TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections

Inamoto, Sakiko; Kwartler, Callie S.; Lafont, Andrea; Liang, Yan; Fadulu, Van Tran; Duraisamy, Senthil; Willing, Marcia; Estrera, Anthony L.; Safi, Hazim J.; Hannibal, Mark C.; Carey, John C.; Wiktorowicz, John E.; Tan, Filemon K.; Feng, Xin; Pannu, Hariyadarshi; Milewicz, Dianna M.

doi:10.1093/cvr/cvq230

Cited by 114 publications

(108 citation statements)

References 36 publications

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“…Contractile dysfunction is thought to underlie aortic aneurysm and dissection due to MYH11 and ACTA2 mutations in humans (25), and dedifferentiation of aortic SMCs harboring TGFBR2 missense mutations from clinical specimens has been described (10). In mice, Myh11 mutation and Acta2 deletion cause a milder phenotype characterized by abnormalities in vascular contractility without overt aortic disease; additional vascular injury in these strains unmasks a gain in proliferative function of SMCs (29,30).…”

Section: Discussionmentioning

confidence: 99%

“…Given that all aortic cell types in the latter group retain signaling potential, the requisites for paracrine overdrive of TGF-β signaling in response to excessive ligand production are maintained, including in the aortic media. In this light, it is notable that both mice and people with heterozygous mutations in the genes encoding fibrillin-1, TβRI, TβRII, Smad3, and TGF-β2 show enhanced Smad-dependent TGF-β signaling in the aortic media in association with postnatal aneurysm progression and dissection (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and that phenotypic rescue in mice with agents such as losartan correlates with a reduction in TGF-β signaling in aortic SMCs (17). More recently, it was shown that loss-of-function mutations in the gene encoding the prototypical TGF-β repressor SKI, a perturbation predicted and observed to increase TGF-β signaling, cause aortic root aneurysm p-myosin phosphatase target subunit-1 (p-MYPT1), p-AKT (Thr308), p-S6K, S6K, p-S6, S6 (all from Cell Signaling), ERK1/2 (Santa Cruz Biotechnology Inc.), SMA, SM22, SMMHC (all from Abcam), and β-actin (Sigma-Aldrich), followed by horseradish peroxidase-conjugated secondary antibodies (Jackson ImmunoResearch).…”

Section: Methodsmentioning

confidence: 99%

“…In humans, Loeys-Dietz syndrome, which is caused by heterozygous mutations in TGFBR1 or TGFBR2, often presents in young adults with complications of aortic dissection or aneurysm rupture (8). Even though the mutant receptors cannot transduce TGF-β-mediated signals (9,10), tissues obtained at surgery paradoxically suggest enhanced TGF-β signaling in vivo (8,11). Excessive TGF-β activity is also observed in the media of aortic aneurysms from patients with Marfan syndrome caused by mutations of FBN1 (encoding fibrillin-1) as well as in patients with a phenotype similar to that seen in Loeys-Dietz and Marfan disorders, which is caused by mutations in TGFB2 or SMAD3 (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

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Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

et al. 2014

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TGF-β is essential for vascular development; however, excess TGF-β signaling promotes thoracic aortic aneurysm and dissection in multiple disorders, including Marfan syndrome. Since the pathology of TGF-β overactivity manifests primarily within the arterial media, it is widely assumed that suppression of TGF-β signaling in vascular smooth muscle cells will ameliorate aortic disease. We tested this hypothesis by conditional inactivation of Tgfbr2, which encodes the TGF-β type II receptor, in smooth muscle cells of postweanling mice. Surprisingly, the thoracic aorta rapidly thickened, dilated, and dissected in these animals. Tgfbr2 disruption predictably decreased canonical Smad signaling, but unexpectedly increased MAPK signaling. Type II receptor-independent effects of TGF-β and pathological responses by nonrecombined smooth muscle cells were excluded by serologic neutralization. Aortic disease was caused by a perturbed contractile apparatus in medial cells and growth factor production by adventitial cells, both of which resulted in maladaptive paracrine interactions between the vessel wall compartments. Treatment with rapamycin restored a quiescent smooth muscle phenotype and prevented dissection. Tgfbr2 disruption in smooth muscle cells also accelerated aneurysm growth in a murine model of Marfan syndrome. Our data indicate that basal TGF-β signaling in smooth muscle promotes postnatal aortic wall homeostasis and impedes disease progression.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

