Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Extracellular control of TGFβ signalling in vascular development and disease

Key Points

  • Transforming growth factor-β (TGFβ) isoforms are synthesized as precursor proteins that are proteolytically processed and secreted by cells in an inactive form. Latent TGFβ complexes, which are bound via large latent TGFβ-binding proteins (LTBPs) to fibrillin-1, are sequestered and can be rapidly released by proteases in response to tissue perturbations.

  • TGFβs initiate diverse cellular responses by binding to and activating specific type I and type II Ser/Thr kinase receptors and intracellular SMAD effectors. TGFβs regulate the function of endothelial and vascular smooth muscle cells (and many other cell types) in a highly context-dependent manner.

  • The vital importance of TGFβ signalling in vascular development was recognized when several human vascular pathologies were associated with mutations in TGFβ receptor genes, and mouse models that were deficient in Tgfbr1 or TGFβ receptors were found to have severe angiogenesis defects that caused embryonic lethality.

  • Transgenic mouse models of Marfan syndrome exposed a surprising and crucial function of elastic extracellular matrix components in regulating TGFβ signalling.

  • By interacting with unprocessed TGFβ, emilin-1 protects TGFβ from proteolytic processing by furin endoprotease and inhibits TGFβ signalling. Loss of emilin-1 leads to a reduction in the arterial lumen diameter with a resultant increase in vascular resistance and hypertension due to excessive TGFβ signalling.

  • Elevated levels of the soluble TGFβ co-receptor endoglin cause endothelial dysfunction and have been coupled to pre-eclampsia.

  • In summary, a growing number of studies show that extracellular control of TGFβ signalling is vital for both development and maintenance of the vasculature.

Abstract

The intracellular mechanism of transforming growth factor-β (TGFβ) signalling via kinase receptors and SMAD effectors is firmly established, but recent studies of human cardiovascular syndromes such as Marfan syndrome and pre-eclampsia have refocused attention on the importance of regulating the availability of active extracellular TGFβ. It seems that elastic extracellular matrix (ECM) components have a crucial role in controlling TGFβ signalling, while soluble and membrane bound forms of TGFβ co-receptors add further layers of regulation. Together, these extracellular interactions determine the final bioavailability of TGFβ to vascular cells, and dysregulation is associated with an increasing number of vascular pathologies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Signal transduction by TGFβ family members.
Figure 2: Regulation of TGFβ bioavailability.
Figure 3: TGFβ signalling in vasculogenesis and angiogenesis.
Figure 4: Vascular remodelling in PAH and HHT.
Figure 5: TGFβ-associated defects in Marfan and Loeys–Dietz syndromes.

Similar content being viewed by others

References

  1. Massague, J. & Gomis, R. R. The logic of TGFβ signaling. FEBS Lett. 580, 2811–2820 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Feng, X. H. & Derynck, R. Specificity and versatility in TGF-β signaling through Smads. Annu. Rev. Cell Dev. Biol. 21, 659–693 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Blobe, G. C., Schiemann, W. P. & Lodish, H. F. Role of transforming growth factor β in human disease. N. Engl. J. Med. 342, 1350–1358 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Annes, J. P., Munger, J. S. & Rifkin, D. B. Making sense of latent TGFβ activation. J. Cell Sci. 116, 217–224 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Robinson, P. N. et al. The molecular genetics of Marfan syndrome and related disorders. J. Med. Genet. 43, 769–787 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Grainger, D. J. TGF-β and atherosclerosis in man. Cardiovasc. Res. 74, 213–222 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Ruiz-Ortega, M., Rodriguez-Vita, J., Sanchez-Lopez, E., Carvajal, G. & Egido, J. TGF-β signaling in vascular fibrosis. Cardiovasc. Res. 74, 196–206 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Bierie, B. & Moses, H. L. TGF-β and cancer. Cytokine Growth Factor Rev. 17, 29–40 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Dubois, C. M., Laprise, M. H., Blanchette, F., Gentry, L. E. & Leduc, R. Processing of transforming growth factor β1 precursor by human furin convertase. J. Biol. Chem. 270, 10618–10624 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Beck, S. et al. Extraembryonic proteases regulate Nodal signalling during gastrulation. Nature Cell Biol. 4, 981–985 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Kanzaki, T. et al. TGF-β1 binding protein: a component of the large latent complex of TGF-β1 with multiple repeat sequences. Cell 61, 1051–1061 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. Saharinen, J., Taipale, J. & Keski-Oja, J. Association of the small latent transforming growth factor-β with an eight cysteine repeat of its binding protein LTBP-1. EMBO J. 15, 245–253 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dallas, S. L. et al. Characterization and autoregulation of latent transforming growth factor β (TGF β) complexes in osteoblast-like cell lines. Production of a latent complex lacking the latent TGF β-binding protein. J. Biol. Chem. 269, 6815–6821 (1994).

