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) ␣ 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 ␣, which in turn activated SHP-1. Elastic lamina degradation peptides extracted from arterial specimens could also activate SIRP ␣ and SHP-1. The knockdown of SIRP ␣ 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 ␣ and SHP-1 potentially mediate the inhibitory effect of elastic laminae on monocyte adhesion.Arterial elastic laminae have long been considered a structure that determines the strength and elasticity of blood vessels (1-6). Recent studies, however, have demonstrated that arterial elastic laminae also participate in the regulation of arterial morphogenesis and pathogenesis (7-12). An important contribution of elastic laminae is to confine smooth muscle cells (SMCs) 2 to the arterial media by inhibiting SMC proliferation (8, 9) and migration (10), thus preventing intimal hyperplasia under physiological conditions. Arterial elastic laminae also exhibit thrombosis-resistant properties. When implanted in an artery, elastic lamina scaffolds are associated with significantly lower leukocyte adhesion and thrombosis compared with collagen matrix scaffolds (10).These observations suggest an inhibitory role for elastic laminae relative to collagen matrix. Although such a role is well documented, the mechanisms remain poorly understood.Leukocytes are known to express the inhibitory receptor SIRP ␣ (also known as Src homology 2 domain-containing tyrosine phosphatase substrate-1), a transmembrane glycoprotein receptor that exerts an inhibitory effect on cell mitogenic (13-18) and inflammatory (19,20) activities. Upon ligand binding, SIRP ␣ transmits inhibitory signals through tyrosine phosphorylation of its intracellular immunoreceptor tyrosine-based inhibitory motif (15-18, 21, 22). The phosphorylation of the immunoreceptor tyrosine-based inhibitory motif initiates the recruitment of Src homology 2 domain-containing protein-tyrosine phosphatase (SHP)-1 to SIRP ␣, which is known as a substrate of SHP-1 (21, 22). The recruitment of SH...

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Liu, Shu Q., Christopher Tieche, Dalin Tang, and Paul Alkema. Pattern formation of vascular smooth muscle cells subject to nonuniform fluid shear stress: role of PDGF-␤ receptor and Src. Am J Physiol Heart Circ Physiol 285: H1081-H1090, 2003. First published May 8, 2003 10.1152/ ajpheart.00434.2003.-Blood vessels are subject to fluid shear stress, a hemodynamic factor that inhibits the mitogenic activities of vascular cells. The presence of nonuniform shear stress has been shown to exert graded suppression of cell proliferation and induces the formation of cell density gradients, which in turn regulate the direction of smooth muscle cell (SMC) migration and alignment. Here, we investigated the role of platelet-derived growth factor (PDGF)-␤ receptor and Src in the regulation of such processes. In experimental models with vascular polymer implants, SMCs migrated from the vessel media into the neointima of the implant under defined fluid shear stress. In a nonuniform shear model, blood shear stress suppressed the expression of PDGF-␤ receptor and the phosphorylation of Src in a shear level-dependent manner, resulting in the formation of mitogen gradients, which were consistent with the gradient of cell density as well as the alignment of SMCs. In contrast, uniform shear stress in a control model elicited an even influence on the activity of mitogenic molecules without modulating the uniformity of cell density and did not significantly influence the direction of SMC alignment. The suppression of the PDGF-␤ receptor tyrosine kinase and Src with pharmacological substances diminished the gradients of mitogens and cell density and reduced the influence of nonuniform shear stress on SMC alignment. These observations suggest that PDGF-␤ receptor and Src possibly serve as mediating factors in nonuniform shear-induced formation of cell density gradients and alignment of SMCs in the neointima of vascular polymer implants. signal transduction; mitogen gradients; cell density gradients; cell migration; cell alignment BLOOD FLOW-ASSOCIATED fluid shear stress regulates cellular activities, including cell proliferation, migration, and apoptosis (1, 7-9, 11, 14, 21, 36, 44, 48, 59, 63). Investigations using cell culture models have demonstrated that disturbed flow with reduced fluid shear stress and increased shear stress gradients potentially enhance the proliferative activity of vascular cells (7,9,11,35,37,45,51), whereas laminar flow exerts an opposite effect (1,33,35,37,45,66). These shearinduced cellular activities possibly contribute to the regulation of vascular morphogenesis and structural adaptation. While it is difficult to observe these processes during development, experimental and clinical observations have demonstrated an inverse correlation of fluid shear stress with neointimal formation during vascular adaptation in response to altered blood flow (2,5,16,29,35,37,66). These investigations have verified the role of fluid shear stress in the regulation of mitogenic activities in vascular cells.Previous studies hav...

Liu, Shu Q., Christopher Tieche, Dalin Tang, and Paul Alkema. Pattern formation of vascular smooth muscle cells subject to nonuniform fluid shear stress: role of PDGF-␤ receptor and Src. Am J Physiol Heart Circ Physiol 285: H1081-H1090, 2003. First published May 8, 2003 10.1152/ ajpheart.00434.2003.-Blood vessels are subject to fluid shear stress, a hemodynamic factor that inhibits the mitogenic activities of vascular cells. The presence of nonuniform shear stress has been shown to exert graded suppression of cell proliferation and induces the formation of cell density gradients, which in turn regulate the direction of smooth muscle cell (SMC) migration and alignment. Here, we investigated the role of platelet-derived growth factor (PDGF)-␤ receptor and Src in the regulation of such processes. In experimental models with vascular polymer implants, SMCs migrated from the vessel media into the neointima of the implant under defined fluid shear stress. In a nonuniform shear model, blood shear stress suppressed the expression of PDGF-␤ receptor and the phosphorylation of Src in a shear level-dependent manner, resulting in the formation of mitogen gradients, which were consistent with the gradient of cell density as well as the alignment of SMCs. In contrast, uniform shear stress in a control model elicited an even influence on the activity of mitogenic molecules without modulating the uniformity of cell density and did not significantly influence the direction of SMC alignment. The suppression of the PDGF-␤ receptor tyrosine kinase and Src with pharmacological substances diminished the gradients of mitogens and cell density and reduced the influence of nonuniform shear stress on SMC alignment. These observations suggest that PDGF-␤ receptor and Src possibly serve as mediating factors in nonuniform shear-induced formation of cell density gradients and alignment of SMCs in the neointima of vascular polymer implants. signal transduction; mitogen gradients; cell density gradients; cell migration; cell alignment BLOOD FLOW-ASSOCIATED fluid shear stress regulates cellular activities, including cell proliferation, migration, and apoptosis (1, 7-9, 11, 14, 21, 36, 44, 48, 59, 63). Investigations using cell culture models have demonstrated that disturbed flow with reduced fluid shear stress and increased shear stress gradients potentially enhance the proliferative activity of vascular cells (7,9,11,35,37,45,51), whereas laminar flow exerts an opposite effect (1,33,35,37,45,66). These shearinduced cellular activities possibly contribute to the regulation of vascular morphogenesis and structural adaptation. While it is difficult to observe these processes during development, experimental and clinical observations have demonstrated an inverse correlation of fluid shear stress with neointimal formation during vascular adaptation in response to altered blood flow (2,5,16,29,35,37,66). These investigations have verified the role of fluid shear stress in the regulation of mitogenic activities in vascular cells.Previous studies hav...

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.

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