MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II.
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.
Department of Internal Medicine and Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Hariyadarshi
H
Pannu
Van
V
Tran-Fadulu
Christina L
CL
Papke
Steve
S
Scherer
Yaozhong
Y
Liu
Caroline
C
Presley
Dongchuan
D
Guo
Anthony L
AL
Estrera
Hazim J
HJ
Safi
Allan R
AR
Brasier
G Wesley
GW
Vick
A J
AJ
Marian
C S
CS
Raman
L Maximilian
LM
Buja
Dianna M
DM
Milewicz
D000328:Adult; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000502:physiology*; D017545:Aortic Aneurysm, Thoracic / Q000150:complications / Q000235:genetics / Q000473:pathology; D002675:Child, Preschool; D004374:Ductus Arteriosus, Patent / Q000150:complications / Q000235:genetics / Q000473:pathology; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D014652:Vascular Diseases / Q000235:genetics* / Q000473:pathology
C509903:MYH11 protein, human; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I; D018995:Myosin Heavy Chains