Fhayli Wassim, Ghandour Zeinab, Mariko Boubacar, Pezet Mylène, Faury Gilles
Laboratoire Hypoxie: Physiopathologie Cardiovasculaire et Respiratoire (HP2), INSERM U 1042, Université Joseph Fourier, Bâtiment Jean Roget, Facultés de Médecine et de Pharmacie, Domaine de La Merci, 38706 La Tronche, France.
Biol Aujourdhui. 2012;206(2):87-102. doi: 10.1051/jbio/2012009. Epub 2012 Jul 4.
Large arteries allow the vascular system to be more than a simple route in which the blood circulates within the organism. The elastic fibers present in the wall endow these vessels with elasticity and are responsible for the smoothing of the blood pressure and flow, which are delivered discontinuously by the heart. This function is very important to ensure appropriate hemodynamics. Elastic fibers are composed of elastin (90%) and fibrillin-rich microfibrils (10%) which provide the vessels with elasticity and are also signals able to bind to relatively specific cell membrane receptors. Stimulation of the high affinity elastin receptor by elastin peptides or tropoelastin--the elastin precursor--triggers an increase in intracellular free calcium in vascular cells, especially endothelial cells, associated with attachment, migration or proliferation. Similar effects of the stimulation of endothelial cells by microfibrils or fibrillin-1 fragments, which bind to integrins, have been demonstrated. This dual function--mechanical and in signaling--makes the elastic fibers an important actor of the development and ageing processes taking place in blood vessels. An alteration of the elastin (Eln) or fibrillin (Fbn) gene products leads to severe genetic pathologies of the cardiovascular system, such as supravalvular aortic stenosis, or Williams Beuren syndrome--in which elastin deficiency induces aortic stenoses--or Marfan syndrome, in which on the contrary fibrillin-1 deficiency promotes the appearance of aortic aneurysms. Genetically-engineered mouse models of these pathologies (such as Eln+/- mice and Fbn-1+/mgΔ mice, Eln+/-Fbn-1+/- mice) have permitted a better understanding of the pathogenesis of these syndromes. In particular, it has been shown that elastin and fibrillin-1 roles can be complementary in some aspects, while they can be opposed in some other situations. For instance, the double heterozygosity in elastin and fibrillin-1 leads to increased arterial wall stress--compared to the level induced by one of these two deficiencies alone--while the decrease in diameter induced by Eln deficiency is partly compensated by an additional deficiency in Fbn-1. Also, it is now clear that early modifications of elastin or fibrillin-1 availability can alter the normal signaling action of these proteins and lead to long term modifications of the vascular physiology and ageing processes.
大动脉使得血管系统不仅仅是血液在生物体内循环的简单通道。血管壁中存在的弹性纤维赋予这些血管弹性，并负责使心脏间断输送的血压和血流变得平滑。此功能对于确保适当的血液动力学非常重要。弹性纤维由弹性蛋白（90%）和富含原纤维蛋白的微原纤维（10%）组成，它们赋予血管弹性，也是能够与相对特异性细胞膜受体结合的信号分子。弹性蛋白肽或原弹性蛋白（弹性蛋白前体）刺激高亲和力弹性蛋白受体，会引发血管细胞尤其是内皮细胞内游离钙增加，这与细胞黏附、迁移或增殖相关。已证实微原纤维或原纤维蛋白-1片段（它们与整合素结合）刺激内皮细胞也有类似作用。这种机械和信号双重功能使弹性纤维成为血管发育和衰老过程中的重要因素。弹性蛋白（Eln）或原纤维蛋白（Fbn）基因产物的改变会导致心血管系统的严重遗传性疾病，如主动脉瓣上狭窄或威廉姆斯-贝伦综合征（其中弹性蛋白缺乏会诱发主动脉狭窄），或马凡综合征（相反，原纤维蛋白-1缺乏会促使主动脉瘤出现）。这些疾病的基因工程小鼠模型（如Eln+/-小鼠和Fbn-1+/mgΔ小鼠、Eln+/-Fbn-1+/-小鼠）有助于更好地理解这些综合征的发病机制。特别是，已表明弹性蛋白和原纤维蛋白-1的作用在某些方面可能互补，而在其他一些情况下可能相反。例如，弹性蛋白和原纤维蛋白-1的双杂合性会导致动脉壁应力增加（与单独一种缺陷所诱导的水平相比），而Eln缺陷导致的直径减小部分会被Fbn-1的额外缺陷所补偿。此外，现在很清楚，弹性蛋白或原纤维蛋白-1可用性的早期改变会改变这些蛋白质的正常信号作用，并导致血管生理和衰老过程的长期改变。
