Negative Regulation of Monocyte Adhesion to Arterial Elastic Laminae by Signal Regulatory Protein α and Src Homology 2 Domain-containing Protein-Tyrosine Phosphatase-1

Abstract

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...

Expression of Versican V3 by Arterial Smooth Muscle Cells Alters Tumor Growth Factor β (TGFβ)-, Epidermal Growth Factor (EGF)-, and Nuclear Factor κB (NFκB)-dependent Signaling Pathways, Creating a Microenvironment That Resists Monocyte Adhesion

“…Upon adhesion to ECM molecules, such as collagen and fibronectin, ␤1 integrin facilitates leukocyte infiltration into the site of injury (43)(44)(45). In contrast, some ECM structures are poor substrates for leukocyte accumulation and activation, such as elastin (46,47). Elastic laminae extracted from rat aorta are resistant to leukocyte adhesion and transmigration in vivo and in vitro compared with the collagen-enriched adventitia extracted from the same aorta (46,47).…”

“…In contrast, some ECM structures are poor substrates for leukocyte accumulation and activation, such as elastin (46,47). Elastic laminae extracted from rat aorta are resistant to leukocyte adhesion and transmigration in vivo and in vitro compared with the collagen-enriched adventitia extracted from the same aorta (46,47). Deficiency in fibulin 2 and fibulin 5 in animals results in disrupted elastic laminae accompanied by an increase in vascular adhesion molecules and tissue factor expression as well as thrombus formation after carotid artery ligation injury (23), suggesting that the elastin-enriched ECM present in healthy aortas protects against vascular injury.…”

Signal Regulatory Proteins (SIRPS) Are Secreted Presynaptic Organizing Molecules

“…In initial studies, we showed that fibroblast growth factor (FGF) 2 22 and its close relatives, FGFs 7 and 10, promote differentiation of neuromuscular and cerebellar synapses (7,10). Some neuronal populations were unresponsive to these FGFs, however, and FGFs accounted for less than half of the active material in brain extracts.…”

Enhancement of Endothelial Cell Retention on ePTFE Vascular Constructs by siRNA-Mediated SHP-1 or SHP-2 Gene Silencing

“…Targeting adhesion-promoting factors for activation or targeting adhesion-inhibiting factors for deactivation can both serve to increase cell adhesion strength. 28 In the present study, we used siRNA to silence the expression of the SHP-1 gene or SHP-2 gene since both SHP-1 18,19,29 and SHP-2 14,35 have been shown to inhibit cell adhesion in a variety of cell types. .…”

“…28 Src homology-2 domain containing protein tyrosine phosphatase (SHP)-1 and SHP-2 are related protein tyrosine phosphatases that are known to influence focal contact formation and cell adhesion. Although they exert their effects via distinct mechanisms, their respective influences on cell adhesion are both ultimately inhibitory and, therefore, decreased expression of either SHP-1 18,19,26,28 or SHP-2 14,35 has been shown to promote cell adhesion.…”