doi: 10.1161/ATVBAHA.108.174029
© 2008 American Heart Association, Inc.
Editorials |
Morphing the Topography of Atherosclerosis
An Unexpected Role for PECAM-1
From the Toronto General Research Institute, University Health Network and the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Correspondence to Dr Myron Cybulsky, University Health Network, 200 Elizabeth Street, Eaton 11, Toronto ON M5G 2C4, Canada. E-mail myron.cybulsky{at}utoronto.ca
Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) is a complex adhesion and signaling molecule expressed by endothelial cells, platelets, and leukocytes.1,2 On endothelial cells this transmembrane glycoprotein member of the immunoglobulin gene superfamily is concentrated at intercellular junctions and cycles through vesicle-like structures contiguous with the lateral plasma membrane, termed the lateral border recycling compartment.3 Homophilic adhesive interactions between PECAM-1 on leukocytes and endothelial cells mediate leukocyte migration through endothelial cell monolayers (diapedesis) in vitro and in vivo and through the perivascular basement membrane.2,4 As a signaling molecule, PECAM-1 transduces signals required for proinflammatory adhesion molecule expression by endothelial cells. However, PECAM-1 can also inhibit inflammatory and immune responses.2 Thus, PECAM-1 has the potential to influence atherogenesis in more than one way.
See accompanying articles on pages 1996 and 2003
Usually the deficiency of a molecule leads to an overall increase, decrease, or no change in murine atherosclerotic lesion burden, but the distribution of lesions in the arterial tree remains unchanged, with the majority of lesions occurring in the aortic root, the lesser (inner) curvature of the ascending aorta and near ostia of arterial branches in the descending aorta.5 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, two articles detail independent obserations that deficiency of PECAM-1 results in an altered distribution of atherosclerotic lesions.
Goel et al6 evaluated atherosclerotic lesion development in LDL receptor deficient (ldlr–/–) mice by measuring lipid accumulation using oil red O staining in en face preparations of the aorta and cross-sections of the aortic root, as well as micro computed tomography of osmium tetroxide stained proximal aorta and its branches. They found that PECAM-1 deficiency renders ldlr–/– mice more susceptible to atherosclerotic lesion development in the aorta, and specifically in the aortic root, the aortic arch adjacent to ostia of the innominate, left common carotid and left subclavian arteries, the proximal regions of these arteries, and the descending thoracic and abdominal aorta (Supplemental Table 1). Yet, lesion formation was reduced in the lesser curvature of the aortic arch. Bone marrow transplantation experiments did not recapitulate decreased lesion formation in the lesser curvature of the arch in pecam1–/– mice. Nevertheless, analysis of the aortic root in these experiments suggested that PECAM-1 expressed by endothelial cells inhibits lesion formation, and analysis of the whole aorta suggested that expression of PECAM-1 by both endothelial cells and bone marrow–derived leukocytes or platelets is required for atheroprotection (Supplemental Table 2).
Harry et al7 studied PECAM-1 functions in the apolipoprotein E–deficient (apoe–/–) background after feeding a Western diet for 13 weeks. Relative to apoe–/– mice, pecam1–/–apoe–/– mice had reduced overall atherosclerotic lesion area in the aorta, specifically the lesser curvature of the aortic arch, but comparable lesions in the descending thoracic and abdominal aorta (Supplemental Table 1). Bone marrow transplantation studies suggested that PECAM-1 expressed by endothelium is the main determinant of atherosclerosis in the aortic arch, and that hematopoietic PECAM-1 may promote lesion formation in the abdominal aorta (Supplemental Table 2). Because endothelial cells in the lesser curvature of the aortic arch are exposed to disturbed blood flow, experiments also focused on this region and revealed reduced nuclear translocation of NF-
B in PECAM-1–deficient mice. Consistent with these findings, in vitro experiments revealed that inhibition of PECAM-1 expression with siRNA reduced NF-B activation and vascular cell adhesion molecule (VCAM)-1 expression, which were induced by exposing cells for 24 hours to complex hemodynamic forces found in arterial regions predisposed to atherosclerosis. VCAM-1 expression and macrophage accumulation were reduced in atherosclerotic lesions of in pecam1–/–apoe–/– mice.
