Decreased Production of Collagen Type III in Cultured Smooth Muscle Cells from Varicose Vein Patients Is due to a Degradation by MMPs: Possible Implication of MMP-3

Abstract

An alteration of extracellular matrix is involved in varicose veins. We have previously shown that collagen III production, but not its mRNA expression, is decreased in cultured smooth muscle cells (SMC) from varicose veins, involving an over-production of collagen I. In this study, the mechanisms involved in this collagen III reduction are explored. Steady state levels of collagen III mRNA and its ability to translate a protein were evaluated. Neither stability nor functionality of the α1(III) coding mRNA were affected in cells from varicose veins. Potential intracellular degradations of collagen III were investigated with inhibitors of intracellular proteases but the production was unaffected. The level of N-terminal propeptides of collagen III in the extracellular medium was determined and was similar in SMC from control and varicose veins. The stability of collagen III was determined by time-course experiments and a degradation of the protein was observed in cells from varicose veins. The production of collagen III was partially restored in cells from varicose veins in the presence of Marimastat, a matrix metalloproteinase (MMP) inhibitor. The mRNA expression and protein production of MMP3 were increased in cells from varicose veins. Fibronectin, a potential substrate of MMP3, was decreased in SMC from varicose veins. In conclusion, collagen III, and probably fibronectin, are degraded extracellularly in SMC from varicose veins by a mechanism involving MMPs, and maybe MMP3 by a direct or an indirect pathway. The degradation of collagen III and fibronectin may have repercussions for the mechanical properties of the venous wall.

Identification of Differentially Expressed Genes in Human Varicose Veins: Involvement of Matrix Gla Protein in Extracellular Matrix Remodeling

“…These observations are in agreement with previous studies showing significant decrease in collagen III protein, whereas collagen III mRNA was not altered in cultured SMC and dermal fibroblasts derived from patients with varicose veins [14]. This decrease in collagen III content has been recently ascribed to an MMP3-dependent degradation in cultured varicose SMC [40]. The implication of TIMP/MMP balance in ECM degradation has been previously investigated in varicose vein [16].…”

Selective loss of extracellular matrix proteins is linked to biophysical properties of varicose veins assessed by ultrasonography

“…A selective decrease in type III collagen compared with type I collagen has been observed in varicose veins 21 , which was attributed to diminished synthesis of type III collagen by venous smooth muscle cells 22 . Type III collagen synthesis was not inhibited at the transcriptional but at a post-translational level 23 .…”

Pulmonary Vascular Destabilization in the Premetastatic Phase Facilitates Lung Metastasis

“…Basement membrane in the tunica of mature blood vessels consists of fibronectin and collagens, which facilitate maintenance of vascular integrity, and is the potential substrate for MMP3 and MMP10 (30,32,33). In concert with Angpt2, MMP3 and MMP10 would be expected to further exacerbate the abnormalities in vascular integrity.…”