The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development

Robson, Andrew; Allinson, Kathleen R.; Anderson, Robert H.; Henderson, Deborah J.; Arthur, Helen M.

doi:10.1002/dvdy.22376

Cited by 38 publications

(31 citation statements)

References 37 publications

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“…Similarly, the majority of mice that had myocardial specific depletion of Tgfbr2 also developed normal hearts. This finding was observed in two independent studies using two different Cre lines, Mlc2v-Cre and cTnT-Cre, (Jiao et al, 2006;Robson et al, 2010) confirming that TGFb signaling has little role in cardiomyocyte cells during heart development.…”

Section: Larsson Et Al 2001supporting

confidence: 77%

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TGFβ signaling and congenital heart disease: Insights from mouse studies

Arthur

Bamforth

2011

Birth Defects Research

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Transforming growth factor β (TGFβ) regulates one of the major signaling pathways that control tissue morphogenesis. In vitro experiments using heart explants indicated the importance of this signaling pathway for the generation of cushion mesenchymal cells, which ultimately contribute to the valves and septa of the mature heart. Recent advances in mouse genetics have enabled in vivo investigation into the roles of individual ligands, receptors, and coreceptors of this pathway, including investigation of the tissue specificity of these roles in heart development. This work has revealed that (1) cushion mesenchyme can form in the absence of TGFβ signaling, although mesenchymal cell numbers may be misregulated; (2) TGFβ signaling is essential for correct remodeling of the cushions, particularly those of the outflow tract; (3) TGFβ signaling also has a role in ensuring accurate remodeling of the pharyngeal arch arteries to form the mature aortic arch; and (4) mesenchymal cells derived from the epicardium require TGFβ signaling to promote their differentiation to vascular smooth muscle cells to support the coronary arteries. In addition, a mouse genetics approach has also been used to investigate the disease pathogenesis of Loeys-Dietz syndrome, a familial autosomal dominant human disorder characterized by a dilated aortic root, and associated with mutations in the two TGFβ signaling receptor genes, TGFBR1 and TGFBR2. Further important insights are likely as this exciting work progresses.

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Section: Larsson Et Al 2001supporting

confidence: 77%

“…(2) embryonic lethal at ED15.5 when Cre activated at ED 11.5, VSD, cerebral hemorrhage VSD Carvalho et al, 2007;Jiao et al, 2006;Robson et al, 2010 Tgfbr2/vascular smooth muscle/epicardium (1) Embryonic lethal at approximately ED 17, VSD, aortic dilatation, coronary vessel defects;…”

Section: Larsson Et Al 2001mentioning

confidence: 99%

TGFβ signaling and congenital heart disease: Insights from mouse studies

Arthur

Bamforth

2011

Birth Defects Research

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“…As the αVβ8 integrin has been shown to mediate TGFβ activation in vitro (Cambier et al, 2005), this suggested that αVβ8 on neuroepithelial cells activates TGFβ, which subsequently promotes vascular integrity. The similarities in phenotype of neuroepithelialspecific Itgav and Itgb8 mutants with endothelial-specific mutations of Tgfbr2 (Robson et al, 2010), Alk5 (Nguyen et al, 2011) and Smad2/Smad3 (Itoh et al, 2012) support this proposal. In each mutant, vessels were 'stalled' in their growth from the pia mater towards the ventricle.…”

