Negative regulation of monocyte adhesion to arterial elastic laminae by signal regulatory protein alpha and Src homology 2 domain-containing protein-tyrosine phosphatase-1.

Elastic laminae are extracellular matrix constituents that not only contribute to the stability and elasticity of arteries but also play a role in regulating arterial morphogenesis and pathogenesis. We demonstrate here that an important function of arterial elastic laminae is to prevent monocyte adhesion, which is mediated by the inhibitory receptor signal regulatory protein (SIRP) alpha and Src homology 2 domain-containing protein-tyrosine phosphatase (SHP)-1. In a matrix-based arterial reconstruction model in vivo, elastic laminae were resistant to leukocyte adhesion and transmigration compared with the collagen-dominant arterial adventitia. The density of leukocytes within the elastic lamina-dominant media was about 58-70-fold lower than that within the adventitia from 1 to 30 days. An in vitro assay confirmed the inhibitory effect of elastic laminae on monocyte adhesion. The exposure of monocytes to elastic laminae induced activation of SIRP alpha, which in turn activated SHP-1. Elastic lamina degradation peptides extracted from arterial specimens could also activate SIRP alpha and SHP-1. The knockdown of SIRP alpha and SHP-1 by specific small interfering RNA diminished the inhibitory effect of elastic laminae, resulting in a significant increase in monocyte adhesion. These observations suggest that SIRP alpha and SHP-1 potentially mediate the inhibitory effect of elastic laminae on monocyte adhesion.

Vascular elastic laminae: anti-inflammatory properties and potential applications to arterial reconstruction.

Biomaterials, including non-biodegradable and biodegradable polymers, and collagen and fibrin matrices, have been used in experimental and clinical arterial reconstruction. While these biomaterials exhibit various characteristics suitable for arterial reconstruction, the patency of biomaterial-based arterial substitutes remains problematic because of inflammation and thrombogenesis. Endothelial cell seeding of biomaterials has been proposed and used for reducing the thrombogenicity of biomaterials. However, difficulties in cell retention hamper the application of such an approach. Although autogenous vein grafts offer satisfactory results, not all patients possess veins available for arterial replacements. Thus, a critical issue in arterial reconstruction is developing arterial substitutes that are inflammation/thrombosis-resistant while possessing the characteristics of natural arteries. Here we show that allogenic vascular elastic laminae exhibit anti-inflammatory properties and may be considered a potential material for arterial reconstruction. In this article, we briefly review the composition, structure, and function of vascular elastic laminae, summarize recent discoveries on the role of elastic laminae in regulating leukocyte adhesion and vascular smooth muscle cell proliferation and migration, and discuss potential applications of allogenic elastic laminae to arterial reconstruction.

Neointima formation on vascular elastic laminae and collagen matrices scaffolds implanted in the rat aortae.

Synthetic polymers, including polytetrafluoroethylene and Dacron, and biomatrix proteins, including collagen and fibrin, have been used for the construction of vascular substitutes. However, these materials induce inflammatory reactions, contributing to thrombosis, smooth muscle cell (SMC) proliferation, and neointima formation, processes leading to the failure of vascular substitutes. Thus, a pressing issue in vascular reconstruction is to construct vascular substitutes with surface materials that are inflammation-resistant. Here, we demonstrate that the vascular elastic laminae exhibit such a property. Aortic specimens from donor rats were treated with 0.1M NaOH for various times, resulting in elastic lamina-collagen matrix scaffolds with and without the basal lamina. Matrix scaffolds were implanted into the host aorta with three different surface materials, including the elastic lamina, basal lamina, and adventitial collagen, and observed for leukocyte adhesion, endothelial migration, cell proliferation, and neointimal formation on these surfaces. It was found that the elastic lamina was associated with significantly lower leukocyte adhesion, BrdU incorporation, and neointima formation than the basal lamina and adventitial collagen, while the migration of endothelial cells was comparable on all three surfaces. The adventitial collagen matrix was associated with leukocyte infiltration from blood and subsequent SMC migration from the host aorta, whereas the elastic laminae were resistant to such processes. The morphology of the implanted elastic laminae appeared normal at all times. These observations suggest that the vascular elastic laminae exhibit inflammation-resistant properties and inhibit SMC mitogenic activities compared with collagen-containing matrices and may be considered a potential surface material for vascular reconstruction.

Pattern formation of vascular smooth muscle cells subject to nonuniform fluid shear stress: mediation by gradient of cell density.

Smooth muscle cells (SMCs) are organized in various patterns in blood vessels. Whereas straight blood vessels mainly contain circumferentially aligned SMCs, curved blood vessels are composed of axially aligned SMCs in regions with vortex blood flow. The vortex flow-dependent feature of SMC alignment suggests a role for nonuniform fluid shear stress in regulating the pattern formation of SMCs. Here, we demonstrate that, in experimental models with vascular polymer implants designed for the observation of neointima formation and SMC migration under defined fluid shear stress, nonuniform shear stress possibly plays a role in regulating the direction of SMC migration and alignment in the neointima of the vascular implant. It was found that fluid shear stress inhibited cell growth, and the presence of nonuniform shear stress influenced the distribution of total cell density and induced the formation of cell density gradients, which in turn directed SMC migration and alignment. In contrast, uniform fluid shear stress in a control model influenced neither the distribution of total cell density nor the direction of SMC migration and alignment. In both the uniform and nonuniform shear models, the gradient of total cell density was consistent with the alignment of SMCs. These observations suggest that nonuniform shear stress may regulate the pattern formation of SMCs, possibly via mediating the gradient of cell density in the neointima of vascular polymer implants.