Migration and Growth Are Attenuated in Vascular Smooth Muscle Cells With Type VIII Collagen-Null Alleles

Abstract

Objective-Type VIII collagen is upregulated after vascular injury and in atherosclerosis. However, the role of type VIII collagen endogenously expressed by smooth muscle cells (SMCs) and in the context of the vascular matrix microenvironment, which is rich in type I collagen, is not known. To address this, we have compared aortic SMCs from wild-type (WT) mice to SMCs from type VIII collagen-deficient (KO) mice when plated on type I collagen. Methods and Results-Type VIII collagen was upregulated after wounding of WT SMCs. KO SMCs exhibited greater adhesion to type I collagen than WT SMCs (optical density [OD 595 ]ϭ0.458Ϯ0.044 versus 0.193Ϯ0.071). By contrast, the WT SMCs spread more (389Ϯ75% versus 108Ϯ14% increase in cell area), migrated further (total distance 80.6Ϯ6.2 m versus 64.2Ϯ4.4 m), and exhibited increased [ 3 H]-thymidine uptake (160 000Ϯ22 300 versus 63 100Ϯ12 100 counts per minute) when compared with KO SMCs. Gelatin zymograms showed that WT SMCs expressed latent matrix metalloproteinase 2, whereas KO SMCs did not. Addition of exogenous type VIII collagen returned levels of KO SMC adhesion (OD 595 ϭ0.316Ϯ0.038), migration (79.5Ϯ5.8 m), and latent matrix metalloproteinase 2 expression to levels comparable to WT SMCs. Conclusions-This study suggests that SMCs can modify the matrix microenvironment by producing type VIII collagen, using it to overlay type I collagen, and generating a substrate favorable for migration. (Arterioscler Thromb Vasc Biol. 2006;26:56-61.)Key Words: atherosclerosis Ⅲ restenosis Ⅲ collagen Ⅲ smooth muscle cell migration Ⅲ MMP C ollagens compose a large portion of the extracellular matrix in the vessel wall and play important roles maintaining the strength and structural integrity of blood vessels. During atherosclerosis, collagen accumulation contributes to lesion growth and vessel contraction, and collagen degradation leads to plaque instability and rupture. 1 In addition to their roles providing structural support in the arterial wall, in vitro studies suggest that collagens can act as signaling molecules stimulating changes in the phenotype and behavior of smooth muscle cells (SMCs), endothelial cells, and macrophages. Recent research suggests that SMCs respond differently to different types or physical states of collagen. For example, intact type I collagen maintains SMC quiescence, whereas denatured or degraded collagen stimulates proliferation and migration. [2][3][4] Type VIII collagen is a member of the short chain collagen family, composed of ␣1 (VIII) and ␣2 (VIII) chains. It is produced by corneal and aortic endothelial cells, as well as mesangial cells, and is upregulated during the proliferation of these cells and during angiogenesis. [5][6][7][8] In normal arteries, it has been localized to the subendothelial intima and is present in very low amounts in the media and adventitia. 9 Type VIII collagen expression is dramatically increased after balloon injury of the rat carotid 10,11 or the porcine coronary artery. 12 In the rat balloon injury model, type VIII coll...

Mechanism of Gender-Specific Differences in Aortic Stiffness With Aging in Nonhuman Primates

“…That specific collagen type, which is upregulated in response to vascular injury, 37 has a role opposite to that of collagen type 1 in that it promotes vascular smooth muscle cell migration. 38 The upregulation of this transcript, together with the downregulation of other isoforms in aging males, again supports the notion that this group is more susceptible to neointimal proliferation, vascular smooth muscle cell migration, and potentially atherosclerosis. The second major difference was in elastin density, which decreased selectively in old males.…”

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

“…Collagen VIII has previously been shown to facilitate migration of smooth muscle cells. 230,232,233 Consistently, the migratory capacity was markedly reduced in collagen VIII KO cardiac fibroblast. Thus, collagen VIII appeared to mediate not only differentiation of fibroblasts into myofibroblasts, but also important aspects of myofibroblast function.…”

“…Collagen VIII can direct adherence to ECM molecules, such as the structural collagen I, 230 and is suggested to serve as a molecular bridge between different ECM molecules. 136 In…”

“…Rather, it can regulate tissue remodeling by mediating fibrotic signaling and processes in smooth muscle cells. [230][231][232] Thus, we speculated that collagen VIII could regulate the integrity of the LV indirectly by promoting fibrotic remodeling by cardiac fibroblasts. In line with this, we showed attenuated TGF-β1 signaling, reduced production of structural collagens I and III and decreased myofibroblast differentiation after pressure overload in mice lacking collagen VIII.…”

Maternal exposure to carbon black nanoparticle increases collagen type VIII expression in the kidney of offspring

“…An increase in glomerular capillary length that leads to glomerular hypertrophy has been observed in mice with diabetic nephropathy (Guo et al, 2005). It has been reported that vascular smooth muscle cells expressing type VIII collagen can modify the microenvironment and can spread and migrate on the tissue without type I collagen (Adiguzel et al, 2006). There is no report of the downregulation of type I collagen during the formation of fibrosis; therefore, the meaning of the downregulation of Col1a1 remains unclear.…”