Collectively, these studies revealed that in the lesser curvature of the aortic arch, PECAM-1 promotes atherosclerosis in both ldlr–/– and apoe–/– backgrounds, whereas in the descending thoracic and abdominal aorta PECAM-1 either protects from atherosclerosis (ldlr–/– background) or has no effect (apoe–/– background) (Figure). This brings up the interesting question of why PECAM-1 has differential effects on atherogenesis that are dependent on the location of lesions and background (ldlr–/– versus apoe–/–). The answer remains to be elucidated by future studies, which I suspect will reveal mechanisms that regulate the balance between pro- and antiinflammatory functions of PECAM-1.
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Proinflammatory functions of PECAM-1 relate to leukocyte diapedesis2,4 and participation in a mechanosensory complex that mediates endothelial responses to fluid shear stress.8 PECAM-1 senses hemodynamic forces exerted by blood flowing across endothelial cells. Together with VE-cadherin, which acts as an adaptor, it transactivates VEGFR2 signaling that triggers activation of integrins followed by activation of NF-B. Antiinflammatory functions of PECAM-1 include downmodulation of immunologic responsiveness and lymphocyte recruitment in experimental allergic encephalomyelitis and collagen-induced arthritis models,9–11 maintenance of endothelial cell integrity (permselectivity) and resistance to apoptosis in models of endotoxic shock,12,13 and modulation of eNOS-mediated dilatation of arteries and arterioles induced by increased wall shear stress.14,15
PECAM-1 signaling is mediated to a large extent through tyrosine phosphorylation of two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) located in PECAM-1 cytoplasmic domain, which promotes binding of SH2 domain-containing protein tyrosine phosphatase (SHP-2) and activation of downstream signaling pathways, including the extracellular signal regulated kinase (ERK) signaling.1 PECAM-1 tyrosine phosphorylation is directly involved in mechanosensing of fluid shear stress and direct pulling forces, and Fyn, a member of the Src family of kinases, was identified as an essential component of a PECAM-1–based mechanosensory complex in endothelial cells.16 ITIM phosphorylation possibly triggered by homophilic adhesive interactions may account for antiinflammatory functions attributed to PECAM-1 in endothelial cells and leukocytes.1 This is consistent with observations by Goel et al and Harry et al6,7 that hematopoietic PECAM-1 is required for atheroprotection in the descending aorta.
PECAM-1 is expressed by endothelium throughout the aorta, yet its proatherogenic role predominates only in the lesser curvature of the arch. Endothelial cells in this region exhibit a polygonal shape or a randomly aligned elongated morphology,17,18 which suggests that they are exposed to disturbed hemodynamic forces. Hemodynamic measurements of the mouse arch support this conclusion but indicate less hemodynamic heterogeneity such as secondary flows in the lesser curvature and much higher time-averaged shear stress relative to the much larger human arch.19–21 Changes in uniform laminar shear stress trigger activation of multiple signaling pathways in endothelial cells, and as cells acclimatize to the new hemodynamic environment signaling becomes quiescent. In contrast, activation of some signaling pathways may persist under conditions of disturbed flow, possibly because it is difficult for endothelium to acclimatize to continuous flow oscillations. Experiments by Harry et al revealed activation of NF-B in endothelial cells of the lesser curvature that was dependent on PECAM-1 expression. It would be interesting to know whether PECAM-1 ITIM motifs are constitutively phosphorylated in the lesser curvature, but not in other regions of the aorta.
PECAM-1 signaling in endothelial cells of the descending aorta may also be downmodulated downstream of PECAM-1. Distinct gene expression occurs in regions of arteries that are protected from atherosclerosis relative to predisposed regions.22 For example, relatively reduced cytoplasmic levels of NF-B components in atheroprotected regions may downmodulate NF-B signal transduction when cells are exposed to an activation stimulus.17 Thus, the potential for NF-B signaling in atheroprotected regions may be impaired despite intact PECAM-1 signaling. Another possibility is different basement membrane composition in atheroprotected regions, which could influence integrin signaling and modulate the activation of NF-B. It is likely that several factors contribute to regulating the balance between pro and antiinflammatory functions of PECAM-1 in atheroprotected versus atheroprone arterial regions. Their elucidation will be an important endeavor, because it may provide novel approaches for converting an atheroprone region to one that is atheroprotected.
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Acknowledgments |
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Disclosures
None.
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References |
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Arterioscler Thromb Vasc Biol 2008 28: 2003-2008.
Arterioscler Thromb Vasc Biol 2008 28: 1996-2002.
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