    CAS  PubMed  Google Scholar 

  14. Saharinen, J. & Keski-Oja, J. Specific sequence motif of 8-Cys repeats of TGF-β binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-β. Mol. Biol. Cell 11, 2691–2704 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Isogai, Z. et al. Latent transforming growth factor β -binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J. Biol. Chem. 278, 2750–2757 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Nunes, I., Gleizes, P. E., Metz, C. N. & Rifkin, D. B. Latent transforming growth factor-β binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-β. J. Cell Biol. 136, 1151–1163 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Flaumenhaft, R. et al. Role of the latent TGF-β binding protein in the activation of latent TGF-β by co-cultures of endothelial and smooth muscle cells. J. Cell Biol. 120, 995–1002 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Rifkin, D. B. Latent transforming growth factor-β (TGF-β) binding proteins: orchestrators of TGF-β availability. J. Biol. Chem. 280, 7409–7412 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Dabovic, B. et al. Bone abnormalities in latent TGF-[β] binding protein (Ltbp)-3-null mice indicate a role for Ltbp-3 in modulating TGF-β bioavailability. J. Cell Biol. 156, 227–232 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sterner-Kock, A. et al. Disruption of the gene encoding the latent transforming growth factor-β binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer. Genes Dev. 16, 2264–2273 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chaudhry, S. S. et al. Fibrillin-1 regulates the bioavailability of TGFβ1. J. Cell Biol. 176, 355–367 (2007). An internal proteolytic fragment of fibrillin-1 is shown to regulate the bioavailability of TGFβ by inducing the release of the large latent complex bound to microfibrils.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ge, G. & Greenspan, D. S. BMP1 controls TGFβ1 activation via cleavage of latent TGFβ-binding protein. J. Cell Biol. 175, 111–120 (2006). Bone morphogenetic protein-1 (BMP1)-like metalloprotease is shown to cleave large latent TGFβ binding protein 1 (LTBP1) at two specific sites, thereby liberating the large latent TGFβ complex (LLC) from the extracellular matrix (ECM).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pappano, W. N., Steiglitz, B. M., Scott, I. C., Keene, D. R. & Greenspan, D. S. Use of Bmp1/Tll1 doubly homozygous null mice and proteomics to identify and validate in vivo substrates of bone morphogenetic protein 1/tolloid-like metalloproteinases. Mol. Cell Biol. 23, 4428–4438 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Crawford, S. E. et al. Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell 93, 1159–1170 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Sheppard, D. Integrin-mediated activation of latent transforming growth factor β. Cancer Metastasis Rev. 24, 395–402 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Yang, Z. et al. Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null mice. J. Cell Biol. 176, 787–793 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mu, D. et al. The integrin avβ8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-β1. J. Cell Biol. 157, 493–507 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fontana, L. et al. Fibronectin is required for integrin alphavβ6-mediated activation of latent TGF-β complexes containing LTBP-1. FASEB J. 19, 1798–1808 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Zhu, J. et al. β8 integrins are required for vascular morphogenesis in mouse embryos. Development 129, 2891–2903 (2002).

    CAS  PubMed  Google Scholar 

  30. Bader, B. L., Rayburn, H., Crowley, D. & Hynes, R. O. Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell 95, 507–519 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Goumans, M. J. et al. Balancing the activation state of the endothelium via two distinct TGF-β type I receptors. EMBO J. 21, 1743–1753 (2002).

