Histopathologic Findings in Ascending Aortas From Individuals With Loeys-Dietz Syndrome (LDS)

Maleszewski, Joseph J.; Miller, Dylan V.; Lu, Jie; Dietz, Harry C.; Halushka, Marc K.

doi:10.1097/pas.0b013e31817f3661

Cited by 110 publications

(97 citation statements)

References 22 publications

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“…Vascular specimens from Loeys-Dietz patients and nonsyndromic cases of patients with bicuspid aortic valve and aortic aneurysm demonstrate increased TGF-β signaling. Reduction of TGF-β signaling through the administration of neutralizing antibodies or chemical antagonists can attenuate the phenotypes (51,52,(54)(55)(56). Notch and TGF-β signaling have been shown to cooperate to promote vascular smooth muscle differentiation (57), although we were unable to detect increases in phospho-Smad2/3 in our Notch and neural crest mutants (data not shown).…”

Section: Discussionmentioning

confidence: 77%

Cardiac neural crest orchestrates remodeling and functional maturation of mouse semilunar valves

Jain¹,

Engleka²,

Rentschler³

et al. 2011

J. Clin. Invest.

155

142

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Congenital anomalies of the aortic valve are common and are associated with progressive valvular insufficiency and/or stenosis. In addition, aneurysm, coarctation, and dissection of the ascending aorta and aortic arch are often associated conditions that complicate patient management and increase morbidity and mortality. These associated aortopathies are commonly attributed to turbulent hemodynamic flow through the malformed valve leading to focal defects in the vessel wall. However, numerous surgical and pathological studies have identified widespread cystic medial necrosis and smooth muscle apoptosis throughout the aortic arch in affected patients. Here, we provide experimental evidence for an alternative model to explain the association of aortic vessel and valvular disease. Using mice with primary and secondary cardiac neural crest deficiencies, we have shown that neural crest contribution to the outflow endocardial cushions (the precursors of the semilunar valves) is required for late gestation valvular remodeling, mesenchymal apoptosis, and proper valve architecture. Neural crest was also shown to contribute to the smooth muscle layer of the wall of the ascending aorta and aortic arch. Hence, defects of cardiac neural crest can result in functionally abnormal semilunar valves and concomitant aortic arch artery abnormalities. IntroductionEarly stages of cardiac valve development have been extensively studied and include a well-recognized example of epithelial-mesenchymal transformation (EMT) in which endothelial cells underlying the primitive endocardial cushions respond to extracellular signals to invade the underlying matrix, change shape, and proliferate. This process of EMT results in relatively bulky and cellular endocardial cushions by mid-gestation. Subsequently, endocardial cushions remodel to form the thin valve leaflets that prevent reversal of blood flow in the mature heart. The signals and cellular events that mediate valve remodeling are poorly characterized, although apoptosis and alterations in extracellular matrix production have been described (1-5).Semilunar valve development is distinguished from atrioventricular valve development by the infiltration of migrating neural crest, which orchestrates important aspects of outflow tract septation and aortic arch artery remodeling (6, 7). A subpopulation of cardiac neural crest cells differentiate into vascular smooth muscle cells that populate the walls of the ascending aorta, aortic arch, and head vessels, and defects of neural crest cells in animal models produce coarctation and interruption of the aortic arch and a wide range of related outflow tract and aortic arch artery defects (7-9). Despite abundant contributions of neural crest to the mesenchyme of the outflow tract endocardial cushions during midgestation, few neural crest derivatives are present in the mature semilunar valve leaflets (10).Cardiac neural crest cells delaminate from the dorsal neural tube at approximately E8.5 in the mouse and migrate through the pharyngeal arches on th...

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Section: Discussionmentioning

confidence: 77%

Cardiac neural crest orchestrates remodeling and functional maturation of mouse semilunar valves

Jain¹,

Engleka²,

Rentschler³

et al. 2011

J. Clin. Invest.

155

142

View full text Add to dashboard Cite

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“…[18][19][20] It is not clear yet whether the initially impaired fetal elastogenesis and aberrant collagen deposition directly contribute to early aortic dissections in children with LDS. 11 However, the result of our study provides a novel insight into the pathomechanism of these features. We have demonstrated a significant reduction in the deposition of elastic fibers in cultured LDS fibroblasts with TGFbR1 gene mutations and faulty deposition of collagen fibers in the cultures of LDS fibroblasts with TGFb-R2 gene mutations.…”

Section: Discussionmentioning

confidence: 84%

“…[8][9][10] The molecular mechanism leading to aortic dissections in LDS has not been fully characterized, but elastic fiber fragmentation and abnormal collagen deposition was demonstrated in aortic explants from LDS patients. 11 In our study, gene expression analysis, biochemical assays, immunohistochemistry and electron microscopy (EM) were used to compare the production of four major elastic fiber components (elastin, fibrillin 1, fibulin 1 and fibulin 4) and the production of collagen type I in fibroblasts derived from 12 LDS patients with different mutations in both TGFb-R1 and TGFb-R2. We also explored whether dexamethasone, which directly interacts with the elastin gene promoter to induce transcription of tropoelastin mRNA, 12 would improve production of elastic fibers in the cultures of LDS dermal fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys–Dietz syndrome fibroblasts: a possible treatment?

et al. 2011

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Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by facial dysmorphism, cleft palate, dilation of the aortic arch, blood vessel tortuosity and a high risk of aortic dissection. It is caused by mutations in the transforming growth factor b-receptor 1 and 2 (TGFb-R1 and TGFb-R2) genes. Fibroblasts derived from 12 Loeys-Dietz syndrome patients, six with TGFB-R1 mutations and six with TGFB-R2 mutations, were analyzed using RT-PCR, biochemical assays, immunohistochemistry and electron microscopy for production of elastin, fibrillin 1, fibulin 1 and fibulin 4 and deposition of collagen type I. All LDS fibroblasts with TGFb-R1 mutations demonstrated decreased expression of elastin and fibulin 1 genes and impaired deposition of elastic fibers. In contrast, fibroblasts with TGFb-R2 mutations consistently demonstrated intracellular accumulation of collagen type I in the presence of otherwise normal elastic fiber production. Treatment of the cell cultures with dexamethasone induced remarkable upregulation in the expression of tropoelastin, fibulin 1-and fibulin 4-encoding mRNAs, leading to normalization of elastic fiber production in fibroblasts with TGFb-R1 mutations. Treatment with dexamethasone also corrected the abnormal secretion of collagen type I from fibroblasts with TGFb-R2 gene mutations. As the organogenesis-relevant elastic fiber production occurs exclusively in late fetal and early neonatal life, these findings may have implications for treatment in early life. Further studies are required to determine if dexamethasone treatment of fetuses prenatally diagnosed with LDS would prevent or alleviate the connective tissue and vascular defects seen in this syndrome.

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“…We stained aortic sections with Movat's stain and antisera to phosphorylated Smad2 or CTGF as previously described. 39,63 Statistical Analyses…”

Section: Clinical Specimensmentioning

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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Histopathologic Findings in Ascending Aortas From Individuals With Loeys-Dietz Syndrome (LDS)

Cited by 110 publications

References 22 publications

Cardiac neural crest orchestrates remodeling and functional maturation of mouse semilunar valves

Cardiac neural crest orchestrates remodeling and functional maturation of mouse semilunar valves

Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys–Dietz syndrome fibroblasts: a possible treatment?

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

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