et al. 2014

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“…32 Although there has been controversy with respect to the inactivating nature of mutations in TGF-b pathway components, aortic tissues from individuals with syndromic aortic aneurysms including MFS consistently display an increase in canonical TGF-b signaling. [39][40][41][42][43] To explore the relationship between ADPKD and MFS, we bred mice with targeted alleles of Pkd1 and Fbn1 and found that loss of one Pkd1 allele worsened the aortic phenotype of Fbn1 mutant mice. Moreover, this genetic interaction was associated with further upregulation of canonical TGF-b signaling.…”

Section: Discussionmentioning

confidence: 99%

A Pkd1-Fbn1 Genetic Interaction Implicates TGF-β Signaling in the Pathogenesis of Vascular Complications in Autosomal Dominant Polycystic Kidney Disease

Chen

Wang

Judge

et al. 2014

Journal of the American Society of Nephrology

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Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure that is due to mutations in two genes, PKD1 and PKD2. Vascular complications, including aneurysms, are a well recognized feature of ADPKD, and a subgroup of families exhibits traits reminiscent of Marfan syndrome (MFS). MFS is caused by mutations in fibrillin-1 (FBN1), which encodes an extracellular matrix protein with homology to latent TGF-b binding proteins. It was recently demonstrated that fibrillin-1 deficiency is associated with upregulation of TGF-b signaling. We investigated the overlap between ADPKD and MFS by breeding mice with targeted mutations in Pkd1 and Fbn1. Double heterozygotes displayed an exacerbation of the typical Fbn1 heterozygous aortic phenotype. We show that the basis of this genetic interaction results from further upregulation of TGF-b signaling caused by Pkd1 haploinsufficiency. In addition, we demonstrate that loss of PKD1 alone is sufficient to induce a heightened responsiveness to TGF-b. Our data link the interaction of two important diseases to a fundamental signaling pathway.

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“…1, 8 Indeed, several lines of evidence indicate augmented TGF-b signalling in aortic lesions in vivo. 6,9,10 This is intriguing as many pathogenic mutations associated with TAAD have a loss-of-function effect. 2,11,12 Recently, two studies have shown that haploinsufficiency for TGFB2 causes a familial syndrome of TAAD with additional clinical manifestations overlapping MFS and LDS.…”

Section: Introductionmentioning

confidence: 99%

A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm

et al. 2013

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A number of autosomal dominantly inherited disorders, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), are associated with predisposition to thoracic aortic aneurysms and dissections (TAADs). In the majority of cases, mutations in genes encoding components of the transforming growth factor-b (TGF-b) signaling pathway, such as FBN1, TGFBR1, TGFBR2 and SMAD3, underlie the disease. Recently, a familial syndromic form of TAAD with other clinical features that overlap the MFS-LDS spectrum has been described to be caused by heterozygous loss-of-function mutations in TGFB2, encoding the TGF-b2 ligand of TGF-b serine/threonine kinase receptors (TGFBRs). We analyzed the TGFB2 gene by sequencing in a cohort of 88 individuals with a Marfan-like phenotype and/or TAAD, who did not have mutations in known genes causing thoracic aortic disease. We identified the novel heterozygous c.1165dupA mutation in exon 7 of TGFB2 in three members of a family, a 51-year-old male, his brother and nephew with aortic aneurysms, cervical arterial tortuosity and/or skeletal abnormalities as well as craniofacial dysmorphisms. The 1-bp duplication causes a frameshift leading to a stable transcript with a premature stop codon after seven TGF-b2-unrelated amino acids (p.Ser389Lysfs*8). As the resulting protein is unlikely functional and by considering data from the literature, we support the notion that functional haploinsufficiency for TGF-b2 predisposes to thoracic aortic disease. Taken together, TGFB2 is a rarely mutated gene in patients with syndromic TAAD, and the clinical features of our TGFB2 mutation-positive individuals fit in the scheme of LDS, rather than MFS-related disorders.

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TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections

Cited by 114 publications

References 36 publications

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis

A Pkd1-Fbn1 Genetic Interaction Implicates TGF-β Signaling in the Pathogenesis of Vascular Complications in Autosomal Dominant Polycystic Kidney Disease

A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm

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