    Article  CAS  Google Scholar 

  32. Massague, J., Cheifetz, S., Boyd, F. T. & Andres, J. L. TGF-β receptors and TGF-β binding proteoglycans: recent progress in identifying their functional properties. Ann. N. Y. Acad. Sci. 593, 59–72 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Lebrin, F., Deckers, M., Bertolino, P. & ten Dijke, P. TGF-β receptor function in the endothelium. Cardiovasc. Res. 65, 599–608 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Goumans, M. J. et al. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFβ /ALK5 signaling. Mol. Cell 12, 817–828 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Sankar, S., Mahooti-Brooks, N., Centrella, M., McCarthy, T. L. & Madri, J. A. Expression of transforming growth factor type III receptor in vascular endothelial cells increases their responsiveness to transforming growth factor β 2. J. Biol. Chem. 270, 13567–13572 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Lopez-Casillas, F., Payne, H. M., Andres, J. L. & Massague, J. Betaglycan can act as a dual modulator of TGF-β access to signaling receptors: mapping of ligand binding and GAG attachment sites. J. Cell Biol. 124, 557–568 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Lebrin, F. et al. Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction. EMBO J. 23, 4018–4028 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Blanco, F. J. et al. Interaction and functional interplay between endoglin and ALK-1, two components of the endothelial transforming growth factor-β receptor complex. J. Cell Physiol. 204, 574–584 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Adams, R. H. & Alitalo, K. Molecular regulation of angiogenesis and lymphangiogenesis. Nature Rev. Mol. Cell Biol. 8, 464–478 (2007). Excellent review on the molecular mechanisms that underlie the formation and function of blood and lymphatic vessels.

    Article  CAS  Google Scholar 

  40. Goumans, M. J. & Mummery, C. Functional analysis of the TGFβ receptor/Smad pathway through gene ablation in mice. Int. J. Dev. Biol. 44, 253–265 2000).

    CAS  PubMed  Google Scholar 

  41. Akhurst, R. J., Lehnert, S. A., Faissner, A. & Duffie, E. TGF β in murine morphogenetic processes: the early embryo and cardiogenesis. Development 108, 645–656 (1990).

    CAS  PubMed  Google Scholar 

  42. Bartram, U. et al. Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in TGF-β2-knockout mice. Circulation 103, 2745–2752 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Kaartinen, V. et al. Abnormal lung development and cleft palate in mice lacking TGF-β3 indicates defects of epithelial-mesenchymal interaction. Nature Genet. 11, 415–421 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Tang, Y. et al. Epistatic interactions between modifier genes confer strain-specific redundancy for Tgfb1 in developmental angiogenesis. Genomics 85, 60–70 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Deckers, M. M. et al. Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology 143, 1545–1553 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Vinals, F. & Pouyssegur, J. Transforming growth factor β1 (TGF-β1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-a signaling. Mol. Cell Biol. 21, 7218–7230 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ma, J., Wang, Q., Fei, T., Han, J. D. & Chen, Y. G. MCP-1 mediates TGF-β -induced angiogenesis by stimulating vascular smooth muscle cell migration. Blood 109, 987–994 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Ferrari, G. et al. VEGF, a prosurvival factor, acts in concert with TGF-β1 to induce endothelial cell apoptosis. Proc. Natl Acad. Sci. USA 103, 17260–17265 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yang, X. et al. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-β. EMBO J. 18, 1280–1291 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jadrich, J. L., O'Connor, M. B. & Coucouvanis, E. The TGF β activated kinase TAK1 regulates vascular development in vivo. Development 133, 1529–1541 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Roman, B. L. et al. Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development 129, 3009–3019 (2002).

    CAS  PubMed  Google Scholar 

  52. Hirschi, K. K., Burt, J. M., Hirschi, K. D. & Dai, C. Gap junction communication mediates transforming growth factor-β activation and endothelial-induced mural cell differentiation. Circ. Res. 93, 429–437 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Carvalho, R. L. et al. Defective paracrine signalling by TGFβ in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia. Development 131, 6237–6247 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Kumar, M. S. & Owens, G. K. Combinatorial control of smooth muscle-specific gene expression. Arterioscler. Thromb. Vasc. Biol. 23, 737–747 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Carvalho, R. et al. Compensatory mechanisms activated during vasculogenesis in mice by TGFβ-receptor deletion. J. Cell Sci. (in the press).

  56. Jiao, K. et al. Tgfβ signaling is required for atrioventricular cushion mesenchyme remodeling during in vivo cardiac development. Development 133, 4585–4593 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Seki, T., Hong, K. H. & Oh, S. P. Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development. Lab. Invest. 86, 116–129 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Harradine, K. A. & Akhurst, R. J. Mutations of TGFβ signaling molecules in human disease. Ann. Med. 38, 403–414 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. McAllister, K. A. et al. Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nature Genet. 8, 345–351 (1994).

    Article  CAS  PubMed  Google Scholar 

  60. Johnson, D. W. et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nature Genet. 13, 189–195 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Gu, Y. et al. Functional analysis of mutations in the kinase domain of the TGF-β receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia. Blood 107, 1951–1954 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Jonker, L. & Arthur, H. M. Endoglin expression in early development is associated with vasculogenesis and angiogenesis. Mech. Dev. 110, 193–196 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Fernandez, L. A. et al. Blood outgrowth endothelial cells from hereditary haemorrhagic telangiectasia patients reveal abnormalities compatible with vascular lesions. Cardiovasc. Res. 68, 235–248 (2005).

