Background: Integrins play an important role for vascular smooth muscle cell (VSMC) migration during the development of atherosclerosis and restenosis. Integrin alpha(v)-subunit consists of disulphide-bound 125-kDa heavy and 25-kDa light chains, which are generated by endoproteolytic cleavage. This type of activation requires the presence of suitable proprotein convertases (PCs). Based on ex vivo and in vitro data, the PC5 isozyme has been suggested to be the major integrin convertase. We have recently demonstrated that PC5 is upregulated during vascular remodeling in rodents, colocalizing with alpha(v) in VSMCs. The aim of this study was to investigate the activation of alpha(v) by PCs in VSMCs and its consequences for alpha(v)-dependent cell functions.
Methods And Results: Immunoblotting demonstrated that inhibition of PC activity by the specific pharmacological inhibitor dec-CMK inhibits alpha(v) cleavage in VSMCs. These results were confirmed using PC5-specific antisense oligonucleotides. PC5-antisense oligonucleotides and dec-CMK inhibited VSMC adhesion to the alpha(v)beta3/beta5 ligand vitronectin (both P<0.05). Furthermore, PC5-asODNs inhibited VSMC migration on vitronectin-coated wells (P<0.05). Inhibition of PC activity and consequently alpha(v) cleavage inhibited the adhesion-dependent focal adhesion kinase(Y397)-autophosphorylation and subsequent Akt activation, whereas phosphorylation of extracellular signal-regulated kinase 1/2 was not affected. In human endarterectomy lesions, PC5 colocalized with alpha(v) integrin in VSMCs in the atherosclerotic plaques.
Conclusions: The present study demonstrates that alpha(v) endoproteolytic activation is necessary for integrin-mediated adhesion and migration as well as signaling and requires PC5 in VSMCs. The colocalization of PC5 and alpha(v) in human carotid plaques indicates that PC5 might play a key role for alpha(v) activation in vivo.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1161/01.CIR.0000112583.50762.DE | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Irisin and Metastatic Melanoma: Selective Anti-Invasiveness Activity in BRAF Wild-Type Cells.
Int J Mol Sci
January 2025
Department of Translational Biomedicine and Neuroscience, University of Bari, 70124 Bari, Italy.
Irisin is a newly discovered 12 kDa messenger protein involved in energy metabolism. Irisin affects signaling pathways in several types of cancer; however, the role of irisin in metastatic melanoma (MM) has not been described yet. We explored the biological effects of irisin in in vitro models of MM cells (HBL, LND1, Hmel1 and M3) capable of the oncogenic activation of BRAF.
View Article and Find Full Text PDFMFGE8 induces anti-PD-1 therapy resistance by promoting extracellular vesicle sorting of PD-L1.
Cell Rep Med
January 2025
Department of Orthopaedics of the Second Affiliated Hospital and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address:
Anti-PD-1 therapy, effective in patients with various advanced tumors, still encounters the challenge of insensitivity in most patients. Here, we demonstrate that PD-L1 on tumor cell-derived extracellular vesicles (TEVs) is critical for anti-PD-1 therapy resistance. Reducing endogenous and transferring exogenous TEVs abrogates and induces anti-PD-1 therapy resistance, respectively.
View Article and Find Full Text PDFThe potential of autologous patient-derived circulating extracellular vesicles to improve drug delivery in rheumatoid arthritis.
Clin Exp Immunol
January 2025
Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat Gan, Israel.
Recognizing the need for innovative therapeutic approaches in the management of autoimmune diseases, our current investigation explores the potential of autologous extracellular vesicles (EVs), derived from the blood of rheumatoid arthritis patients, to serve as therapeutic vectors to improve drug delivery. We found that circulating EVs derived from arthritic mice (collagen-induced arthritis model) express the joint/synovia homing receptor, αVβ3 integrin. Importantly, both autologous labeled EVs, derived from the blood of arthritic mice (collagen antibody-induced arthritis model) and healthy mice-derived EVs, exhibit targeted migration toward inflamed synovia without infiltrating healthy joints, as demonstrated by an in vivo imaging system.
View Article and Find Full Text PDFSpecifically blocking αvβ8-mediated TGF-β signaling to reverse immunosuppression by modulating macrophage polarization.
J Exp Clin Cancer Res
January 2025
Mabwell (Shanghai) Bioscience Co., Ltd, Shanghai, 201210, China.
Background: Targeting the TGF-β pathway in tumor therapy has proven challenging due to the highly context-dependent functions of TGF-β. Integrin αvβ8, a pivotal activator of TGF-β, has been implicated in TGF-β signaling within tumors, as demonstrated by the significant anti-tumor effects of anti-αvβ8 antibodies. Nevertheless, the expression profile of αvβ8 remains a subject of debate, and the precise mechanisms underlying the anti-tumor effects of anti-αvβ8 antibodies are not yet fully elucidated.
View Article and Find Full Text PDFBiocompatibility Analysis of the Silver-Coated Microporous Titanium Implants Manufactured with 3D-Printing Technology.
Nanomaterials (Basel)
November 2024
Department of Orthopaedics and Rehabilitation Medicine, Tufts University School of Medicine, Boston, MA 02111, USA.
3D-printed microporous titanium scaffolds enjoy good biointegration with the residuum's soft and bone tissues, and they promote excellent biomechanical properties in attached prostheses. Implant-associated infection, however, remains a major clinical challenge. Silver-based implant coatings can potentially reduce bacterial growth and inhibit biofilm formation, thereby reducing the risk of periprosthetic infections.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!