Multifaced Roles of the αvβ3 Integrin in Ehlers-Danlos and Arterial Tortuosity Syndromes' Dermal Fibroblasts

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.

Keywords: Ehlers–Danlos syndromes; apoptosis; arterial tortuosity syndrome; extracellular matrix; fibroblast-to-myofibroblast transition; fibronectin; αvβ3 integrin.

Figure 1

Organization of FN–ECM and expression of the α5β1 and αvβ3 integrin receptors in control and HCTDs dermal fibroblasts. Among the analyzed HCTDs (Table 7), all EDS fibroblasts, except for spEDS-B3GALT6, and ATS cells show the FN–ECM disarray, the reduced expression of the canonical FN integrin receptor α5β1 and the consequent recruitment of the αvβ3 integrin. This peculiar phenotype is not observed in cells derived from MFS, LDS, and OI patients. Dermal fibroblasts were immunoreacted with antibodies against FN, α5β1, and αvβ3 integrins as previously described [102,106,107]. Scale bar: 10 μm.

Figure 2

Schematic representation of the αvβ3 integrin- and EGFR-mediated signaling pathways ensuring the rescue from anoikis in cEDS and vEDS fibroblasts.

Figure 3

Schematic representation of the αvβ3 integrin-ILK-Snail1 transduction pathway involved in the myofibroblast-like phenotype of hEDS and HSD cells.