    Article  CAS  Google Scholar 

  64. Urness, L. D., Sorensen, L. K. & Li, D. Y. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nature Genet. 26, 328–331 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Sorensen, L. K., Brooke, B. S., Li, D. Y. & Urness, L. D. Loss of distinct arterial and venous boundaries in mice lacking endoglin, a vascular-specific TGFβ coreceptor. Dev. Biol. 261, 235–250 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Letarte, M. et al. Reduced endothelial secretion and plasma levels of transforming growth factor-β1 in patients with hereditary hemorrhagic telangiectasia type 1. Cardiovasc. Res. 68, 155–164 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Sadick, H. et al. Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-β1 as well as high ALK1 tissue expression. Haematologica 90, 818–828 (2005).

    CAS  PubMed  Google Scholar 

  68. Scharpfenecker, M. et al. BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J. Cell Sci. 120, 964–972 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Allinson, K., Carvalho, R. L. C., van den Brink, S., Mummery, C. L. & Arthur, H. M. Generation of a floxed allele of the mouse endoglin gene. Genesis 45, 391–395 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Morrell, N. W. et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-β (1) and bone morphogenetic proteins. Circulation 104, 790–795 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Yang, X. et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ. Res. 96, 1053–1063 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Yu, P. B., Beppu, H., Kawai, N., Li, E. & Bloch, K. D. Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary artery smooth muscle cells. J. Biol. Chem. 280, 24443–24450 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Foletta, V. C. et al. Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J. Cell Biol. 162, 1089–1098 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. West, J. et al. Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ. Res. 94, 1109–1114 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Harrison, R. E. et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J. Med. Genet. 40, 865–871 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mizuguchi, T. et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nature Genet. 36, 855–860 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Loeys, B. L. et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature Genet. 37, 275–281 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Pannu, H. et al. Mutations in transforming growth factor-β receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation 112, 513–520 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Topouzis, S. & Majesky, M. W. Smooth muscle lineage diversity in the chick embryo. Two types of aortic smooth muscle cell differ in growth and receptor-mediated transcriptional responses to transforming growth factor-β. Dev. Biol. 178, 430–445 (1996).

    Article  CAS  PubMed  Google Scholar 

  80. Waldo, K. L. et al. Secondary heart field contributes myocardium and smooth muscle to the arterial pole of the developing heart. Dev. Biol. 281, 78–90 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Neptune, E. R. et al. Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome. Nature Genet. 33, 407–411 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Habashi, J. P. et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312, 117–121 (2006). Aortic aneurysm in a mouse model of MFS is shown to be associated with increased TGFβ signalling and can be prevented by TGFβ-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Carta, L. et al. Fibrillins 1 and 2 perform partially overlapping functions during aortic development. J. Biol. Chem. 281, 8016–8023 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Judge, D. P. et al. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J. Clin. Invest. 114, 172–181 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Denton, C. P. et al. Fibroblast-specific expression of a kinase-deficient type II transforming growth factor β (TGFβ) receptor leads to paradoxical activation of TGFβ signaling pathways with fibrosis in transgenic mice. J. Biol. Chem. 278, 25109–25119 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Wang, W. et al. Essential role of Smad3 in angiotensin II-induced vascular fibrosis. Circ. Res. 98, 1032–1039 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhou, Y., Poczatek, M. H., Berecek, K. H. & Murphy-Ullrich, J. E. Thrombospondin 1 mediates angiotensin II induction of TGF-β activation by cardiac and renal cells under both high and low glucose conditions. Biochem. Biophys. Res. Commun. 339, 633–641 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Yanagisawa, H. et al. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature 415, 168–171 (2002).

    Article  PubMed  Google Scholar 

  89. Nakamura, T. et al. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature 415, 171–175 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. McLaughlin, P. J. et al. Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. Mol. Cell Biol. 26, 1700–1709 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hanada, K. et al. Perturbations of vascular homeostasis and aortic valve abnormalities in fibulin-4 deficient mice. Circ. Res. 100, 738–746 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Cambien, F. et al. Polymorphisms of the transforming growth factor-β 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Temoin de l'Infarctus du Myocarde (ECTIM) Study. Hypertension 28, 881–887 (1996).

