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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:497.)
© 2005 American Heart Association, Inc.

Brief Reviews

LDL Receptor–Related Protein and the Vascular Wall

Implications for Atherothrombosis

Vicenta Llorente-Cortés; Lina Badimon

From the Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Correspondence to Dra Lina Badimon, Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. E-mail lbmucv{at}cid.csic.es

	Abstract

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LDL receptor–related protein 1 (LRP1) is highly expressed in the vascular wall and is mainly associated with macrophages and vascular smooth muscle cells (VSMCs). Overexpression of LRP1 in atherosclerotic lesions has been demonstrated in several animal models and human lesions. Clinical studies have suggested a relation between alterations in LRP1 expression and coronary heart disease. Indeed, it has been demonstrated that LRP1 gene expression is increased in blood mononuclear cells from patients with coronary obstruction and that the LRP1 mRNA-protein expression ratio is altered in coronary patients. Taken together, these results seem to suggest that LRP1 may be a pivotal receptor in the etiology of atherosclerosis. Our group has contributed to the elucidation of the physiopathologic role of LRP1 in the vascular wall by demonstrating that LRP1-mediated, matrix-retained LDL internalization could be crucial for VSMC–foam cell formation, that LRP1 is upregulated by lipid during human atherosclerotic lesion progression, and that LRP1-mediated aggregated LDL uptake causes the prothrombotic transformation of the vascular wall. Therefore, LRP1 seems to play a pathologic function during atherosclerotic lesion progression; however, LRP1 also seems to be essential for embryonic development and for the maintenance of vascular integrity. The protective effect of LRP1 in the vessel wall seems to be mainly due to its role in controlling certain signaling pathways. In this review, we will focus on the description of the main physiopathologic functions of LRP1 in the vascular wall.

Our group has contributed to elucidate the physiopathological role of LRP1 in vascular wall by demonstrating that LRP1-mediated matrix-retained LDL internalization is crucial for VSMC-foam cell formation, that LRP1 is upregulated by lipid during human atherosclerotic lesion progression and that LRP1-mediated agLDL uptake causes prothrombotic transformation of the vascular wall.

Key Words: low-density lipoprotein receptor–related protein 1 • aggregated LDL • tissue factor • vascular smooth muscle cells • proteoglycans

	Introduction

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Foam cells in atherosclerotic lesions derive from macrophages and vascular smooth muscle cells (VSMCs). Although macrophage–foam cell formation has been extensively studied, little is known about how VSMCs become foam cells. Macrophages become foam cells through the uptake of diversely modified LDLs, whereas the mechanism of lipid accumulation in the intima and its uptake by VSMCs was not fully elucidated until recently. In VSMCs, the LDL receptor is downregulated by excess LDL and the scavenger receptors are barely expressed, whereas LDL receptor–related protein 1 (LRP1) is highly expressed. Aggregates of LDL (agLDL) generated in vitro by vortexing have similar physicochemical characteristics to those found in the vessel wall retained by extracellular matrix proteoglycans.^1,2 Our results clearly showed that these agLDLs induced cholesterol accumulation in human coronary VSMCs up to the level considered the hallmark of foam cell formation. Fluorescence microscopy experiments revealed that agLDLs were internalized in diffuse and large vesicles, which were clearly different from the smaller, well-defined vesicles involved in normal LDL uptake.^3,4 This result suggested a different pathway for the internalization of agLDLs. We hypothesized that the particular structure of the LRP1, composed of multiple copies of 3 of the 4 structural motifs found in the extracellular binding domain of the LDL receptor, would facilitate the interaction with agLDL, composed of hundreds of LDL particles. Indeed, immunocytochemistry and fluorescence microscopy analysis indicated high expression of LRP1 in VSMCs (Figure 1A) and high colocalization with agLDL (Figure 1B). Biochemical approaches demonstrated that LRP1 ligands and anti-LRP1 antibodies prevented agLDL internalization. Finally, in antisense LRP1-oligodeoxynucleotide–treated cells, agLDLs were unable to induce cholesteryl ester (CE) accumulation owing to protein deficiency. Therefore, in VSMCs, cells with very high levels of LRP1 expression, LRP1 mediates the binding and internalization of agLDL and in the absence of LRP1 function, VSMCs are unable to accumulate cholesterol.^5,6

