12 PMID: 17061023
  78. Regulation of RANKL-induced osteoclastic differentiation by vascular cells.
    J Mol Cell Cardiol. 2005 Aug;39(2):389-93 PMID: 15893766
  79. Cellular and molecular pathobiology of pulmonary arterial hypertension.
    J Am Coll Cardiol. 2004 Jun 16;43(12 Suppl S):13S-24S PMID: 15194174
  80. Bone morphogenetic protein expression in human atherosclerotic lesions.
    J Clin Invest. 1993 Apr;91(4):1800-9 PMID: 8473518
  81. Bone morphogenetic protein (BMP) type II receptor is required for BMP-mediated growth arrest and differentiation in pulmonary artery smooth muscle cells.
    J Biol Chem. 2008 Feb 15;283(7):3877-88 PMID: 18042551
  82. Vascular calcification: pathobiological mechanisms and clinical implications.
    Circ Res. 2006 Nov 10;99(10):1044-59 PMID: 17095733
  83. Transforming growth factor-beta signaling and tumor angiogenesis.
    Front Biosci (Landmark Ed). 2009 Jun 01;14:4848-61 PMID: 19482591
  84. Endothelial-mesenchymal interactions in vitro reveal molecular mechanisms of smooth muscle/pericyte differentiation.
    Stem Cells Dev. 2004 Oct;13(5):509-20 PMID: 15588508
  85. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice.
    Development. 1995 Jun;121(6):1845-54 PMID: 7600998
  86. Nitric oxide regulates transforming growth factor-beta signaling in endothelial cells.
    Circ Res. 2005 Nov 25;97(11):1115-23 PMID: 16239590
  87. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis.
    Nat Genet. 2011 Feb;43(2):121-6 PMID: 21217753
  88. Identification of serum endoglin as a novel prognostic marker after acute myocardial infarction.
    J Cell Mol Med. 2008 Jun;12(3):955-61 PMID: 18494936
  89. Studies on TGF-beta 1 gene expression in the intima of the human aorta in regions with high and low probability of developing atherosclerotic lesions.
    Mod Pathol. 1995 Jun;8(5):478-82 PMID: 7675764
  90. Recent advances in understanding Marfan syndrome: should we now treat surgical patients with losartan?
    J Thorac Cardiovasc Surg. 2008 Feb;135(2):389-94 PMID: 18242274
  91. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension.
    Circ Res. 2005 May 27;96(10):1053-63 PMID: 15845886
  92. Role of the TGF-beta/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension.
    Am J Respir Crit Care Med. 2008 Apr 15;177(8):896-905 PMID: 18202349
  93. Bone morphogenetic protein-induced MSX1 and MSX2 inhibit myocardin-dependent smooth muscle gene transcription.
    Mol Cell Biol. 2006 Dec;26(24):9456-70 PMID: 17030628
  94. Acetylsalicylic acid inhibits cell proliferation by involving transforming growth factor-beta.
    Circulation. 2003 Feb 4;107(4):626-9 PMID: 12566377
  95. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension.
    Nat Genet. 2000 Sep;26(1):81-4 PMID: 10973254
  96. Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension.
    Genet Med. 2005 Mar;7(3):169-74 PMID: 15775752
  97. Up-regulation of the fibrogenic cytokine TGF-beta1 by oxysterols: a mechanistic link between cholesterol and atherosclerosis.
    FASEB J. 2001 Jul;15(9):1619-21 PMID: 11427505
  98. Protein and mRNA expression levels of VEGF-A and TGF-beta1 in different types of human coronary atherosclerotic lesions.