    Article  CAS  PubMed  Google Scholar 

  93. Zacchigna, L. et al. Emilin1 links TGF-β maturation to blood pressure homeostasis. Cell 124, 929–942 (2006). Mice lacking emilin-1, a Cys-rich secreted glycoprotein that prevents maturation of pro-TGFβ precursor by furin convertases, display elevated blood pressure due to increased TGFβ signalling in the vasculature.

    Article  CAS  PubMed  Google Scholar 

  94. August, P. & Suthanthiran, M. Transforming growth factor β signaling, vascular remodeling, and hypertension. N. Engl. J. Med. 354, 2721–2723 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Venkatesha, S. et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nature Med. 12, 642–649 (2006). Soluble endoglin is shown to lead to dysregulated TGFβ signalling in the vasculature and may act in concert with VEGFR1 to induce severe pre-eclampsia.

    Article  CAS  PubMed  Google Scholar 

  96. Cudmore, M. et al. Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation 115, 1789–1797 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Lopez-Novoa, J. M. Soluble endoglin is an accurate predictor and a pathogenic molecule in pre-eclampsia. Nephrol. Dial. Transplant. 22, 712–714 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Akhurst, R. J. Large- and small-molecule inhibitors of transforming growth factor-β signaling. Curr. Opin. Investig. Drugs 7, 513–521 (2006).

    CAS  PubMed  Google Scholar 

  99. Derynck, R., Akhurst, R. J. & Balmain, A. TGF-β signaling in tumor suppression and cancer progression. Nature Genet. 29, 117–129 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Akhurst, R. J. TGF β signaling in health and disease. Nature Genet. 36, 790–792 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Kano, M. R. et al. Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling. Proc. Natl Acad. Sci. USA 104, 3460–3465 (2007). Application of a small-molecule TGFβ type I receptor inhibitor at a low dose decreased pericyte coverage of the endothelium specifically in the tumour neovasculature, and promoted accumulation of anticancer nanocarriers in tumours.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jerkic, M. et al. Reduced angiogenic responses in adult endoglin heterozygous mice. Cardiovasc. Res. 69, 845–854 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Duff, S. E., Li, C., Garland, J. M. & Kumar, S. CD105 is important for angiogenesis: evidence and potential applications. FASEB J. 17, 984–992 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Tan, G. H. et al. Combination of low-dose cisplatin and recombinant xenogeneic endoglin as a vaccine induces synergistic antitumor activities. Int. J. Cancer 112, 701–706 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. van Laake, L. W. et al. Endoglin has a crucial role in blood cell-mediated vascular repair. Circulation 114, 2288–2297 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Ramirez, F. & Rifkin, D. B. Cell signaling events: a view from the matrix. Matrix Biol. 22, 101–107 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Coucke, P. J. et al. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nature Genet. 38, 452–457 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Gregory, K. E. et al. The prodomain of BMP-7 targets the BMP-7 complex to the extracellular matrix. J. Biol. Chem. 280, 27970–27980 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Arteaga-Solis, E. et al. Regulation of limb patterning by extracellular microfibrils. J. Cell Biol. 154, 275–281 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Choudhary, B. et al. Cardiovascular malformations with normal smooth muscle differentiation in neural crest-specific type II TGFβ receptor (Tgfbr2) mutant mice. Dev. Biol. 289, 420–429 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Cohn, R. D. et al. Angiotensin II type 1 receptor blockade attenuates TGF-β-induced failure of muscle regeneration in multiple myopathic states. Nature Med. 13, 204–210 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Kamei, M. et al. Endothelial tubes assemble from intracellular vacuoles in vivo. Nature 442, 453–456 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Barbara, N. P., Wrana, J. L. & Letarte, M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-β superfamily. J. Biol. Chem. 274, 584–594 (1999).

    Article  CAS  PubMed  Google Scholar 

  114. George, E. L., Georges-Labouesse, E. N., Patel-King, R. S., Rayburn, H. & Hynes, R. O. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 119, 1079–1091 (1993).

    CAS  PubMed  Google Scholar 

  115. Lawler, J. et al. Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J. Clin. Invest. 101, 982–992 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Huang, X. Z. et al. Inactivation of the integrin β 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J. Cell Biol. 133, 921–928 (1996).

