Transforming growth factor Beta2 is required for valve remodeling during heart development

Azhar, Mohamad; Brown, Kristen; Gard, Connie; Chen, Hwudaurw; Rajan, Sudarsan; Elliott, David A.; Stevens, Mark V.; Camenisch, Todd D.; Conway, Simon J.; Doetschman, Thomas

doi:10.1002/dvdy.22702

Cited by 64 publications

(60 citation statements)

References 80 publications

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“…13 Given the paradoxical roles of increased and/or decreased TGFb signalling in MFS-like disorders, 13 it would be important to determine how TGFb and WNT/b-catenin signalling integrate in the pathogenesis of MVD. Finally, this proposition is also consistent with the findings indicating that loss of TGFb2 or Axin2 in mice cause thickened valves at birth, 9,14 suggesting that Axin2 deletion by shifting the balance from TGFb/ SMAD3 toward WNT/b-catenin signalling could contribute to MVD (Figure 2). Since Tgfb2 knockout mice die at birth, 14,15 further studies should be done to determine if the loss of TGFb2 in VICs causes MVD in adult mice and whether MVD in Tgfb2 conditional knockout mice is also associated with decreased expression of Axin2 as well as reduced SMAD3 activation.…”

Section: Have Not Demonstrated If An Alteredsupporting

confidence: 90%

Increased canonical WNT/β-catenin signalling and myxomatous valve disease

et al. 2017

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Section: Have Not Demonstrated If An Alteredsupporting

confidence: 90%

Increased canonical WNT/β-catenin signalling and myxomatous valve disease

et al. 2017

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“…We characterized recombinant TGFBRII-Fc fusion protein as a potent inhibitor of TGF-b1 and TGF-b3 signaling that did not affect the signaling of TGF-b2, which is an important regulator of endothelial-tomesenchymal transition, extracellular matrix remodeling, and cardiac valve formation (24,26). Consistent with this activity, TGFBRII-Fc blocked canonical Smad 2/3 signaling via TGF-b1 and TGF-b3, but did not block TGF-b2, and prevented TGF-b1-mediated switching of pulmonary artery smooth muscle cells from a synthetic to a contractile phenotype in vitro (34,35).…”

Section: Discussionmentioning

confidence: 99%

A Selective Transforming Growth Factor-β Ligand Trap Attenuates Pulmonary Hypertension

Yung

Nikolić

Paskin-Flerlage

et al. 2016

Am J Respir Crit Care Med

119

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Rationale: Transforming growth factor-b (TGF-b) ligands signal via type I and type II serine-threonine kinase receptors to regulate broad transcriptional programs. Excessive TGF-b-mediated signaling is implicated in the pathogenesis of pulmonary arterial hypertension, based in part on the ability of broad inhibition of activin-like kinase (ALK) receptors 4/5/7 recognizing TGF-b, activin, growth and differentiation factor, and nodal ligands to attenuate experimental pulmonary hypertension (PH). These broad inhibition strategies do not delineate the specific contribution of TGF-b versus a multitude of other ligands, and their translation is limited by cardiovascular and systemic toxicity.Objectives: We tested the impact of a soluble TGF-b type II receptor extracellular domain expressed as an immunoglobulin-Fc fusion protein (TGFBRII-Fc), serving as a selective TGF-b1/3 ligand trap, in several experimental PH models.Methods: Signaling studies used cultured human pulmonary artery smooth muscle cells. PH was studied in monocrotaline-treated Sprague-Dawley rats, SU5416/hypoxia-treated Sprague-Dawley rats, and SU5416/hypoxia-treated C57BL/6 mice. PH, cardiac function, vascular remodeling, and valve structure were assessed by ultrasound, invasive hemodynamic measurements, and histomorphometry.Measurements and Main Results: TGFBRII-Fc is an inhibitor of TGF-b1 and TGF-b3, but not TGF-b2, signaling. In vivo treatment with TGFBRII-Fc attenuated Smad2 phosphorylation, normalized expression of plasminogen activator inhibitor-1, and mitigated PH and pulmonary vascular remodeling in monocrotaline-treated rats, SU5416/hypoxia-treated rats, and SU5416/hypoxia-treated mice. Administration of TGFBRII-Fc to monocrotaline-treated or SU5416/hypoxia-treated rats with established PH improved right ventricular systolic pressures, right ventricular function, and survival. No cardiac structural or valvular abnormalities were observed after treatment with TGFBRII-Fc.Conclusions: Our findings are consistent with a pathogenetic role of TGF-b1/3, demonstrating the efficacy and tolerability of selective TGF-b ligand blockade for improving hemodynamics, remodeling, and survival in multiple experimental PH models.Keywords: transforming growth factor-b; pulmonary artery; vascular smooth muscle cells; vascular remodeling; pulmonary hypertension Pulmonary arterial hypertension (PAH) is a highly morbid condition characterized by elevated pulmonary vascular resistance and arterial pressures, driven by a progressive pulmonary vasculopathy that leads to right ventricular hypertrophy (RVH), and ultimately, RV failure and death (1, 2). In PAH, arteriolar remodeling is characterized by medial hypertrophy, neointimal and obstructive lesions consisting of proliferating myofibroblast and endothelial lineages, and multichanneled plexiform

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“…A common phenotypic outcome resulting from a variety of disparate genetic mutations in mouse models is a hyperplastic cushion with failure to condense or form quiescent fibroblasts. This can result from mutations in TGFβ, VEGF, BMP, or other pathways (Azhar et al, 2011; Galvin et al, 2000; Lee et al, 2006), which suggests that all of these factors integrate, albeit complexly, into cellular decisions to interact with and remodel their microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Cadherin-11 coordinates cellular migration and extracellular matrix remodeling during aortic valve maturation

Bowen

Zhou

Sung

et al. 2015

Developmental Biology

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Proper remodeling of the endocardial cushions into thin fibrous valves is essential for gestational progression and long-term function. This process involves dynamic interactions between resident cells and their local environment, much of which is not understood. In this study, we show that deficiency of the cell-cell adhesion protein cadherin-11 (cad-11) results in significant embryonic and perinatal lethality primarily due to valve related cardiac dysfunction. While endocardial to mesenchymal transformation is not abrogated, mesenchymal cells do not homogeneously cellularize the cushions. These cushions remain thickened with disorganized ECM, resulting in pronounced aortic valve insufficiency. Mice that survive to adulthood maintain thickened and stenotic semilunar valves, but interestingly do not develop calcification. Cad-11 −/− aortic valve leaflets contained reduced sox9 activity, β1 integrin expression, and RhoA-GTP activity, suggesting that remodeling defects are due to improper migration and/or cellular contraction. Cad-11 deletion or siRNA knockdown reduced migration, eliminated collective migration, and impaired 3D matrix compaction by aortic valve interstitial cells (VIC). Cad-11 depleted cells in culture contained few filopodia, stress fibers, or contact inhibited locomotion. Transfection of Cad-11 depleted cells with constitutively active RhoA restored cell phenotypes. Together, these results identify cadherin-11 mediated adhesive signaling for proper remodeling of the embryonic semilunar valves.

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Transforming growth factor Beta2 is required for valve remodeling during heart development

Cited by 64 publications

References 80 publications

Increased canonical WNT/β-catenin signalling and myxomatous valve disease

Increased canonical WNT/β-catenin signalling and myxomatous valve disease

A Selective Transforming Growth Factor-β Ligand Trap Attenuates Pulmonary Hypertension

Cadherin-11 coordinates cellular migration and extracellular matrix remodeling during aortic valve maturation

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