    Int J Mol Med. 2005 Apr;15(4):603-10 PMID: 15754021
  99. Angiogenesis and vascular malformations: antiangiogenic drugs for treatment of gastrointestinal bleeding.
    World J Gastroenterol. 2007 Dec 7;13(45):5979-84 PMID: 18023086
  100. Transforming growth factor-beta1 causes pulmonary microvascular endothelial cell apoptosis via ALK5.
    Am J Physiol Lung Cell Mol Physiol. 2009 May;296(5):L825-38 PMID: 19270180
  101. Signaling by ALK5 mediates TGF-beta-induced ET-1 expression in endothelial cells: a role for migration and proliferation.
    J Cell Sci. 2007 Apr 1;120(Pt 7):1256-66 PMID: 17376964
  102. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome.
    Nat Genet. 2003 Mar;33(3):407-11 PMID: 12598898
  103. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.
    J Med Genet. 2003 Dec;40(12):865-71 PMID: 14684682
  104. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.
    Nat Genet. 1996 Jun;13(2):189-95 PMID: 8640225
  105. Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome.
    Am Heart J. 2007 Oct;154(4):624-31 PMID: 17892982
  106. Defective pulmonary vascular remodeling in Smad8 mutant mice.
    Hum Mol Genet. 2009 Aug 1;18(15):2791-801 PMID: 19419974
  107. Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival.
    Dev Biol. 2003 Dec 1;264(1):275-88 PMID: 14623248
  108. Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth.
    J Biol Chem. 2011 Aug 26;286(34):30034-46 PMID: 21737454
  109. Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth.
    Am J Pathol. 1999 Aug;155(2):411-9 PMID: 10433934
  110. Global expression profiling of fibroblast responses to transforming growth factor-beta1 reveals the induction of inhibitor of differentiation-1 and provides evidence of smooth muscle cell phenotypic switching.
    Am J Pathol. 2003 Feb;162(2):533-46 PMID: 12547711
  111. Phosphatidylinositol 3-kinase/Akt pathway is involved in transforming growth factor-beta1-induced phenotypic modulation of 10T1/2 cells to smooth muscle cells.
    Cell Signal. 2006 Aug;18(8):1270-8 PMID: 16310342
  112. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors.
    EMBO J. 2002 Apr 2;21(7):1743-53 PMID: 11927558
  113. Trapping of BMP receptors in distinct membrane domains inhibits their function in pulmonary arterial hypertension.
    Am J Physiol Lung Cell Mol Physiol. 2011 Aug;301(2):L218-27 PMID: 21622843
  114. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells.
    Blood. 2007 Mar 1;109(5):1953-61 PMID: 17068149
  115. TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis.
    Dev Biol. 1996 Oct 10;179(1):297-302 PMID: 8873772
  116. The significance of CD105, TGFbeta and CD105/TGFbeta complexes in coronary artery disease.
    Atherosclerosis. 2000 Sep;152(1):249-56 PMID: 10996361
  117. The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo.
    Genes Dev. 1998 Jan 1;12(1):107-19 PMID: 9420335
  118. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).
    Lancet. 2004 Mar 13;363(9412):852-9 PMID: 15031030
  119. Transforming growth factor-β inhibition attenuates pulmonary arterial hypertension in rats.
    Int J Clin Exp Med. 2010 Oct 23;3(4):332-40 PMID: 21072267
  120. Activation of vascular bone morphogenetic protein signaling in diabetes mellitus.
    Circ Res. 2011 Feb 18;108(4):446-57 PMID: 21193740
  121. Transforming growth factor-beta signaling pathway in patients with Kawasaki disease.
    Circ Cardiovasc Genet. 2011 Feb;4(1):16-25 PMID: 21127203
  122. The role of transforming growth factor beta in atherosclerosis: novel insights and future perspectives.
    Curr Opin Lipidol. 2002 Oct;13(5):523-9 PMID: 12352016
  123. TGF-betas and TGF-beta receptors in atherosclerosis.
    Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):103-14 PMID: 10708958
  124. Transdifferentiation of pulmonary arteriolar endothelial cells into smooth muscle-like cells regulated by myocardin involved in hypoxia-induced pulmonary vascular remodelling.
