Absence of TGFβ signaling in embryonic vascular smooth muscle leads to reduced lysyl oxidase expression, impaired elastogenesis, and aneurysm

Choudhary, Bibha; Zhou, Jingjing; Thomas, Simmy; Kaartinen, Vesa; Sucov, Henry M.

doi:10.1002/dvg.20466

Cited by 74 publications

(76 citation statements)

References 28 publications

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“…Consistent with this observation, conditional ablation of the Tgfbr2 gene in vascular SMCs recapitulated many of the features observed in Mkl2 -/-embryos, including aneurysmal dilation and dissection of the aorta during late embryonic development (Choudhary et al, 2009). However, these conclusions conflict with the observation that individuals with Marfan syndrome and Loeys-Dietz syndrome exhibit activation of TGF signaling and gain of TGF function in the arterial wall (Pearson et al, 2008).…”

Section: Research Articlesupporting

confidence: 69%

“…Genetic studies in mice and humans have shown that disruption of TGF signaling pathways results in defects in vasculogenesis and angiogenesis that are attributable, at least in part, to vascular SMCs (Pardali et al, 2010). Mice in which the Tgbr2 gene was conditionally ablated in vascular SMC precursors display arterial dilation and aneurysm formation, which leads to late embryonic lethality (Choudhary et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Myocardin-like protein 2 regulates TGFβ signaling in embryonic stem cells and the developing vasculature

Bowens

Cheng

et al. 2012

Development

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SUMMARYThe molecular mechanisms that regulate and coordinate signaling between the extracellular matrix (ECM) and cells contributing to the developing vasculature are complex and poorly understood. Myocardin-like protein 2 (MKL2) is a transcriptional co-activator that in response to RhoA and cytoskeletal actin signals physically associates with serum response factor (SRF), activating a subset of SRF-regulated genes. We now report the discovery of a previously undescribed MKL2/TGF signaling pathway in embryonic stem (ES) cells that is required for maturation and stabilization of the embryonic vasculature.

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Section: Research Articlesupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Myocardin-like protein 2 regulates TGFβ signaling in embryonic stem cells and the developing vasculature

Bowens

Cheng

et al. 2012

Development

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“…Regardless, hypotheses such as this are now directly testable using our mouse model of the human mutation. More generally, beyond individuals with TAAD caused by LOX mutations, there is evidence that LOX may also play a role in modifying other forms of TAAD (32)(33)(34), which suggests that therapeutic manipulation of LOX activity may prove beneficial in other inherited aortopathies.…”

Section: Discussionmentioning

confidence: 99%

Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans

Lee

Halabi

Hoffman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

159

117

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Thoracic aortic aneurysms and dissections (TAAD) represent a substantial cause of morbidity and mortality worldwide. Many individuals presenting with an inherited form of TAAD do not have causal mutations in the set of genes known to underlie disease. Using whole-genome sequencing in two first cousins with TAAD, we identified a missense mutation in the lysyl oxidase (LOX) gene (c.893T > G encoding p.Met298Arg) that cosegregated with disease in the family. Using clustered regularly interspaced short palindromic repeats (CRISPR)/clustered regularly interspaced short palindromic repeats-associated protein-9 nuclease (Cas9) genome engineering tools, we introduced the human mutation into the homologous position in the mouse genome, creating mice that were heterozygous and homozygous for the human allele. Mutant mice that were heterozygous for the human allele displayed disorganized ultrastructural properties of the aortic wall characterized by fragmented elastic lamellae, whereas mice homozygous for the human allele died shortly after parturition from ascending aortic aneurysm and spontaneous hemorrhage. These data suggest that a missense mutation in LOX is associated with aortic disease in humans, likely through insufficient cross-linking of elastin and collagen in the aortic wall. Mutation carriers may be predisposed to vascular diseases because of weakened vessel walls under stress conditions. LOX sequencing for clinical TAAD may identify additional mutation carriers in the future. Additional studies using our mouse model of LOX-associated TAAD have the potential to clarify the mechanism of disease and identify novel therapeutics specific to this genetic cause.

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“…Prenatal or perinatal ablation of TGF-b signaling in mouse models by deletion of Tgfbr2 in VSMCs with a VSMC-specific Cre (Langlois et al 2010), neural crest-and mesoderm-specific Cre (Choudhary et al 2009), or an inducible VSMC-specific Cre (Li et al 2014) results in defective elastogenesis, vessel wall dilation, aneurysm, and dissection. However, deletion of Tgfbr2 in VSMCs after 8 weeks of age has no apparent consequence on VSMC function and vessel wall homeostasis (Li et al 2014), suggesting that complete loss of TGF-b signaling in adult VSMCs does not cause major pathology in the adult vessel wall.…”

Section: Tgf-b Signaling In Vascular Homeostasismentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Absence of TGFβ signaling in embryonic vascular smooth muscle leads to reduced lysyl oxidase expression, impaired elastogenesis, and aneurysm

Cited by 74 publications

References 28 publications

Myocardin-like protein 2 regulates TGFβ signaling in embryonic stem cells and the developing vasculature

Myocardin-like protein 2 regulates TGFβ signaling in embryonic stem cells and the developing vasculature

Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

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