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.

Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

“…Although it is well known that the disruption of the collagen III triple helical structure leads to abnormal protein folding, different biological aspects of the vEDS pathogenesis are not yet fully studied. In line with cEDS and hEDS transcriptome profiling, vEDS fibroblasts show the differential expression of several genes encoding structural constituents of the ECM, further supporting the notion that abnormal ECM remodeling is a common denominator of these conditions [50,97].…”

“…The alteration of the ER redox state may also trigger pro-death signals through the regulation of members of the Bcl-2 family and activation of caspase-dependent apoptosis [106,107]. Consistently, we previously demonstrated that vEDS fibroblasts are in a pre-apoptotic state, due to downregulation of the Bcl-2 anti-apoptotic protein and increased levels of caspase enzymes, and activate a cell survival mechanism through an αvβ3-EGFR crosstalk [45,50]. However, in vEDS cells an enhanced expression of unfolded protein response-related genes was not identified, consistent with the recent findings on cultured dermal fibroblasts from Col3a1 transgenic mice that did not show elevated levels of the unfolded protein response markers Bip and Chop [102].…”

“…Moreover, depletion of autophagy regulators is associated with induction of pro-apoptotic signals, decrease of collagen degradation via lysosome pathway, and regulation of cell adhesion [90,91]. In line with these observations, the aberrant expression of collagen V and defective remodeling of ECM in cEDS cells might affect ER homeostasis and autophagy, and consequently activate a pro-survival mechanism mediated by a crosstalk between αvβ3 integrin and EGF receptor [45,50]. Additional studies are needed to better elucidate the contribution of these processes in the molecular pathology of cEDS.…”

“…Our in vitro findings demonstrated that cEDS patients’ fibroblasts show disassembly of many ECM components, including collagen V and III, fibronectin, and fibrillins, and disorganization of collagen- and fibronectin-specific α2β1 and α5β1 integrin receptors [44,45,46,47]. cEDS cells also exhibit a reduced in vitro migration capability, an abnormal wound healing response, and a crosstalk involving the αvβ3 integrin and epidermal growth factor (EGF) receptor that rescues them from anoikis [44,45,46,47,48,49,50]. In line with these in vitro findings, Col5a1 and Col5a2 deficient mice show a defective wound healing response and reduced cell migration [51,52].…”

“…Although hEDS/HSD etiology remains elusive, patients’ skin fibroblasts show a disorganization of the ECM like that observed in cells derived from the other EDS types. In particular, hEDS/HSD, cEDS, and vEDS fibroblasts exhibit a marked disorganization of collagen and fibronectin ECM and their specific α2β1 and α5β1 integrin receptors and showed the preferential expression of the αvβ3 integrin [44,49,50,123].…”