    Int J Exp Pathol. 2006 Dec;87(6):463-74 PMID: 17222214
  125. Basic fibroblast growth factor antagonizes transforming growth factor-beta1-induced smooth muscle gene expression through extracellular signal-regulated kinase 1/2 signaling pathway activation.
    Arterioscler Thromb Vasc Biol. 2004 Aug;24(8):1384-90 PMID: 15217807
  126. Bone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: implications on hypertension.
    Circ Res. 2010 Oct 15;107(8):984-91 PMID: 20724703
  127. A role for smad6 in development and homeostasis of the cardiovascular system.
    Nat Genet. 2000 Feb;24(2):171-4 PMID: 10655064
  128. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.
    Nat Genet. 2005 Mar;37(3):275-81 PMID: 15731757
  129. Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis.
    Cancer Res. 2010 May 15;70(10):4141-50 PMID: 20424116
  130. The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice.
    Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3667-72 PMID: 9520423
  131. Chordin-like 1, a bone morphogenetic protein-4 antagonist, is upregulated by hypoxia in human retinal pericytes and plays a role in regulating angiogenesis.
    Mol Vis. 2008 Jun 20;14:1138-48 PMID: 18587495
  132. Smad7 is required for the development and function of the heart.
    J Biol Chem. 2009 Jan 2;284(1):292-300 PMID: 18952608
  133. Bone morphogenetic proteins in vascular calcification.
    Circ Res. 2005 Jul 22;97(2):105-14 PMID: 16037577
  134. Histamine-modulated transdifferentiation of dermal microvascular endothelial cells.
    Exp Cell Res. 1992 Apr;199(2):279-91 PMID: 1544369
  135. RhoA modulates Smad signaling during transforming growth factor-beta-induced smooth muscle differentiation.
    J Biol Chem. 2006 Jan 20;281(3):1765-70 PMID: 16317010
  136. Smad expression in human atherosclerotic lesions: evidence for impaired TGF-beta/Smad signaling in smooth muscle cells of fibrofatty lesions.
    Arterioscler Thromb Vasc Biol. 2004 Aug;24(8):1391-6 PMID: 15166010
  137. Transforming growth factor-beta receptor requirements for the induction of the endothelin-1 gene.
    Exp Biol Med (Maywood). 2006 Jun;231(6):700-3 PMID: 16740983
  138. Endoglin in angiogenesis and vascular diseases.
    Angiogenesis. 2008;11(1):79-89 PMID: 18283546
  139. Snail is required for TGFbeta-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells.
    J Cell Sci. 2008 Oct 15;121(Pt 20):3317-24 PMID: 18796538
  140. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes.
    Development. 1997 Jul;124(13):2659-70 PMID: 9217007
  141. TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice.
    J Clin Invest. 2010 Feb;120(2):422-32 PMID: 20101093
  142. Absence of TGFbeta signaling in embryonic vascular smooth muscle leads to reduced lysyl oxidase expression, impaired elastogenesis, and aneurysm.
    Genesis. 2009 Feb;47(2):115-21 PMID: 19165826
  143. Transforming growth factor-beta1 effects on endothelial monolayer permeability involve focal adhesion kinase/Src.
    Am J Respir Cell Mol Biol. 2007 Oct;37(4):485-93 PMID: 17585111
  144. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells.
    Am J Physiol Lung Cell Mol Physiol. 2003 Sep;285(3):L740-54 PMID: 12740218
  145. BMP-2 gene expression and effects on human vascular smooth muscle cells.
    J Vasc Res. 1999 Mar-Apr;36(2):120-5 PMID: 10213907
  146. Induction of bone-type alkaline phosphatase in human vascular smooth muscle cells: roles of tumor necrosis factor-alpha and oncostatin M derived from macrophages.
