Deficient Circumferential Growth Is the Primary Determinant of Aortic Obstruction Attributable to Partial Elastin Deficiency
Deficient Circumferential Growth Is the Primary Determinant of Aortic Obstruction Attributable to Partial Elastin Deficiency
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DOI：
10.1161/atvbaha.117.309079
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发表时间：
2017-05-01
影响因子：
8.7
通讯作者：
Tellides, George
中科院分区：
文献类型：
--
作者：
Jiao, Yang;Li, Guangxin;Tellides, George
Objective-Williams 综合征的特征是由于 ELN（编码弹性蛋白的基因）杂合性缺失而导致的阻塞性主动脉病。病变被认为主要是由于平滑肌细胞（SMC）过度增殖和随之而来的内侧扩张造成的，尽管主动脉最初的较小口径和硬度增加可能导致管腔狭窄。这种异常对阻塞表型的相对贡献尚未确定。方法和结果——我们量化了人类 ELN 不完全抢救的 Eln(-/-) 小鼠胸主动脉管腔狭窄的决定因素。中度阻塞主要是由于周向生长不足，尤其是升段，尽管轴向生长增加。在这些较小直径的弹性蛋白缺乏的主动脉中，内侧增厚是明显的，其内侧面积与较大直径的对照主动脉相似。在出生后发育的多个阶段，突变型和野生型基因型之间的横截面 SMC 数量没有差异。弹性蛋白含量减少与内侧纤维化和主动脉扩张性降低有关，因为结构刚度增加但材料刚度保留。缺乏弹性蛋白的 SMC 在体外表现出比体内更强的收缩至增殖表型调节。我们证实，威廉姆斯综合征受试者的升主动脉中层增厚，内侧胶原蛋白增加，但没有证据表明内侧面积或 SMC 数量增加。结论：周向生长不足是部分弹性蛋白缺乏导致的中度阻塞性主动脉疾病的主要机制。我们的研究结果表明，Williams 综合征的不同主动脉表现是由弹性蛋白含量分级引起的，SMC 增生导致内侧扩张，需要额外的弹性蛋白损失叠加在 ELN 单倍体不足上。
Objective-Williams syndrome is characterized by obstructive aortopathy attributable to heterozygous loss of ELN, the gene encoding elastin. Lesions are thought to result primarily from excessive smooth muscle cell (SMC) proliferation and consequent medial expansion, although an initially smaller caliber and increased stiffness of the aorta may contribute to luminal narrowing. The relative contributions of such abnormalities to the obstructive phenotype had not been defined.Approach and Results-We quantified determinants of luminal stenosis in thoracic aortas of Eln(-/-) mice incompletely rescued by human ELN. Moderate obstruction was largely because of deficient circumferential growth, most prominently of ascending segments, despite increased axial growth. Medial thickening was evident in these smaller diameter elastin-deficient aortas, with medial area similar to that of larger diameter control aortas. There was no difference in cross-sectional SMC number between mutant and wild-type genotypes at multiple stages of postnatal development. Decreased elastin content was associated with medial fibrosis and reduced aortic distensibility because of increased structural stiffness but preserved material stiffness. Elastin-deficient SMCs exhibited greater contractile-to-proliferative phenotypic modulation in vitro than in vivo. We confirmed increased medial collagen without evidence of increased medial area or SMC number in a small ascending aorta with thickened media of a Williams syndrome subject.Conclusions-Deficient circumferential growth is the predominant mechanism for moderate obstructive aortic disease resulting from partial elastin deficiency. Our findings suggest that diverse aortic manifestations in Williams syndrome result from graded elastin content, and SMC hyperplasia causing medial expansion requires additional elastin loss superimposed on ELN haploinsufficiency.