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.
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.
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Massague, J. & Gomis, R. R. The logic of TGFβ signaling. FEBS Lett. 580, 2811–2820 (2006).
Feng, X. H. & Derynck, R. Specificity and versatility in TGF-β signaling through Smads. Annu. Rev. Cell Dev. Biol. 21, 659–693 (2005).
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).
Annes, J. P., Munger, J. S. & Rifkin, D. B. Making sense of latent TGFβ activation. J. Cell Sci. 116, 217–224 (2003).
Robinson, P. N. et al. The molecular genetics of Marfan syndrome and related disorders. J. Med. Genet. 43, 769–787 (2006).
Grainger, D. J. TGF-β and atherosclerosis in man. Cardiovasc. Res. 74, 213–222 (2007).
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).
Bierie, B. & Moses, H. L. TGF-β and cancer. Cytokine Growth Factor Rev. 17, 29–40 (2006).
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).
Beck, S. et al. Extraembryonic proteases regulate Nodal signalling during gastrulation. Nature Cell Biol. 4, 981–985 (2002).
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).
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).
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).
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).
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).
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).
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).
Rifkin, D. B. Latent transforming growth factor-β (TGF-β) binding proteins: orchestrators of TGF-β availability. J. Biol. Chem. 280, 7409–7412 (2005).
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).
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).
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.
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).
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).
Crawford, S. E. et al. Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell 93, 1159–1170 (1998).
Sheppard, D. Integrin-mediated activation of latent transforming growth factor β. Cancer Metastasis Rev. 24, 395–402 (2005).
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).
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).
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).
Zhu, J. et al. β8 integrins are required for vascular morphogenesis in mouse embryos. Development 129, 2891–2903 (2002).
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).
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).
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).
Lebrin, F., Deckers, M., Bertolino, P. & ten Dijke, P. TGF-β receptor function in the endothelium. Cardiovasc. Res. 65, 599–608 (2005).
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).
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).
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).
Lebrin, F. et al. Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction. EMBO J. 23, 4018–4028 (2004).
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).
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.
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).
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).
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).
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).
Tang, Y. et al. Epistatic interactions between modifier genes confer strain-specific redundancy for Tgfb1 in developmental angiogenesis. Genomics 85, 60–70 (2005).
Deckers, M. M. et al. Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology 143, 1545–1553 (2002).
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).
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).
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).
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).
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).
Roman, B. L. et al. Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development 129, 3009–3019 (2002).
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).
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).
Kumar, M. S. & Owens, G. K. Combinatorial control of smooth muscle-specific gene expression. Arterioscler. Thromb. Vasc. Biol. 23, 737–747 (2003).
Carvalho, R. et al. Compensatory mechanisms activated during vasculogenesis in mice by TGFβ-receptor deletion. J. Cell Sci. (in the press).
Jiao, K. et al. Tgfβ signaling is required for atrioventricular cushion mesenchyme remodeling during in vivo cardiac development. Development 133, 4585–4593 (2006).
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).
Harradine, K. A. & Akhurst, R. J. Mutations of TGFβ signaling molecules in human disease. Ann. Med. 38, 403–414 (2006).
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).
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).
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).
Jonker, L. & Arthur, H. M. Endoglin expression in early development is associated with vasculogenesis and angiogenesis. Mech. Dev. 110, 193–196 (2002).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
West, J. et al. Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ. Res. 94, 1109–1114 (2004).
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).
Mizuguchi, T. et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nature Genet. 36, 855–860 (2004).
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).
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).
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).
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).
Neptune, E. R. et al. Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome. Nature Genet. 33, 407–411 (2003).
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.
Carta, L. et al. Fibrillins 1 and 2 perform partially overlapping functions during aortic development. J. Biol. Chem. 281, 8016–8023 (2006).
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).
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).
Wang, W. et al. Essential role of Smad3 in angiotensin II-induced vascular fibrosis. Circ. Res. 98, 1032–1039 (2006).
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).
Yanagisawa, H. et al. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature 415, 168–171 (2002).
Nakamura, T. et al. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature 415, 171–175 (2002).
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).
Hanada, K. et al. Perturbations of vascular homeostasis and aortic valve abnormalities in fibulin-4 deficient mice. Circ. Res. 100, 738–746 (2007).
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).
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.
August, P. & Suthanthiran, M. Transforming growth factor β signaling, vascular remodeling, and hypertension. N. Engl. J. Med. 354, 2721–2723 (2006).
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.
Cudmore, M. et al. Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation 115, 1789–1797 (2007).
Lopez-Novoa, J. M. Soluble endoglin is an accurate predictor and a pathogenic molecule in pre-eclampsia. Nephrol. Dial. Transplant. 22, 712–714 (2007).
Akhurst, R. J. Large- and small-molecule inhibitors of transforming growth factor-β signaling. Curr. Opin. Investig. Drugs 7, 513–521 (2006).
Derynck, R., Akhurst, R. J. & Balmain, A. TGF-β signaling in tumor suppression and cancer progression. Nature Genet. 29, 117–129 (2001).
Akhurst, R. J. TGF β signaling in health and disease. Nature Genet. 36, 790–792 (2004).
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.
Jerkic, M. et al. Reduced angiogenic responses in adult endoglin heterozygous mice. Cardiovasc. Res. 69, 845–854 (2006).
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).
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).
van Laake, L. W. et al. Endoglin has a crucial role in blood cell-mediated vascular repair. Circulation 114, 2288–2297 (2006).
Ramirez, F. & Rifkin, D. B. Cell signaling events: a view from the matrix. Matrix Biol. 22, 101–107 (2003).
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).
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).
Arteaga-Solis, E. et al. Regulation of limb patterning by extracellular microfibrils. J. Cell Biol. 154, 275–281 (2001).
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).
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).
Kamei, M. et al. Endothelial tubes assemble from intracellular vacuoles in vivo. Nature 442, 453–456 (2006).
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).
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).
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).
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).
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).
Srinivasan, S. et al. A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2. Hum. Mol. Genet. 12, 473–482 (2003).
Larsson, J. et al. Abnormal angiogenesis but intact hematopoietic potential in TGF-β type I receptor-deficient mice. EMBO J. 20, 1663–1673 (2001).
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).
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).
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).
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.
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).
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.
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.
An extracellular matrix glycoprotein that is a structural component of microfibrils.
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.
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.
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.
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.
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.
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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
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