    Circ Res. 2002 Jul 12;91(1):9-16 PMID: 12114316
  147. Transforming growth factor beta signaling in adult cardiovascular diseases and repair.
    Cell Tissue Res. 2012 Jan;347(1):203-23 PMID: 21953136
  148. Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension.
    Circ Res. 2005 Sep 2;97(5):496-504 PMID: 16100039
  149. TGF-beta 1 and 25-hydroxycholesterol stimulate osteoblast-like vascular cells to calcify.
    J Clin Invest. 1994 May;93(5):2106-13 PMID: 8182141
  150. Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production.
    Brain Res. 2005 Mar 21;1038(2):208-15 PMID: 15757636
  151. Mutations in the TGF-beta type 1 receptor, ALK1, in combined primary pulmonary hypertension and hereditary haemorrhagic telangiectasia, implies pathway specificity.
    J Heart Lung Transplant. 2001 Feb;20(2):175 PMID: 11250282
  152. A transforming growth factor beta (TGFbeta) control element drives TGFbeta-induced stimulation of smooth muscle alpha-actin gene expression in concert with two CArG elements.
    J Biol Chem. 1997 Apr 18;272(16):10948-56 PMID: 9099754
  153. Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary artery smooth muscle cells.
    J Biol Chem. 2005 Jul 1;280(26):24443-50 PMID: 15883158
  154. Increased expression of the transforming growth factor-beta signaling pathway, endoglin, and early growth response-1 in stable plaques.
    Stroke. 2009 Feb;40(2):439-47 PMID: 19074480
  155. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension.
    Hum Mol Genet. 2002 Jun 15;11(13):1517-25 PMID: 12045205
  156. Signaling molecules in nonfamilial pulmonary hypertension.
    N Engl J Med. 2003 Feb 6;348(6):500-9 PMID: 12571257
  157. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries.
    Circ Res. 2009 Mar 27;104(6):733-41 PMID: 19197075
  158. Circulating transforming growth factor beta1 (TGFbeta1) is elevated by extensive exercise.
    Eur J Appl Physiol. 2002 Mar;86(5):406-10 PMID: 11882926
  159. VE-cadherin is a critical endothelial regulator of TGF-beta signalling.
    EMBO J. 2008 Apr 9;27(7):993-1004 PMID: 18337748
  160. ALK5 and Smad4 are involved in TGF-beta1-induced pulmonary endothelial permeability.
    FEBS Lett. 2005 Jul 18;579(18):4031-7 PMID: 16004987
  161. Pulmonary artery hypertension: caveolin-1 and eNOS interrelationship: a new perspective.
    Cardiol Rev. 2007 May-Jun;15(3):143-9 PMID: 17438380
  162. Autoimmunity associated with TGF-beta1-deficiency in mice is dependent on MHC class II antigen expression.
    J Clin Invest. 1996 Nov 1;98(9):2109-19 PMID: 8903331
  163. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study.
    J Am Coll Cardiol. 2004 Apr 7;43(7):1149-53 PMID: 15063421
  164. Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction.
    Nat Genet. 1995 Dec;11(4):415-21 PMID: 7493022
  165. Progress and challenges in translating the biology of atherosclerosis.
    Nature. 2011 May 19;473(7347):317-25 PMID: 21593864
  166. Mouse embryonic stem cells with aberrant transforming growth factor beta signalling exhibit impaired differentiation in vitro and in vivo.
    Differentiation. 1998 Jul;63(3):101-13 PMID: 9697304
  167. Alterations of growth factor transcripts in rat lungs during development of monocrotaline-induced pulmonary hypertension.
    Biochem Pharmacol. 1993 Sep 14;46(6):1086-91 PMID: 8216353
  168. Effect of growth factors on human vascular endothelial cell prostacyclin production.
    Arteriosclerosis. 1990 Jul-Aug;10(4):653-7 PMID: 2114869
  169. Vascular calcification in chronic kidney disease.
    J Bone Miner Metab. 2006;24(2):176-81 PMID: 16502129
  170. TGF-beta signalling from cell membrane to nucleus through SMAD proteins.
    Nature. 1997 Dec 4;390(6659):465-71 PMID: 9393997
  171. Transforming growth factor-beta1 mechanisms in aortic valve calcification: increased alkaline phosphatase and related events.