View larger version (40K): [in this window] [in a new window]   Figure 1. A, LRP1 expression by human VSMCs. VSMC stained with anti-LRP1 antibodies against either -chain or ß-chain, modified from Llorente-Cortes et al, Arterioscler Thromb Vasc Biol. 2000;20:1572–1579. B, Colocalization of agLDL and LRP1 in human VSMCs. Confocal microscopy of VSMCs incubated with anti-LRP1 (green) antibodies and 1,1'dioctadecyl-3,3,3',3'-tetramethlindocarbocyanine (DiI)–normal LDL or DiI-agLDL (red). Photomicrographs show VSMCs incubated with DiI-agLDL and anti-LRP1 ß-chain or DiI–normal LDL and anti-LRP1 ß-chain; magnification x5000. Modified from Llorente-Cortes et al, Arterioscler Thromb Vasc Biol. 2000;20:1572–1579. C. LRP1 structure. All other abbreviations are as defined in text.

See cover

LRP1 has also been described to bind a wide variety of lipoprotein ligands involved in foam cell formation. These lipoprotein ligands include apolipoprotein E (apoE)–enriched VLDL,⁷ lipoprotein lipase (LPL) and LPL–triglyceride-rich lipoprotein complexes,^8,9 and lipoprotein(a).¹⁰ Although most of these studies have been performed in cell lines, the uptake of LPL complexes might play an important role in atherosclerotic lesion progression, because elevated LPL expression has been demonstrated in atherosclerotic plaques.¹¹ LRP1 is also considered to play a role in the uptake of chylomicron remnants in macrophages.¹²

LRP1, contrary to the LDL receptor, has multiple binding sites and is not regulated by intracellular cholesterol (Figure 1C). Therefore, LRP1-mediated internalization can be considered as low-specificity, high-capacity mechanism that allows the uptake of large amounts of ligand. Because LRP1 is highly expressed in atherosclerotic plaques and because subendothelial LDL retention and aggregation are key events in atherogenesis, the uptake of lipoprotein ligands through LRP1 could have a crucial role in VSMC-lipid deposition in atherosclerotic plaques. In fact, we have also demonstrated that VSMCs derived from advanced atherosclerotic plaques showed higher intracellular lipid deposition because of their higher LRP1 expression levels (Figure 2). The results obtained in vitro in plaque-derived cells are in agreement with the increase in lipid accumulation and LRP1 expression during coronary atherosclerotic lesion progression.¹³ In summary, these results indicate that LRP1-mediated LDL internalization likely contributes to lipid accumulation in the arterial wall.

View larger version (65K): [in this window] [in a new window]   Figure 2. A, Representative Masson’s trichrome staining and LRP1 and LDL receptor immunostaining in initial (lesion I) and advanced (lesion V) lesions. l indicates lumen; i, intima; m, media; and c, lipid core; magnification x100. B, Real-time polymerase chain reaction analysis of LRP1 and LDL receptor in normal and plaque-derived VSMCs. Each symbol represents a different patient, and lines connect the results obtained in nonatherosclerotic and atherosclerotic areas from the same patient. Results are expressed as mean (SEM) of 3 independent experiments performed with VSMCs from H95, H108, and H112 patients. *P<0.05 vs normal VSMCs. Modified from Llorente-Cortes et al. Eur J Clin Invest. 2004;34:182–190. All other abbreviations are as defined in text.

