Guo Dong-Chuan, Pannu Hariyadarshi, Tran-Fadulu Van, Papke Christina L, Yu Robert K, Avidan Nili, Bourgeois Scott, Estrera Anthony L, Safi Hazim J, Sparks Elizabeth, Amor David, Ades Lesley, McConnell Vivienne, Willoughby Colin E, Abuelo Dianne, Willing Marcia, Lewis Richard A, Kim Dong H, Scherer Steve, Tung Poyee P, Ahn Chul, Buja L Maximilian, Raman C S, Shete Sanjay S, Milewicz Dianna M
Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Nat Genet. 2007 Dec;39(12):1488-93. doi: 10.1038/ng.2007.6. Epub 2007 Nov 11.
The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.
血管平滑肌细胞（SMC）的主要功能是收缩，以调节血压和血流。SMC收缩力需要SMCα-肌动蛋白（由ACTA2编码）和β-肌球蛋白重链（由MYH11编码）之间的循环相互作用。在这里，我们表明ACTA2中的错义突变导致14%的遗传性升主动脉瘤和夹层（TAAD）。对来自ACTA2突变杂合个体的SMC中肌动蛋白丝的结构分析和免疫荧光表明，这些突变干扰肌动蛋白丝组装，并预计会降低SMC收缩。来自受影响个体的主动脉组织显示主动脉中层变性、中层SMC局灶性增生和紊乱，以及由于中层SMC增殖导致的滋养血管狭窄动脉。这些数据，连同先前报道的导致家族性TAAD的MYH11突变，表明SMC收缩在维持升主动脉结构完整性方面的重要性。