    Ann Thorac Surg. 2007 Mar;83(3):946-53 PMID: 17307438
  172. Endothelial-mesenchymal transition occurs during embryonic pulmonary artery development.
    Endothelium. 2005 Jul-Aug;12(4):193-200 PMID: 16162442
  173. PDGF, TGF-beta, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate.
    J Cell Biol. 1998 May 4;141(3):805-14 PMID: 9566978
  174. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death.
    Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):770-4 PMID: 8421714
  175. Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states.
    Nat Med. 2007 Feb;13(2):204-10 PMID: 17237794
  176. Heart and liver defects and reduced transforming growth factor beta2 sensitivity in transforming growth factor beta type III receptor-deficient embryos.
    Mol Cell Biol. 2003 Jun;23(12):4371-85 PMID: 12773577
  177. Smad5 is essential for left-right asymmetry in mice.
    Dev Biol. 2000 Mar 1;219(1):71-8 PMID: 10677256
  178. Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction.
    Mol Cell Biol. 1999 Apr;19(4):2495-504 PMID: 10082515
  179. Gene expression profile of the Gs-coupled prostacyclin receptor in human vascular smooth muscle cells.
    Biochem Pharmacol. 2004 Feb 15;67(4):757-65 PMID: 14757176
  180. Loss of distinct arterial and venous boundaries in mice lacking endoglin, a vascular-specific TGFbeta coreceptor.
    Dev Biol. 2003 Sep 1;261(1):235-50 PMID: 12941632
  181. Effects of transforming growth factor beta and interleukin-1 beta on expression of cyclooxygenase 1 and 2 and phospholipase A2 mRNA in lung fibroblasts and endothelial cells in culture.
    Biochem Biophys Res Commun. 1993 Dec 30;197(3):1465-74 PMID: 8280164
  182. Regulation of endothelial barrier function by TGF-β type I receptor ALK5: potential role of contractile mechanisms and heat shock protein 90.
    J Cell Physiol. 2012 Feb;227(2):759-71 PMID: 21465483
  183. Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors.
    Bioorg Med Chem Lett. 2008 Aug 1;18(15):4388-92 PMID: 18621530
  184. Transcriptional activity of genes encoding Transforming Growth Factor beta and its receptors in peripheral blood mononuclear cells from patients with acute coronary syndromes.
    Int J Cardiol. 2006 Aug 10;111(2):275-9 PMID: 16307809
  185. Distinct patterns of transforming growth factor-beta isoform and receptor expression in human atherosclerotic lesions. Colocalization implicates TGF-beta in fibrofatty lesion development.
    Circulation. 1999 Jun 8;99(22):2883-91 PMID: 10359732
  186. Elastin-derived peptides and TGF-beta1 induce osteogenic responses in smooth muscle cells.
    Biochem Biophys Res Commun. 2005 Aug 26;334(2):524-32 PMID: 16005428
  187. Transforming growth factor-beta 3 is required for secondary palate fusion.
    Nat Genet. 1995 Dec;11(4):409-14 PMID: 7493021
  188. Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE-/- mice.
    Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):2117-24 PMID: 16840715
  189. Differential regulation of transforming growth factor receptors by angiotensin II and transforming growth factor-beta1 in vascular smooth muscle.
    J Mol Med (Berl). 1999 May;77(5):437-45 PMID: 10426193
  190. Multilineage potential of cells from the artery wall.
    Circulation. 2003 Nov 18;108(20):2505-10 PMID: 14581408
  191. Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo.
