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Abstract：
The αvβ3 integrin, an endothelial cells\' receptor-binding fibronectin (FN) in the extracellular matrix (ECM) of blood vessels, regulates ECM remodeling during migration, invasion, angiogenesis, wound healing and inflammation, and is also involved in the epithelial mesenchymal transition. In vitro-grown human control fibroblasts organize a fibrillar network of FN, which is preferentially bound on the entire cell surface to its canonical α5β1 integrin receptor, whereas the αvβ3 integrin is present only in rare patches in focal contacts. We report on the preferential recruitment of the αvβ3 integrin, due to the lack of FN-ECM and its canonical integrin receptor, in dermal fibroblasts from Ehlers-Danlos syndromes (EDS) and arterial tortuosity syndrome (ATS), which are rare multisystem connective tissue disorders. We review our previous findings that unraveled different biological mechanisms elicited by the αvβ3 integrin in fibroblasts derived from patients affected with classical (cEDS), vascular (vEDS), hypermobile EDS (hEDS), hypermobility spectrum disorders (HSD), and ATS. In cEDS and vEDS, respectively, due to defective type V and type III collagens, αvβ3 rescues patients\' fibroblasts from anoikis through a paxillin-p60Src-mediated cross-talk with the EGF receptor. In hEDS and HSD, without a defined molecular basis, the αvβ3 integrin transduces to the ILK-Snail1-axis inducing a fibroblast-to-myofibroblast-transition. In ATS cells, the deficiency of the dehydroascorbic acid transporter GLUT10 leads to redox imbalance, ECM disarray together with the activation of a non-canonical αvβ3 integrin-TGFBRII signaling, involving p125FAK/p60Src/p38MAPK. The characterization of these different biological functions triggered by αvβ3 provides insights into the multifaced nature of this integrin, at least in cultured dermal fibroblasts, offering future perspectives for research in this field.
摘要：
αvβ3整合素，血管细胞外基质（ECM）中的内皮细胞受体结合纤连蛋白（FN），调节迁移过程中的ECM重塑，入侵,血管生成,伤口愈合和炎症，并参与上皮间质转化。体外生长的人对照成纤维细胞组织了FN的纤维状网络，它优先结合在整个细胞表面上其典型的α5β1整合素受体，而αvβ3整合素仅存在于局灶性接触中的稀有斑块中。我们报道了αvβ3整合素的优先募集，由于缺乏FN-ECM及其典型的整合素受体，在Ehlers-Danlos综合征（EDS）和动脉弯曲综合征（ATS）的真皮成纤维细胞中，这是罕见的多系统结缔组织疾病。我们回顾了我们先前的发现，即揭示了由αvβ3整合素在受经典（cEDS）影响的患者成纤维细胞中引起的不同生物学机制，血管（vEDS），超移动EDS（HEDS），高迁移率频谱障碍（HSD），还有ATS.在cEDS和vEDS中，分别,由于V型和III型胶原蛋白有缺陷，αvβ3通过paxillin-p60Src介导的与EGF受体的交叉作用从失巢凋亡中拯救患者成纤维细胞。在hEDS和HSD中，没有定义的分子基础，αvβ3整联蛋白转导至ILK-Snail1轴,诱导成纤维细胞至肌成纤维细胞的转变。在ATS细胞中，脱氢抗坏血酸转运蛋白GLUT10的缺乏导致氧化还原失衡，ECM混乱以及非规范αvβ3整合素-TGFBRII信号的激活，涉及p125FAK/p60Src/p38MAPK.由αvβ3触发的这些不同生物学功能的表征提供了对这种整合素的多面性的见解，至少在培养的真皮成纤维细胞中，为这一领域的研究提供了未来的前景。
