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Transforming Growth Factor Beta3 is Required for Cardiovascular Development.

ABSTRACT: Transforming growth factor beta3 (TGFB3) gene mutations in patients of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of embryos express Tgfb3, its overarching role remains unclear in cardiovascular development and disease. We used histological, immunohistochemical, and molecular analyses of Tgfb3-/- fetuses and compared them to wildtype littermate controls. The cardiovascular phenotypes were diverse with approximately two thirds of the Tgfb3-/- fetuses having one or more cardiovascular malformations, including abnormal ventricular myocardium (particularly of the right ventricle), outflow tract septal and alignment defects, abnormal aortic and pulmonary trunk walls, and thickening of semilunar and/or atrioventricular valves. Ventricular septal defects (VSD) including the perimembranous VSDs were observed in Tgfb3-/- fetuses with myocardial defects often accompanied by the muscular type VSD. In vitro studies using TGF?3-deficient fibroblasts in 3-D collagen lattice formation assays indicated that TGF?3 was required for collagen matrix reorganization. Biochemical studies indicated the 'paradoxically' increased activation of canonical (SMAD-dependent) and noncanonical (MAP kinase-dependent) pathways. TGF?3 is required for cardiovascular development to maintain a balance of canonical and noncanonical TGF? signaling pathways.

SUBMITTER: Chakrabarti M

PROVIDER: S-EPMC7344558 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Transforming Growth Factor Beta3 is Required for Cardiovascular Development.

Chakrabarti Mrinmay M Al-Sammarraie Nadia N Gebere Mengistu G MG Bhattacharya Aniket A Chopra Sunita S Johnson John J Peña Edsel A EA Eberth John F JF Poelmann Robert E RE Gittenberger-de Groot Adriana C AC Azhar Mohamad M

Journal of cardiovascular development and disease 20200524 2

Transforming growth factor beta3 (<i>TGFB3</i>) gene mutations in patients of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of embryos express <i>Tgfb3</i>, its overarching role remains unclear in cardiovascular development and disease. We used histological, immun ...[more]

PMID: 32456345

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Project description:Embryonic heart valve primordia (cushions) maintain unidirectional blood flow during development despite an increasingly demanding mechanical environment. Recent studies demonstrate that atrioventricular (AV) cushions stiffen over gestation, but the molecular mechanisms of this process are unknown. Transforming growth factor-beta (TGFβ) and serotonin (5-HT) signaling modulate tissue biomechanics of postnatal valves, but less is known of their role in the biomechanical remodeling of embryonic valves. In this study, we demonstrate that exogenous TGFβ3 increases AV cushion biomechanical stiffness and residual stress, but paradoxically reduces matrix compaction. We then show that TGFβ3 induces contractile gene expression (RhoA, aSMA) and extracellular matrix expression (col1α2) in cushion mesenchyme, while simultaneously stimulating a two-fold increase in proliferation. Local compaction increased due to an elevated contractile phenotype, but global compaction appeared reduced due to proliferation and ECM synthesis. Blockade of TGFβ type I receptors via SB431542 inhibited the TGFβ3 effects. We next showed that exogenous 5-HT does not influence cushion stiffness by itself, but synergistically increases cushion stiffness with TGFβ3 co-treatment. 5-HT increased TGFβ3 gene expression and also potentiated TGFβ3 induced gene expression in a dose-dependent manner. Blockade of the 5HT2b receptor, but not 5-HT2a receptor or serotonin transporter (SERT), resulted in complete cessation of TGFβ3 induced mechanical strengthening. Finally, systemic 5-HT administration in ovo induced cushion remodeling related defects, including thinned/atretic AV valves, ventricular septal defects, and outflow rotation defects. Elevated 5-HT in ovo resulted in elevated remodeling gene expression and increased TGFβ signaling activity, supporting our ex-vivo findings. Collectively, these results highlight TGFβ/5-HT signaling as a potent mechanism for control of biomechanical remodeling of AV cushions during development.

Project description:Transforming growth factor β (TGFβ) signaling regulates multifaceted reproductive processes via its transmembrane receptor complex-associated machinery. It has been shown that the type 1 receptor of TGFβ (TGFBR1) is indispensable for female reproductive tract development, pregnancy success, and fertility. However, the role of TGFβ signaling in decidual development and function remains poorly defined. Our objective is to determine the impact of uterine-specific deletion of Tgfbr1 on the differentiation of endometrial stromal cells in pregnant mice, with a focus on the cellular and molecular properties of the decidua. An approach combining histological and immunohistochemical analyses, quantitative PCR, western blot, and RNA-sequencing was utilized. Our results show that decidual development is altered in TGFBR1 conditionally depleted uteri, substantiated by downregulation of genes associated with inflammatory response and uterine natural killer cell abundance, reduced presence of non-decidualized fibroblasts in the antimesometrial region, and impaired decidual cell differentiation. Notably, conditional ablation of TGFBR1 results in the formation of decidua containing more abundant alpha smooth muscle actin (ACTA2)-positive cells at the peripheral region of the antimesometrial side versus controls. This finding is corroborated by upregulation of a subset of smooth muscle marker genes in Tgfbr1 conditionally-deleted decidua. The abnormal cell differentiation is accompanied with increased cell proliferation and enhanced decidual ERK1/2 signaling upon decidual regression. In summary, this study has identified an important role of TGFBR1 in decidual cell differentiation by revealing that conditional ablation of TGFBR1 in the uterus profoundly impacts the cellular and molecular properties of the decidua. Our results suggest that TGFBR1 is required for the development of an integral decidua, a transient but crucial structure that supports embryo development.

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Transforming Growth Factor Beta3 is Required for Cardiovascular Development.

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Transforming Growth Factor Beta3 is Required for Cardiovascular Development.

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