    Nat Med. 2005 Nov;11(11):1188-96 PMID: 16227992
  192. Soluble endoglin modulates aberrant cerebral vascular remodeling.
    Ann Neurol. 2009 Jul;66(1):19-27 PMID: 19670444
  193. Exogenous nitric oxide causes overexpression of TGF-beta1 and overproduction of extracellular matrix in human coronary smooth muscle cells.
    Cardiovasc Res. 2003 Jun 1;58(3):671-8 PMID: 12798441
  194. Association between transforming growth factor-beta and hypertension.
    Am J Hypertens. 2003 Jul;16(7):604-11 PMID: 12850397
  195. Transforming growth factor-beta receptors localize to caveolae and regulate endothelial nitric oxide synthase in normal human endothelial cells.
    Biochem J. 2005 Aug 15;390(Pt 1):199-206 PMID: 15819614
  196. Lack of primary cilia primes shear-induced endothelial-to-mesenchymal transition.
    Circ Res. 2011 Apr 29;108(9):1093-101 PMID: 21393577
  197. Thrombin-induced VEGF expression in human retinal pigment epithelial cells.
    Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2738-46 PMID: 17525207
  198. TGF-β receptor signaling pathways in angiogenesis; emerging targets for anti-angiogenesis therapy.
    Curr Pharm Biotechnol. 2011 Dec;12(12):2108-20 PMID: 21619534
  199. Matrix GLA protein stimulates VEGF expression through increased transforming growth factor-beta1 activity in endothelial cells.
    J Biol Chem. 2004 Dec 17;279(51):52904-13 PMID: 15456771
  200. Age-dependent endothelial nitric oxide synthase uncoupling in pulmonary arteries of endoglin heterozygous mice.
    Am J Physiol Lung Cell Mol Physiol. 2009 Dec;297(6):L1170-8 PMID: 19820034
  201. Role of pericytes in vascular calcification: a review.
    Z Kardiol. 2000;89 Suppl 2:20-7 PMID: 10769400
  202. Sodium-dependent phosphate cotransporters and vascular calcification.
    Curr Opin Nephrol Hypertens. 2007 Jul;16(4):325-8 PMID: 17565274
  203. TGF-beta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop.
    Cell. 1990 Nov 2;63(3):515-24 PMID: 2171777
  204. Bone morphogenetic protein signalling in heritable versus idiopathic pulmonary hypertension.
    Eur Respir J. 2009 Nov;34(5):1100-10 PMID: 19324947
  205. Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification.
    Circ Res. 2010 Aug 20;107(4):485-94 PMID: 20576934
  206. Thalidomide for treatment of severe intestinal bleeding.
    Gut. 2004 Apr;53(4):609-12 PMID: 15016759
  207. Abnormalities of endothelial function in the pathogenesis of stroke: the importance of endothelin.
    J Cardiovasc Pharmacol. 2000;35(4 Suppl 2):S45-48 PMID: 10976781
  208. Role of Smads in TGFβ signaling.
    Cell Tissue Res. 2012 Jan;347(1):21-36 PMID: 21643690
  209. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis.
    Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2626-31 PMID: 10716993
  210. Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5.
    Development. 1999 Apr;126(8):1571-80 PMID: 10079220
  211. Interleukin-1 induces major phenotypic changes in human skin microvascular endothelial cells.
    J Cell Physiol. 1997 Oct;173(1):84-92 PMID: 9326452
  212. Microarray studies in pulmonary arterial hypertension.
    Int J Clin Pract Suppl. 2011 Jan;(169):19-28 PMID: 21176012
  213. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines.
    Atherosclerosis. 1999 Jul;145(1):33-43 PMID: 10428293
  214. Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension.
    Am J Physiol Regul Integr Comp Physiol. 2010 Mar;298(3):R833-42 PMID: 20042692
  215. Molecular mechanisms of vascular calcification: lessons learned from the aorta.
    Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1423-30 PMID: 16601233
  216. TGF-beta is required for vascular barrier function, endothelial survival and homeostasis of the adult microvasculature.