LRP1 and the Extracellular Matrix
Versican is one of the main chondroitin sulfate proteoglycans (CS-PGs) in the tridimensional network of the intimal extracellular space and is highly expressed in human arteries with high susceptibility to atherosclerosis.¹⁴ We have recently reported that versican interaction with LDL has a high capacity to induce LDL aggregation and fusion (Figure 3A). Monomeric LDL particles, similar to native LDL in electrophoretic mobility and size (by electron microscopy), enter the cells through the LDL receptor but are able to induce CE accumulation. Fused LDL particles, similar in size to those obtained by vortex aggregation, are internalized through LRP1.⁶ These results indicate that versican highly increases LDL atherogenicity (Figure 3A). Hurt-Camejo et al¹⁴ and Camejo et al¹⁵ described structural alterations in the apoB-100 surface structure by interaction with CS-PGs. The obtained fused particles were similar in size to those described from atherosclerotic lesions.^1,2 LRP1 involvement in the internalization of versican-fused LDLs further enhances the importance of LRP1 as a lipoprotein receptor involved in VSMC–foam cell formation.⁶

View larger version (42K): [in this window] [in a new window]   Figure 3. Schematic representation of the role of PGs on LDL modification and retention in the arterial intima. A, CS-PGs play a major role in LDL retention and aggregation. Adapted from Llorente-Cortes et al, Arterioscler Thromb Vasc Biol. 2002;22:387–393. B, HS-PGs play a major role in cell uptake mechanisms; the scheme shows how HS-PGs cooperate with LRP in the process of aggregated LDL internalization by human VSMCs. Abbreviations are as defined in text.

To examine the contribution of PGs and LRP1 to agLDL internalization, LRP1-expressing and LRP1-deficient cells (either treated or not with heparinase I and III and chondroitinase ABC) were incubated with agLDL. Although heparinase I and III and chondroitinase ABC treatment completely degrades heparan sulfate proteoglycans (HS-PGs) and CS-PGs, respectively, only HS-PG cleavage has consequences for agLDL internalization in both cell types.¹⁶ Our results are indeed in agreement with the existence of an LRP1-independent pathway involving HS-PGs as receptors in fibroblasts and macrophages.^17–22 However, in human VSMCs, HS-PGs do not play a role as receptors for agLDL because VSMCs do not internalize agLDL in the absence of LRP1.¹⁶ LRP1 alone internalizes most of the agLDLs, although as in fibroblasts, there is a certain synergism between LRP1 and HS-PGs, because HS-PGs facilitate agLDL internalization through LRP1 (Figure 3B). In the fibroblast membrane, with a sparser LRP1 distribution, HS-PGs seem to be indispensable for the binding of agLDL, a multimeric ligand that likely requires extensive binding to many cell surface molecules at once. In contrast, the sheer quantity of LRP1 on the VSMC membrane⁵ may be sufficient for agLDL binding. Smaller ligands, such as tissue factor pathway inhibitor, can be internalized through the LRP1, independently of HS-PGs in fibroblasts,²³ suggesting that the nature of the ligand might also be important in determining the relative role of LRP1 and HS-PGs in ligand internalization.

LRP1 Regulation by Lipid: In Vitro and In Vivo Studies
Although it is clear that LRP1 expression is high in advanced atherosclerotic plaques,^13,24–26 little was known about LRP1 upregulation during atherosclerotic lesion progression. In macrophages, it has been described that LRP1 mRNA levels are increased by colony stimulating factor-1 and insulin,^27,28 whereas they are decreased by transforming growth factor-ß and lipopolysaccharide.^29,30 We demonstrated that agLDL strongly upregulates LRP1 expression at the transcriptional level (Figure 4A). The increase in mRNA LRP1 transcription led to a large increase in LRP1 protein expression. Consequently, by inducing LRP1 expression in human VSMCs, agLDL could lead to a progressive intracellular accumulation of cholesterol in these cells. The LRP1 upregulation observed in vitro has been corroborated in vivo; in situ hybridization analysis revealed that LRP1 expression is upregulated in the vessel wall of hypercholesterolemic animals (Figure 4B),³¹ The relevance of these results has been demonstrated in clinical studies, wherein a relation between alterations in LRP1 expression and coronary heart disease has been reported.³² Indeed, it has been demonstrated that LRP1 gene expression is increased in blood mononuclear cells from patients with coronary obstructions and that the LRP1 mRNA-protein expression ratio is altered in coronary patients.^33,34