Section: Introductionmentioning

confidence: 68%

“…Glomeruloid formation and hemorrhage are relatively late phenotypes, probably secondary to elevated sprouting, branching and proliferation of endothelial cells. In addition to Itgav and Itgb8, brain hemorrhage during embryonic development is observed in other mutant mice, including Gpr124 (Anderson et al, 2011;Cullen et al, 2011;Kuhnert et al, 2010), Nrp1 (Gerhardt et al, 2004;Gu et al, 2003;Kawasaki et al, 1999), Wnt7a/ b-Bcat (Daneman et al, 2009;Liebner et al, 2008;Stenman et al, 2008), Tgfb1/3 (Mu et al, 2008), Tgfbr2 (Nguyen et al, 2011;Robson et al, 2010), Alk5 (Nguyen et al, 2011), Smad4 , Smad2/Smad3 (Itoh et al, 2012) and S1pr1 (Gaengel et al, 2012). Prior work either did not address the cause of hemorrhage (Nrp1, Tgfb1/3, Smad2/Smad3, S1pr1) or attributed it to a dysfunctional BBB [Gpr124 (Anderson et al, 2011), Bcat (Liebner et al, 2008), Smad4 , Itgb8 (Mobley et al, 2009), Itgav-Tgfbr2-Alk5 (Nguyen et al, 2011)].…”

Section: Discussionmentioning

confidence: 99%

Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain

et al. 2014

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Vascular development of the central nervous system and blood-brain barrier (BBB) induction are closely linked processes. The role of factors that promote endothelial sprouting and vascular leak, such as vascular endothelial growth factor A, are well described, but the factors that suppress angiogenic sprouting and their impact on the BBB are poorly understood. Here, we show that integrin αVβ8 activates angiosuppressive TGFβ gradients in the brain, which inhibit endothelial cell sprouting. Loss of αVβ8 in the brain or downstream TGFβ1-TGFBR2-ALK5-Smad3 signaling in endothelial cells increases vascular sprouting, branching and proliferation, leading to vascular dysplasia and hemorrhage. Importantly, BBB function in Itgb8 mutants is intact during early stages of vascular dysgenesis before hemorrhage. By contrast, Pdgfb ret/ret mice, which exhibit severe BBB disruption and vascular leak due to pericyte deficiency, have comparatively normal vascular morphogenesis and do not exhibit brain hemorrhage. Our data therefore suggest that abnormal vascular sprouting and patterning, not BBB dysfunction, underlie developmental cerebral hemorrhage.

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“…This data suggests that TβRII is not involved in initial cushion formation and EMT but rather proliferation of cushion mesenchyme. If deletion of TβRII is induced using tamoxifen at E11.5 using a CreERT system (tamoxifen-activated Cdh5(PAC)-CreERT2) in the endothelium, embryos die at E15.5 due to abnormal ventricular septation, failure of cushion fusion and haemorrhaging in cerebral blood vessels [96].…”

Section: Tgfβ Signalling In Cardiac Valve Developmentmentioning

confidence: 99%

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

Garside

Chang

Karsan

et al. 2012

Cell. Mol. Life Sci.

131

123

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Congenital heart defects affect approximately 1-5% of human newborns each year and of these cardiac defects, 20-30% are due to heart valve abnormalities. Recent literature indicates that key factors and pathways that regulate valve development are also implicated in congenital heart defects and valve disease. Currently, there are limited options for treatment of valve disease and therefore, having a better understanding of valve development can contribute critical insight into congenital valve defects and disease. There are three major signalling pathways required for early specification and initiation of Endothelial-to-Mesenchymal Transformation (EMT) in the cardiac cushions: BMP, TGFβ, and Notch signalling. BMPs secreted from the myocardium setup the environment for the overlying endocardium to become activated, Notch signalling initiates EMT, and both BMP and TGFβ signalling synergizes with Notch to promote the transition of endothelia to mesenchyme and to promote mesenchymal cell invasiveness. Together, these three essential signalling pathways help to form the cardiac cushions and populate them with mesenchyme and, consequently, set off the cascade of events required to develop mature heart valves. Furthermore, integration and cross-talk between these pathways generate highly stratified and delicate valve leaflets and septa of the heart. Here, we discuss BMP, TGFβ, and Notch signalling pathways during mouse cardiac cushion formation and how they together produce a coordinated EMT response in the developing mouse valves.

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The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development

Cited by 38 publications

References 37 publications

TGFβ signaling and congenital heart disease: Insights from mouse studies

TGFβ signaling and congenital heart disease: Insights from mouse studies

Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

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