Fibulin-4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression.
Fibulin-4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression.
复制标题
DOI：
10.1161/circresaha.109.207852
复制
发表时间：
2010-02-19
影响因子：
20.1
通讯作者：
Yanagisawa H
中科院分区：
文献类型：
--
作者：
Huang J;Davis EC;Chapman SL;Budatha M;Marmorstein LY;Word RA;Yanagisawa H
胚胎发育过程中纤维蛋白-4的丢失会导致动脉瘤破裂导致围产儿死亡，而弹性纤维组装缺陷被认为是导致动脉瘤表型的潜在原因。然而，在缺乏弹性蛋白或纤维蛋白-5的小鼠中从未见过动脉瘤，而纤维蛋白-5的缺乏也会导致弹性纤维受损。我们试图确定在没有纤维蛋白-4的情况下动脉瘤发生的机制，并确定纤维蛋白-4在主动脉发育中的作用。我们在小鼠中获得了生殖系和平滑肌细胞(SMC)特异性的纤毛蛋白-4基因缺失(分别为Fbln4GKO和Fbln4SMKO)。Fbln4GKO和Fbln4SMKO不能完全分化，表现为SM特异性收缩基因表达减少和SMC局灶性增殖，并伴有内侧壁退行性改变。在Fbln4GKO和Fbln4SMKO小鼠的瘤壁中观察到ERK1/2信号通路的显著上调，这两个突变体主要发生在升主动脉。在体外，Fbln4GKO SMC表现为未成熟的SMC表型，SM-肌球蛋白重链显著减少，增殖能力增强。Fbln4突变小鼠的血管表型与由SMC收缩基因突变引起的人类胸主动脉瘤的亚型非常相似。我们的研究提供了SMC的内在特性与体内动脉瘤进展之间的潜在联系，并支持Fiblin-4在主动脉壁SMC的末端分化和成熟以及弹性纤维的形成中的双重作用。
Loss of fibulin-4 during embryogenesis results in perinatal lethality due to aneurysm rupture, and defective elastic fiber assembly has been proposed as an underlying cause for the aneurysm phenotype. However, aneurysms are never seen in mice deficient for elastin, or for fibulin-5, which absence also leads to compromised elastic fibers. We sought to determine the mechanism of aneurysm development in the absence of fibulin-4 and establish the role of fibulin-4 in aortic development. We generated germline and smooth muscle cell (SMC)-specific deletion of the fibulin-4 gene in mice (Fbln4GKO and Fbln4SMKO, respectively). Fbln4GKO and Fbln4SMKO aortic walls fail to fully differentiate, exhibiting reduced expression of SM-specific contractile genes and focal proliferation of SMCs accompanied by degenerative changes of the medial wall. Marked upregulation of ERK1/2 signaling pathway was observed in the aneurysmal wall of Fbln4GKO and Fbln4SMKO mice and both mutants developed aneurysm predominantly in the ascending thoracic aorta. In vitro, Fbln4GKO SMCs exhibit an immature SMC phenotype with a marked reduction of SM-myosin heavy chain and increased proliferative capacity. The vascular phenotype in Fbln4 mutant mice is remarkably similar to a subset of human thoracic aortic aneurysms caused by mutations in SMC contractile genes. Our study provides a potential link between the intrinsic properties of SMCs and aneurysm progression in vivo and supports the dual role of fibulin-4 in the formation of elastic fibers as well as terminal differentiation and maturation of SMCs in the aortic wall.