View larger version (59K): [in this window] [in a new window]   Figure 4. A, Time response of LRP1 and LDL receptor to normal LDL and agLDL. Real-time polymerase chain reaction quantification of LRP1 and LDL receptor mRNA in VSMCs incubated in the absence (squares) or presence (triangles) of normal LDL or agLDL (circles) for increasing times. B, In situ hybridization analysis of LRP1 expression in normocholesterolemic and hypercholesterolemic pigs. Arrows indicate LRP1 mRNA expression. Modified from Llorente-Cortes et al, Circulation. 2002; 106:3104–3110. Abbreviations are as defined in text.

However, downregulation of LRP1 by sterols in J774A.1 cells³⁵ suggest that there are differences in the regulation of LRP1 expression by sterols, depending on the cell type. The downregulation of LRP1 in these cells could be likely explained by the mechanism involved on LDL processing. As summarized in Table I (available online at http://atvb.ahajournals.org), LRP1 is involved in a wide variety of ligand internalization mechanisms. Xu et al³⁵ hypothesized that CEs from LDL may be selectively transferred in a process mediated by LRP1 to the plasmatic membrane, where they could be oxygenated by intracellular 12/15 lipoxygenase. Then, CEs could be reincorporated into the LDL particles. Thus, the downregulation of LRP expression by LDL in these cells could be explained by this specific LRP-LDL interaction, interaction that does not lead to LDL internalization, a processes required for the effect of lipids on LRP1 expression.

LRP1 upregulation induced by agLDL in human VSMCs, like LDL receptor downregulation, seems to be dependent on sterol regulatory element-binding protein-2 (SREBP-2) downregulation. Although the LRP1 gene does not have SRE-1 sequences in its promoter, an SRE-1 site in the unusually long 5'-untranslated region has been described.³⁶ In agreement with the results in VSMCs, LRP1 upregulation in hypercholesterolemic aortas is concomitant with the SREBP-2 downregulation previously described by our group.³⁷ Our results obtained in human VSMCs are in agreement with those obtained in macrophages, because LRP1 upregulation has been observed in cells incubated with cholesterol and 25-hydroxycholesterol.³⁸ Our results in vivo are also in agreement with those obtained in blood mononuclear cells, in which dietary cholesterol has been shown to increase LRP1 mRNA levels.³⁹ Therefore, exposure to high LDL concentrations and cellular accumulation of CEs increase LRP1 expression in VSMCs.³¹ Our results suggest that hypercholesterolemia might increase the capacity of VSMCs to take up LDL from the intima by regulating cellular LRP1 levels. In addition, LRP1 upregulation may influence other pathways involved in atherothrombosis, because LRP1 mediates the degradation of molecular complexes involved in thrombogenesis and fibrinolysis.

LRP1 and VSMC Proliferation and Migration
Although it has not been directly demonstrated in vascular wall cells, LRP1 might bind to certain matrix metalloproteinase (MMP) family members, either directly or indirectly, when MMPs are bound to their specific receptors. LRP1 is involved in the catabolism of MMP-9 in fibroblasts.⁴⁰ The ability of LRP1 to modulate the levels of 3 MMPs (MMP-2, MMP-13, and MMP-9) indicates its major role in regulating cellular migration.