    PLoS One. 2009;4(4):e5149 PMID: 19340291
  217. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling.
    Mol Cell. 2003 Oct;12(4):817-28 PMID: 14580334
  218. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.
    Science. 2006 Apr 7;312(5770):117-21 PMID: 16601194
  219. TGF-β-induced mesenchymal transition of MS-1 endothelial cells requires Smad-dependent cooperative activation of Rho signals and MRTF-A.
    J Biochem. 2012 Feb;151(2):145-56 PMID: 21984612
  220. BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis.
    J Cell Sci. 2007 Mar 15;120(Pt 6):964-72 PMID: 17311849
  221. Bone morphogenetic protein-7 modulates genes that maintain the vascular smooth muscle cell phenotype in culture.
    J Bone Joint Surg Am. 2001;83-A Suppl 1(Pt 1):S70-8 PMID: 11263669
  222. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome.
    N Engl J Med. 2008 Jun 26;358(26):2787-95 PMID: 18579813
  223. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice.
    Circ Res. 2001 Nov 9;89(10):930-4 PMID: 11701621
  224. Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells.
    PLoS One. 2008 Aug 06;3(8):e2904 PMID: 18682835
  225. Bone morphogenetic protein 4 mediates myocardial ischemic injury through JNK-dependent signaling pathway.
    J Mol Cell Cardiol. 2010 Jun;48(6):1255-65 PMID: 20096288
  226. Inhibition of glycosphingolipid synthesis by threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and the modulation of IL-1beta-stimulated expression of inducible nitric oxide synthase in rat aortic smooth muscle cells.
    Br J Pharmacol. 1998 Mar;123(5):906-10 PMID: 9535019
  227. Progression of aortic valve stenosis: TGF-beta1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis.
    Ann Thorac Surg. 2003 Feb;75(2):457-65; discussion 465-6 PMID: 12607654
  228. Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction.
    EMBO J. 2004 Oct 13;23(20):4018-28 PMID: 15385967
  229. Regulation of bone morphogenetic protein-4 by matrix GLA protein in vascular endothelial cells involves activin-like kinase receptor 1.
    J Biol Chem. 2006 Nov 10;281(45):33921-30 PMID: 16950789
  230. Bone morphogenetic protein receptor II is a novel mediator of endothelial nitric-oxide synthase activation.
    J Biol Chem. 2011 Sep 23;286(38):33134-40 PMID: 21808054
  231. Transforming growth factor-beta 1 impairs endothelin-1-mediated contraction of brain vessels by inducing mitogen-activated protein (MAP) kinase phosphatase-1 and inhibiting p38 MAP kinase.
    Mol Pharmacol. 2007 Dec;72(6):1476-83 PMID: 17848599
  232. Mechanisms underlying TGF-beta1-induced expression of VEGF and Flk-1 in mouse macrophages and their implications for angiogenesis.
    J Leukoc Biol. 2007 Feb;81(2):557-66 PMID: 17053163
  233. Signaling cross-talk between TGF-beta/BMP and other pathways.
    Cell Res. 2009 Jan;19(1):71-88 PMID: 19002158
  234. Quantitative analysis of TGFBR2 mutations in Marfan-syndrome-related disorders suggests a correlation between phenotypic severity and Smad signaling activity.
    J Cell Sci. 2010 Dec 15;123(Pt 24):4340-50 PMID: 21098638
Article Info
Journal
International journal of biological sciences
Abbr.
Int J Biol Sci
ISSN
1449-2288
DOI
10.7150/ijbs.3805
Email
evangelia.pardali@ukmuenster.de
Published
2012-00-00
Epub
2012-00-01
Pages
195-213
Language
English
Region
Australia
NLM ID
101235568
PMCID
PMC3258560
Subset
IM
External Links
PubMed source DOI: 10.7150/ijbs.3805 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2