Article

MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II

Texas A&M University - Galveston, Galveston, Texas, United States
Human Molecular Genetics (Impact Factor: 6.68). 11/2007; 16(20):2453-62. DOI: 10.1093/hmg/ddm201
Source: PubMed

ABSTRACT Non-syndromic thoracic aortic aneurysms and dissections (TAADs) are inherited in an autosomal dominant manner in approximately 20% of cases. Familial TAAD is genetically heterogeneous and four loci have been mapped for this disease to date, including a locus at 16p for TAAD associated with patent ductus arteriosus (PDA). The defective gene at the 16p locus has recently been identified as the smooth muscle cell (SMC)-specific myosin heavy chain gene (MYH11). On sequencing MYH11 in 93 families with TAAD alone and three families with TAAD/PDA, we identified novel mutations in two families with TAAD/PDA, but none in families with TAAD alone. Histopathological analysis of aortic sections from two individuals with MYH11 mutations revealed SMC disarray and focal hyperplasia of SMCs in the aortic media. SMC hyperplasia leading to significant lumen narrowing in some of the vessels of the adventitia was also observed. Insulin-like growth factor-1 (IGF-1) was upregulated in mutant aortas as well as explanted SMCs, but no increase in transforming growth factor-beta expression or downstream targets was observed. Enhanced expression of angiotensin-converting enzyme and markers of Angiotensin II (Ang II) vascular inflammation (macrophage inflammatory protein-1alpha and beta) were also found. These data suggest that MYH11 mutations are likely to be specific to the phenotype of TAAD/PDA and result in a distinct aortic and occlusive vascular pathology potentially driven by IGF-1 and Ang II.

0 Followers
 · 
101 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiotensin type 1 (AT1) receptors are key effector elements of the renin-angiotensin system, mediating virtually all of the classical physiological actions of angiotensin II. Pharmacological blockade of the AT1 receptor effectively lowers blood pressure in a substantial proportion of patients with hypertension, indicating the pivotal role of these receptors in human hypertension. AT1 receptors are expressed in many different organ systems where they have myriad cellular actions. However, several lines of evidence have suggested that direct actions of AT1 receptors in kidney have a major role in regulation of blood pressure and in the pathogenesis of hypertension. Here we review recent studies suggesting that renal epithelium and vasculature may be key cellular targets, where AT1 receptor activation has powerful physiological impact. We will also examine novel regulatory mechanisms by peptides associated with the C-terminus of the AT1 receptor. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Current Opinion in Pharmacology 02/2015; 21C:122-126. DOI:10.1016/j.coph.2015.01.006 · 4.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acquisition and maintenance of vascular smooth muscle fate are essential for the morphogenesis and function of the circulatory system. Loss of contractile properties or changes in the identity of vascular smooth muscle cells (vSMCs) can result in structural alterations associated with aneurysms and vascular wall calcification. Here we report that maturation of sclerotome-derived vSMCs depends on a transcriptional switch between mouse embryonic days 13 and 14.5. At this time, Notch/Jag1-mediated repression of sclerotome transcription factors Pax1, Scx, and Sox9 is necessary to fully enable vSMC maturation. Specifically, Notch signaling in vSMCs antagonizes sclerotome and cartilage transcription factors and promotes upregulation of contractile genes. In the absence of the Notch ligand Jag1, vSMCs acquire a chondrocytic transcriptional repertoire that can lead to ossification. Importantly, our findings suggest that sustained Notch signaling is essential throughout vSMC life to maintain contractile function, prevent vSMC reprogramming, and promote vascular wall integrity. Copyright © 2014 Elsevier Inc. All rights reserved.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Heritable Thoracic Aortic Disorders (H-TAD) may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. About one dozen genes are now available for clinical molecular testing. Targeted single gene testing is hampered by significant clinical overlap between syndromic H-TAD entities and the absence of discriminating features in isolated cases. Therefore panel testing of multiple genes has now emerged as the preferred approach. So far, no data on mutation detection rate with this technique have been reported.Methods We performed Next Generation Sequencing (NGS) based screening of the seven currently most prevalent H-TAD-associated genes (FBN1, TGFBR1/2, TGFB2, SMAD3, ACTA2 and COL3A1) on 264 samples from unrelated probands referred for H-TAD and related entities. Patients fulfilling the criteria for Marfan syndrome (MFS) were only included if targeted FBN1 sequencing and MLPA analysis were negative.ResultsA mutation was identified in 34 patients (13%): 12 FBN1, one TGFBR1, two TGFBR2, three TGFB2, nine SMAD3, four ACTA2 and three COL3A1 mutations. We found mutations in FBN1 (N¿=¿3), TGFBR2 (N¿=¿1) and COL3A1 (N¿=¿2) in patients without characteristic clinical features of syndromal H-TAD. Six TAD patients harboring a mutation in SMAD3 and one TAD patient with a TGFB2 mutation fulfilled the diagnostic criteria for MFS.ConclusionNGS based H-TAD panel testing efficiently reveals a mutation in 13% of patients. Our observations emphasize the clinical overlap between patients harboring mutations in syndromic and nonsyndromic H-TAD related genes as well as within syndromic H-TAD entities, justifying a widespread application of this technique.
    Orphanet Journal of Rare Diseases 02/2015; 10(1):9. DOI:10.1186/s13023-014-0221-6 · 3.96 Impact Factor

Full-text (2 Sources)

Download
48 Downloads
Available from
May 16, 2014