Our group has demonstrated that the binding of agLDL to LRP1 induces a decrease in MMP-9 expression without altering tissue inhibitor of MMPs expression in human VSMCs.⁴¹ The MMP-9 downregulation by lipid loading could contribute to regulate VSMC migration. LRP controls cell migration and proliferation not only by removing excessive extracellular proteolytic activity but also by regulating the cellular expression of receptors directly involved in these processes, such as urokinase-type plasminogen activator receptor (uPAR)^42–44 and the platelet-derived growth factor (PDGF) receptor.^45,46 uPAR regulates the plasminogen activation system, which consists of a cascade of enzymes that control degradation of the basement membrane and components of the extracellular matrix. When uPAR binds to active uPA, it is not internalized but remains at the cell surface. However, when uPA binds to plasminogen activator inhibitor type-1 (PAI-1) in human monocytes, uPA is rapidly internalized and degraded through LRP1. After internalization, uPAR and LRP1 recycle back to the cell surface while uPA and PAI-1 are degraded in lysosomes. The regeneration of unoccupied uPAR at the cell surface is critical for the maintenance of plasminogen activation and for regulation of cellular migration and invasion.^43,44 Thus, in different cell models, by regulating the recycling of uPAR to the cell surface, LRP1 seem to favor cell migration. LRP1B, a recently discovered member of the LDL receptor family, causes the accumulation of uPA–PAI-1-uPAR-LRP1B complexes on the cell surface owing to its inability to drive endocytosis urokinase receptor regeneration at the cell surface. Thus, LRP1B inhibits uPAR-mediated cell migration.⁴⁷ Contrary to the role of LRP1 favoring cell migration of different cell lines, in human VSMCs LRP1 seems to control cell proliferation and migration.^45,46,48,49 One of the proposed mechanism is the formation of a complex between LRP1 and PDGF receptor.^45,46 In agreement, LRP1 suppression in VSMCs leads to increased cell migration and vascular abnormalities in a tissue-specific knockout mouse line that lacks LRP1 only in VSMCs.⁵⁰ In this model, the deregulation of PDGF-BB signaling is an important component of its abnormal vascular characteristics because of the absence of smooth muscle LRP1.

LRP1 and the Prothrombotic Potential of the Vascular Wall
LRP1 can bind different coagulation factors contributing to the circulating levels of proteins involved in coagulation. The thrombin-antithrombin complexes and factor Xa–₂-macroglobulin complexes are removed from the circulation by a mechanism that involves LRP1.⁵¹ Removal of inactive complexes is unlikely to contribute significantly to the regulation of coagulation. However, LRP1 is also able to remove the active proteins factor VIIIa and factor IXa.^52,53 This implies a possible role for LRP1 in control of the intrinsic pathway that represents an amplifying loop involving the factor VIIIa–factor IX complex. It has been proposed that LRP1 downregulation of factor IX generation is also responsible for binding and removing factor VIII, which functions as a cofactor for factor IXa in the factor X activation enzyme complex in the intrinsic pathway of blood coagulation. Indeed, the amount of factor Xa generated at the surface of endothelial cells is markedly higher that that generated at the surface of monocytes and fibroblasts, in agreement with the lack of LRP1 expression in human umbilical vein endothelial cells.

LRP1 also binds the tissue factor (TF)/factor VIIa complex that mediates the extrinsic pathway of blood coagulation. In cultured vascular endothelial and VSMCs, TF remains in an inactive state via tissue factor pathway inhibitor (TFPI)–dependent⁵⁴ or –independent⁵⁵ localization in caveolae. In contrast, it seems that there is no such translocation of TF to caveolae in monocytes, where TF is localized in clathrin-coated pits.⁵⁶ Hamik et al⁵⁶ proposed than when TF/factor VIIa on the surface of monocytic cells binds TFPI, the resulting TF–factor VIIa–TFPI complex associates with LRP1 and is translocated to clathrin-coated pits. The clathrin-dependent mechanism by which LRP1 internalizes TF is similar to the mechanism of uPAR internalization. However, whereas uPAR is recycled back to the cell surface, TF is not. Furthermore, protease-inhibitor complexes bound to uPAR and TF–factor VIIa–TFPI are apparently degraded in lysosomes. It has also been reported that recombinant TFPI variants lacking the LRP1-binding region were unable to downregulate TF–factor VIIa complexes at the monocyte cell surface. A similar mechanism has been reported at the surface of fibroblasts,⁵⁷ but the serine protease factor Xa is required for downregulation of TF.

