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. 2007 Oct 15;16(20):2453-62.
doi: 10.1093/hmg/ddm201. Epub 2007 Jul 31.

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

Hariyadarshi Pannu  1 , Van Tran-Fadulu, Christina L Papke, Steve Scherer, Yaozhong Liu, Caroline Presley, Dongchuan Guo, Anthony L Estrera, Hazim J Safi, Allan R Brasier, G Wesley Vick, A J Marian, C S Raman, L Maximilian Buja, Dianna M Milewicz
Affiliations

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

Hariyadarshi Pannu et al. Hum Mol Genet. .

Erratum in

  • Hum Mol Genet. 2008 Jan 1;17(1):158

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.

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Conflict of interest statement

Conflict of Interest statement. None declared.

Figures

Figure 1
Figure 1
TAAD/PDA pedigrees with MYH11 mutations and clinical imaging. (A) Affected members of the TAA027 family carry two closely linked missense alterations, L1264P (3791T > C) and R1275L (3824G > T), in the coiled–coil domain, and those of the TAA069 family carry the missense alteration, R712Q (2153C > T), in the MYH11 ATPase head region. (B) MRA three-dimensional reconstruction with gadolinium contrast-enhanced angiogram of thoracic aorta of TAA027:III:2 obtained with a SENSE factor of 4. Arrows indicate location of the aneurysm involving the ascending aorta and sparing the sinuses of Valsalva. (C) Presence of greatly increased vasa vasorum noted at surgery.
Figure 2
Figure 2
Structural analysis of the MYH11 mutations identified in this study. (A) Three-dimensional structure of vertebrate smooth muscle myosin MD bound to Mg-ADP-AIF4− (PDB ID: 1BR2). SH1 and SH2 helices are shown in red and pink, respectively. The converter domain attached to the C-terminus of the SH1 helix is presented in green; the remainder of the structure is shown in gray. (B) A close-up view shows detail of the structural elements highlighted. Arg-712 (red) is located near the end of SH1 helix and its hydrogen-bonding interactions with the neighboring backbone carbonyl groups are shown using dashed lines. The values adjacent to these lines indicate H-bond distances (in Å). (C) Unwinding of the SH1 helix in the scallop myosin S1 structure complexed with Mg-ADP. Note that the converter domain occupies a completely different orientation when compared with the original structure depicted in the middle panel. In addition, the distance of separation between the two reactive thiol groups (C701 and C711, marked by blue asterisks) is reduced to ~7 from ~18 Å in the configuration shown in (B). (D) CLUSTALW alignment of MYH11 orthologs showing conservation of Arg-712 across species. This residue is evolutionally conserved among all species examined, and alteration of the equivalent residue in MYH9 causes hereditary deafness (DFNA17). (E) COILS output showing significantly decreased probability of coiled–coil formation when the L1264P mutation is introduced in the normal protein sequence.
Figure 3
Figure 3
Aortic pathology associated with MYH11 mutations. H&E staining of aortic media from (A) control, (B) Marfan patient and two MYH11 patients [(C) TAA069:II:1 and (D) TAA027:III:2] shows regions of SMC disarray and hyperplasia in the patients with MYH11 mutations. H&E staining of the vasa vasorum showed normal vessels in the control (E, arrow), whereas some vessels in the patient vasa vasorum exhibit fibromuscular dysplasia due to SMC hyperplasia in the vessels and others appear normal (F, arrows). α-actin staining of the vasa vasorum confirms that the fibromuscular dysplasia in patient TAA027:III:2 (H) is due to SMC hyperplasia and is absent in the control (G). Movat staining of aortic media from a control (I) and TAA027:III:2 (J) shows medial degeneration characterized by proteoglycan accumulation (stained blue), loss and fragmentation of elastic fibers (stained black), no collagen accumulation (stained yellow) and areas of SMC (stained red) loss in patient when compared with control aorta. von Willebrand factor staining of endothelial cells shows increased vasa vasorum penetrating deeper into the medial layer in TAA027:III:2 (L) compared with control (K). Scale bar = 100 µm.
Figure 4
Figure 4
Hyperplasia and increased cell proliferation in MYH11 mutant aneurysms. (A) The number of α-actin positive cells per field is significantly higher (P < 0.001) in the aortic aneurysm and the sinuses of Valsalva when compared with two control aortas. (B) PCNA staining shows increased proliferation in the aneurysm media. The percentage of proliferating (PCNA positive) cells in the medial layer from the aortic aneurysm is significantly higher (P < 0.001) than that observed in two control aortas or the sinuses of Valsalva from the aneurysm patient.
Figure 5
Figure 5
Increased IGF-1 expression is present in cells and tissues from patients with MYH11 mutations. (A) Quantitative real-time PCR analysis shows a significant increase in IGF-1 expression in SMCs from TAA:027:III:2, compared with two controls, with no significant change in the patient SMC expression of PDGF-B and TGF-β1. (B) Quantitative realtime PCR analysis of the RAS components renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and the type I angiotensin II receptor (AT1R) shows a significant increase in ACE in the patient SMCs. IGF-1 immunohistochemistry shows increased IGF-1 staining in the aortic media (D) as well as vessels of the vasa vasorum (F) of TAA027:III:2 when compared with control media (C) and vasa vasorum (E). Scale bar = 100 µm.
Figure 6
Figure 6
Increased MIP-1α and MIP-1β expression in MYH11 mutant aorta and SMCs. (A) Analysis of cytokines by organ culture analysis shows a significant increase in the secretion of chemokines MIP-1α and MIP-1β in the MYH11 patient aorta when compared with four control aortas. (B and C) Quantitative real-time PCR analysis shows a similar trend for increased MIP-1α and MIP-1β expression in aortic tissue as well as SMCs from the patient, compared with controls.
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