title: The defining pathology of the new clinical and histopathologic entity ACTA2-related cerebrovascular disease.
abstract: BACKGROUND
  Smooth muscle cell contraction is an essential function of arteries and relies on the integrity of the actin-myosin apparatus. The tissue-specific α2-smooth muscle actin, encoded by ACTA2, is predominantly expressed in vascular smooth muscle cells. ACTA2 mutations predispose to development of aortic aneurysms and early onset coronary and cerebrovascular disease. Based on arteriographic findings, a distinct cerebrovascular disease has been proposed for ACTA2 heterozygous patients carrying the R179H mutation.
  
  
  RESULTS
  We present the first integrated analysis of a severely compromised patient with the R179H mutation and define the arterial pathology of ACTA2-related cerebrovascular disease. Histologically, striking morphological abnormalities were present in cerebral arteries of all sizes. Massive intimal smooth muscle cell proliferation, fragmentation of the elastic laminae and medial fibromuscular proliferation characterized large arteries whereas prominent vessel wall thickening, fibrosis and smooth muscle cell proliferation were unique changes in small arteries. The medial fibrosis and smooth muscle cell proliferation explain the characteristic radiologic appearance of "straight arteries" and suggest impaired function of mutant smooth muscle cells. Actin three-dimensional molecular modeling revealed critical positioning of R179 at the interface between the two strands of filamentous actin and destabilization of inter-strand bundling by the R179H mutation, explaining the severe associated phenotype.
  
  
  CONCLUSIONS
  In conclusion, these characteristic clinical and pathologic findings confirm ACTA2-related cerebrovascular disease as a new cerebrovascular disorder for which new therapeutic strategies need to be designed.
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA. mmgeorgescu@yahoo.com.
authors.forename: Maria-Magdalena
authors.initials: MM
authors.lastname: Georgescu
authors.affiliation: Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
authors.forename: Marco da Cunha
authors.initials: Mda C
authors.lastname: Pinho
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Richardson
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Torrealba
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
authors.forename: L Maximilian
authors.initials: LM
authors.lastname: Buja
authors.affiliation: Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA.
authors.forename: Jack M
authors.initials: JM
authors.lastname: Raisanen
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA. dennis.burns@utsouthwestern.edu.
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Burns
mesh_terms: D000199:Actins / Q000235:genetics*; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D002561:Cerebrovascular Disorders / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D021621:Imaging, Three-Dimensional; D018810:Magnetic Resonance Angiography; D008297:Male; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D011859:Radiography; D014055:Tomography, Emission-Computed
chemical_list: C541116:ACTA2 protein, human; D000199:Actins