Extracellular TF present in the lipid-rich core is highly thrombogenic, and the proximity of TF to the lipid-rich areas might suggest a potential role for LDL in TF expression⁵⁸ (Figure 5A).We have demonstrated that LRP1-mediated agLDL-lipid loading contributes to increased TF expression and activity and TF microparticle (MP) release in human VSMCs (Figure 5B).⁵⁹ We showed that the specific ability of agLDL to induce TF-MP release is not related to agLDL-induced apoptosis and is strictly dependent on LRP1 expression, because no increase in TF release induced by agLDL was observed in LRP1-deficient VSMCs (Figure 5C). LRP1 and inactive TF are localized in certain patches of the membrane, named caveolae.^46,54 The relevance of LRP1 localization in caveolae for TF-MP release and TF activation is supported by our demonstration that the binding of agLDL to LRP1 could influence the enrichment with inactive TF of released MPs.⁵⁹ This inactive TF is mainly in caveolae in its encrypted form. Additionally, as we have demonstrated, agLDL induces the enrichment of the plasma membrane of VSMCs with sphingomyelin, 1 of the main phospholipids in the structure of caveolae. Interestingly, phospholipid membrane composition can influence the topological organization of proteins and their activity.⁶⁰ Furthermore, a sphingomyelin increase in caveolae induced by agLDL likely participates in TF activation. It has been reported that oxidized LDL induces TF activation through cellular lipid peroxidation,⁶¹ which could cause changes in TF structure. Both oxidized LDL and agLDL, though by different mechanisms and receptors, appear to induce cellular membrane perturbations that cause TF activation. In this work, we demonstrated for the first time that LRP1-mediated agLDL-lipid loading of VSMCs was 1 of the mechanisms that induces TF activation and TF-MP release.⁵⁹ These results could have clinical relevance, because there is an increase in the levels of TF-MPs in the peripheral circulation of patients with acute coronary syndromes and in patients with the metabolic syndrome.^62,63 The roles of LRP1 in TF activation in monocytes and VSMCs may differ, depending on TF localization in these cells, and could also explain differences in the mechanisms of TF activation by lipid loading. Whereas lipid loading induces TF release through apoptotic mechanisms in macrophages,^64,65 LRP1-mediated agLDL uptake does not induce cellular apoptosis or release of apoptotic microparticles and is not responsible for the lower proliferation and survival rate associated with plaque VSMCs.^13,59 These results indicate that the interaction of LRP1 with TF could differentially alter the cellular prothrombotic potential, depending on cell type and the LRP1 ligands present in the cellular milieu. In lipid-enriched, advanced atherosclerotic lesions, in which agLDL is 1 of the main modifications of LDL in the arterial intima, agLDL-lipid loading could be an important mechanism of increasing the prothrombotic potential of VSMCs.

View larger version (48K): [in this window] [in a new window]   Figure 5. A, Representative photomicrographs of lipid-rich areas and collagen-rich areas stained for TF (brown). Modified from Toschi et al, Circulation. 1997;95:594–599. B, Fluorescence cytometric analysis of VSMC-secreted MPs. Representative image showing TF- and annexin V–positive MPs released by human VSMCs incubated in the absence of LDL or in the presence of normal LDL or agLDL. Modified from Llorente-Cortes et al, Circulation. 2004;110:452–459. C, Effect of normal LDL and agLDL on TF release in LRP1-expressing and LRP1-deficient VSMCs. Medium was harvested from untreated VSMCs (gray bars), antisense (black bars), and sense (white bars), incubated in the absence or presence of normal LDL or agLDL. AS indicates antisense; S, sense. Modified from Llorente-Cortes et al, Circulation. 2004;110:452–459. All other abbreviations are as defined in text.

Implications for Atherothrombosis
The role of LRP1 in VSMC-lipid loading could be 1 of the most important pathophysiologic roles of LRP1 in the vascular wall for several reasons: (1) VSMCs are the main cellular component of the vascular wall; (2) LRP1 is highly expressed in atherosclerotic lesions in association with VSMCs^13,24–26; (3) matrix-retained agLDL is 1 of the main modified forms of LDL in the arterial intima^1,2,14,15; (4) CS-PGs and HS-PGs contribute to LRP1-mediated agLDL uptake by inducing LDL aggregation and fusion or by inducing agLDL uptake through the LRP1, respectively^6,16; (5) LRP1 is upregulated by hypercholesterolemia, 1 of the main risk factors for atherosclerosis³¹; and (6) LRP1-mediated agLDL uptake induces TF activation and TF-MP release,⁵⁹ likely contributing to the prothrombotic transformation of the vascular wall. However, LRP1 plays an essential role in controlling VSMC proliferation and vascular wall integrity, as has been demonstrated in a tissue-specific knockout mouse line that lacks LRP1 only in VSMCs.⁵⁰ The absence of LRP1 in the vascular wall leads to elastic membrane disturbances and aneurysms. We consider that the protective role of LRP1 in maintaining vascular wall structure is related to the crucial requirement for LRP in embryonic development,⁶⁶ and it is not opposed to a proatherogenic role for LRP1 overexpression in adult cells and human lipid-enriched atherosclerotic plaques. Both LRP1 deficiency and LRP1 overexpression can lead to alterations in cellular functions (Figure 6) and cause vascular disorders. Indeed, the protective effect of LRP1 in the vessel wall might be due to its role in controlling PDGF receptor–dependent signaling pathways.^48–50 Although the dual role of LRP1 as a cargo and signal transduction receptor has been clearly demonstrated,^67,68 these roles seem not to be independent. It has been described that apoE-enriched ß-VLDL blocks PDGF-mediated tyrosine phosphorylation of LRP.⁵⁰ Thus, the binding and internalization of certain ligands through LRP1 could alter LRP-mediated signal transduction. Because the control of LRP1 expression and function can be crucial for regulating atherosclerotic lesion progression, precise knowledge of LRP1 regulation by atherosclerotic factors and about how LRP1 regulates internalization and signal transduction mechanisms is required. This will help to influence LRP1 pathophysiologic functions without altering its essential functions.

View larger version (26K): [in this window] [in a new window]   Figure 6. Schematic and simplified diagram of the main pathways in which LRP1 is involved in VSMCs. 1: LRP1 binds and internalizes agLDL, contributing to intracellular cholesterol accumulation. 2: AgLDL uptake induces membrane TF activation and MP release. 3: Activation of PDGF receptor by PDGFBB results in phosphorylation of the LRP cytoplasmic domain at tyrosine 63. 4: Mitogen-activated JNK may be sequestered into the LRP/JIP multiprotein complexes, preventing nuclear transactivation of the JNK-dependent transcription factors c-jun and/or Elk-1. 5: ApoE-enriched ß-VLDL, a ligand for LRP, reduce PDGF-induced tyrosine phosphorylation of the LRP cytoplasmic domain. All other abbreviations are as defined in text.

	Acknowledgments

 
This work was supported by SAF2003-03187, FIS 01/0354, FIS C-03/01, and FIC-Catalana Occidente. We thank Merck Sharp and Dohme for an unrestricted research grant that helped us to continue this research. We thank Drs S. K. Moestrup and J. Gliemann, Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark, for providing us with LRP1 antibodies that helped us to demonstrate the importance of LRP1 in atherosclerosis progression when there were no commercial antibodies for this receptor. The authors are indebted to the predoctoral and postdoctoral research fellows who have participated in these studies and to the Heart Transplant Team of the Division of Cardiology and Cardiac Surgery of the Hospital Santa Creu i Sant Pau.

Received October 6, 2004; accepted December 6, 2004.

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