    Article  CAS  PubMed  Google Scholar 

  117. Stenvers, K. L. et al. Heart and liver defects and reduced transforming growth factor β2 sensitivity in transforming growth factor β type III receptor-deficient embryos. Mol. Cell Biol. 23, 4371–4385 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Srinivasan, S. et al. A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2. Hum. Mol. Genet. 12, 473–482 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Larsson, J. et al. Abnormal angiogenesis but intact hematopoietic potential in TGF-β type I receptor-deficient mice. EMBO J. 20, 1663–1673 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Beppu, H. et al. 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. 287, L1241–L1247 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Lane, K. B. et al. Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nature Genet. 26, 81–84 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Gallione, C. J. et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 363, 852–859 (2004).

    Article  CAS  PubMed  Google Scholar 

  123. Loeys, B.L. et al. Aneurysm syndromes caused by mutations in the TGF-β receptor. N. Engl. J. Med. 355, 788–798 (2006). Mutations in either TGFBR1 or TGFBR2 are shown to predispose patients to aggressive and widespread vascular disease.

    Article  CAS  PubMed  Google Scholar 

  124. Todorovic, V. et al. Long form of latent TGF-β binding protein 1 (Ltbp1L) is essential for cardiac outflow tract septation and remodeling. Development (in the press).

Download references

Acknowledgements

Research in our laboratories is supported by grants from the Dutch Cancer Society, the EC (Angiotargeting and Tumour Host Genomics), the Ludwig Institute for Cancer Research, the Netherlands Organization for Scientific Research, the British Heart Foundation, Newcastle Hospital Trustees, the Cookson Foundation and the Wellcome Trust. We are grateful to our colleagues for valuable discussion, and apologize to those whose contributions have not been cited because of space constraints.

Author information

Authors and Affiliations

Authors

Related links

Related links

DATABASES

OMIM

arterial tortuosity syndrome

Duchenne's muscular dystrophy

familial thoracic aneurysm disorder

hereditary haemorrhagic telangiectasia type 1

HHT type 2

Loeys-Dietz syndrome

Marfan syndrome

MFS type 2

pulmonary arterial hypertension

FURTHER INFORMATION

Peter ten Dijke's homepage

Helen Arthur's homepage

HHT Foundation International web site

The US National Marfan Foundation web site

Glossary

Pleiotropic

Influencing multiple different traits.

Convertase family of endoproteases

A group of enzymes that make an internal cut in a polypeptide chain to convert it from an inactive to an active form.

Fibrillin

An extracellular matrix glycoprotein that is a structural component of microfibrils.

Microfibril

A fibre component (10 nm in diameter) of the extracellular matrix that is essential for the integrity of elastic fibres, which are particularly abundant in the aorta.

Matrix metalloprotease

One of a family of structurally related extracellular Ca2+-dependent zinc-containing proteases involved in tissue remodelling and ECM degradation.

RGD sequence

An amino acid sequence (Arg-Gly-Asp) found in extracellular matrix proteins that directly binds to integrins.

Morpholino

Chemically synthesized oligonucleotide analogues used to knock down gene expression by specifically binding to target transcripts to inhibit RNA splicing or translation.

Vessel muscularization

The development of smooth muscle cells around a vessel to support and stabilize it.

Pericyte

A smooth muscle-like cell that is intimately associated with endothelial cells of small blood vessels.

Mesenchymal cell

A member of a heterogeneous multipotent cell population that arises mainly from embryonic mesoderm.

Hypertension

Elevated blood pressure.

Arteriovenous malformation

(AVM). Abnormal communication between an artery and a vein producing dilated vessels.

Intussusceptive angiogenesis

The process of blood vessel growth by 'splitting' — the wall of an existing blood vessel extends into the lumen to split a single vessel in two.

Sprouting angiogenesis

The process by which endothelial cells migrate and proliferate into the surrounding matrix to form new vessel branches in response to an angiogenic stimulus.

Anastomosis

A naturally occurring arteriovenous connection that may be dynamically regulated and is particularly frequent in thermoregulatory vascular beds.

Placental syncytiotrophoblast cell

A multinucleated cell found at the boundary of the fetal and maternal layers of the placenta.

Truncus arteriosus

A single vessel that forms early in development and then septates to form the aorta and pulmonary trunk. A persistent truncus arteriosus is one that has failed to septate, compromising the separation of pulmonary and systemic circulations.

Aortopulmonary septation

The process whereby the pulmonary trunk and aorta separate during development.

Rights and permissions

Reprints and permissions

About this article

Cite this article

ten Dijke, P., Arthur, H. Extracellular control of TGFβ signalling in vascular development and disease. Nat Rev Mol Cell Biol 8, 857–869 (2007). https://doi.org/10.1038/nrm2262

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2262

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing