Published online before print September 30, 2004, doi: 10.1161/01.ATV.0000146552.16943.5e
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© 2004 American Heart Association, Inc.
Vascular Biology |
Interaction of Monocytes With Vascular Smooth Muscle Cells Regulates Monocyte Survival and Differentiation Through Distinct Pathways
From the Gonda Goldschmied Diabetes Center, Beckman Research Institute of City of Hope, Duarte, Calif.
Correspondence to Rama Natarajan, PhD, Gonda Goldschmied Diabetes Center, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA 91010. E-mail rnatarajan{at}coh.org
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Abstract |
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Objective— Vascular smooth muscle cells (VSMCs) may regulate monocyte functions within atherosclerotic lesions. We investigated the impact of VSMC/monocyte interactions on monocyte apoptosis and scavenger receptor CD36 expression, key events related to monocyte survival and differentiation.
Methods and Results— Serum deprivation significantly increased THP-1 and human peripheral blood monocyte apoptosis. However, this was significantly reversed by physical binding to human VSMCs (HVSMCs). On binding to HVSMCs, antiapoptotic kinase Akt and its downstream targets were phosphorylated, and Bcl-2 expression was enhanced. Binding-mediated suppression of apoptosis and Akt phosphorylation were attenuated by a phosphoinositide 3-kinase inhibitor and also by an antibody to vascular cell adhesion molecule-1. CD36 expression was also significantly increased in THP-1 cells and in human peripheral blood monocytes after binding to HVSMCs, and this was mediated by both direct contact and soluble factors. Extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase phosphorylation was increased in THP-1 cells after HVSMC coculture. Furthermore, an ERK1/2 inhibitor blocked monocyte CD36 upregulation. Contact-dependent CD36 induction and ERK1/2 phosphorylation in monocytes were inhibited by blocking vascular cell adhesion molecule-1 on HVSMC, whereas soluble factor–induced CD36 expression was attenuated by a monocyte chemoattractant protein-1 neutralizing antibody.
Conclusions— These data provide evidence of novel VSMC-dependent local regulation mechanisms for monocyte survival and differentiation in atherosclerosis.
We investigated the impact of vascular smooth muscle cell (VSMC)/monocyte interactions on monocyte functions. We observed that VSMC/monocyte interactions led to antiapoptotic effects and increased scavenger receptor CD36 expression in monocytes through distinct signaling pathways. These data provide evidence for a novel VSMC-dependent local regulation of monocyte survival, retention, and differentiation in atherosclerosis.
Key Words: atherosclerosis • monocytes • vascular smooth muscle cells • apoptosis • CD36
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Introduction |
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In response to atherogenic stimuli, monocytes in circulation adhere and migrate across the endothelium to the intimal space where they differentiate, take up lipid, and form foam cells. The role of vascular endothelial cells in the recruitment of monocytes during early steps of atherosclerosis has been well studied.1–3 However, these initial processes may be reversible and do not cause clinical consequences.1,2 It is the subsequent prolonged intimal retention of monocyte/macrophage and foam cell formation that are central features of atherogenesis.1,2 However, the mechanisms by which monocytes/macrophages are retained within the vessel wall, survive, and differentiate to foam cells are not well documented. Once they transmigrate into the subendothelial intimal space, these monocyte functions are regulated mainly by the influence of local factors that are not well characterized. Furthermore, very little is known about the role of intimal vascular smooth muscle cells (VSMCs) in regulating subendothelial monocyte functions.
VSMC migration and proliferation are also well-documented hallmarks of early atherosclerotic lesions.1,4 Accumulating evidence suggests that interactions between transmigrated monocytes and VSMCs may contribute to monocyte retention and function within the vasculature. First, the potential of VSMCs to interact with monocytes is suggested by the fact that VSMCs express adhesion molecules within atherosclerotic lesions but not in the normal vascular wall.5 A highly significant association was found between VSMC vascular cell adhesion molecule (VCAM)-1 expression and intimal macrophage content.6 A strong expression of intercellular adhesion molecule (ICAM)-1 on VSMCs in atherosclerosis-prone regions was observed preceding mononuclear cell infiltration in humans.7 VSMCs derived from the neointima of balloon-injured rat aortas supported a greater arrest of monocytes than medial VSMCs in laminar flow assays.8 Furthermore, in vitro studies indicate that contact interactions between monocytes and VSMCs enhance monocyte procoagulant activity and production of metalloproteinase-1 and nitric oxide.9,10 These observations suggest that VSMCs and monocytes are not merely innocent coexistent neighbors but that VSMC/monocyte interactions are additional regulatory signals in the pathogenesis of atherosclerosis.
It is generally accepted that macrophage apoptosis within advanced atherosclerotic plaques can contribute to plaque vulnerability and thrombogenicity.11–13 In comparison, very little monocyte apoptosis is found in early atherosclerotic lesions, such as adaptive intimal thickening and fatty streaks, and this may be responsible for monocyte accumulation subsequent to transmigration into the subendothelial space.14
The formation of lipid-laden foam cells is a hallmark of both early and late atherosclerotic lesions. This is mediated by scavenger receptors (SR) such as SR-A, CD68, and CD36 that mediate uptake of modified low-density lipoprotein (LDL).15 CD36, a member of type B SRs, plays a critical role in the pathogenesis of atherosclerosis.16–19 Markedly upregulated CD36 expression in human and murine atherosclerotic lesions has been demonstrated.20 Furthermore, apolipoprotein E–deficient mice lacking CD36 developed significantly less atherosclerosis than the control mice.21
In this study, we examined for the first time the effects of monocyte adhesion to VSMCs on monocyte survival. Furthermore, we tested the hypothesis that this survival program is also associated with initiation of a monocyte differentiation program as exemplified by the expression of differentiation markers such as CD36 and oxidized LDL (ox-LDL) uptake. We observed that VSMC/monocyte interactions lead to antiapoptotic effects and increased CD36 expression in monocytes. We also examined the role of adhesion molecules and soluble factors as well as key signal transduction events mediating these effects.
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For details, see online Methods, available at http://atvb.ahajournals.org.
Coculture Studies
Cocultures of human VSMCs (HVSMCs) with THP-1 cells or peripheral blood monocytes (PBMCs) were performed in 3 different ways. In the first method, termed "mixed coculture," monocytes were added to confluent HVSMC monolayers in culture dishes for indicated time periods. In this model, monocytes bound to HVSMCs are subjected to the influence of both physical contact and soluble factors, whereas cells remaining in suspension are only influenced by soluble factors. In the second method, termed "fixed coculture," monocytes were added to confluent HVSMCs that were fixed with 3.7% paraformaldehyde (1 hour) to prevent soluble factor release. After fixation, paraformaldehyde was removed from HVSMCs by washing with PBS 8x.22 In this second model, bound monocytes are only affected by direct contact with HVSMCs. The third method is termed as "transwell coculture." In this model, HVSMCs were cultured in the bottom well of 6-well plates. THP-1 cells were then added to the bottom well and transwell insert simultaneously. THP-1 cells growing in the transwell insert are subjected to the influence of soluble factors released from the HVSMC/THP-1 cell cocultures in the bottom wells.
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Binding to HVSMCs Reverses Serum Deprivation–Induced Monocyte Apoptosis Through VCAM-1
THP-1 cells growing in serum-free medium alone (0% FBS) for 48 hours showed clear evidence of apoptosis (65.2±2.8%, P<0.001) compared with cells in 10% FBS (22.0±0.6%) as noted by Annexin V/propidium iodide double staining (Figure 1A) and DNA fragmentation (Figure I, available online at http://atvb.ahajournals.org). Because most apoptotic THP-1 cells were both Annexin V and propidium iodide positive (late apoptotic), only cells in late apoptosis were analyzed further. In contrast, in the mixed cocultures, THP-1 cells that bound to HVSMCs (0% FBS bound) showed only low levels of apoptosis (33.2±1.3%, P<0.001 versus cells in 0% FBS alone, Figure 1A) even though they were in serum-free medium, and this was similar to cells in 10% FBS. Interestingly, unbound THP-1 cells still in suspension in the cocultures (0% FBS unbound) showed no protection from apoptosis (59.0±4.4%, Figure 1A), indicating that only physical contact with HVSMCs, but not soluble factors, was responsible for suppressing THP-1 apoptosis. Similarly, serum depletion for 48 hours also induced early apoptosis in human PBMCs, which was prevented by binding to HVSMCs (Figure 1B).
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VSMC/monocyte binding can be mediated by interactions between adhesion molecules on VSMCs (VCAM-1 and ICAM-1) and their integrin (ß1 and ß2) counterreceptors, respectively, on monocytes. We found that binding-mediated protection of THP-1 cells from apoptosis was partially antagonized by preincubating HVSMCs with a VCAM-1 blocking antibody (Ab) but not control nonspecific IgG (Figure 1C). In contrast, ICAM-1 Ab had no effect (not shown). These results suggest that VCAM-1–ß1 integrin signaling is involved in binding-mediated protection of monocytes from apoptosis.
Binding to HVSMCs Increases Activation of the Akt Pathway and Bcl-2 Expression in THP-1 Cells
We further explored the mechanisms and apoptosis-regulating factor(s) that could be activated in THP-1 cells on binding to HVSMCs. As illustrated in Figure 2A, Akt, a major antiapoptotic kinase that is downstream of phosphoinositide 3-kinase (PI3K), was time-dependently phosphorylated after binding to HVSMCs in the fixed cocultures. Furthermore, Bad, FKHR (forkhead homologue in rhabdomyosarcoma), GSK-3ß (glycogen synthase kinase 3ß), and IKK
(I-
B kinase-), all downstream targets of Akt, were also phosphorylated, indicating the activation of an antiapoptotic PI3K/Akt axis in THP-1 cells. Interestingly, Akt was phosphorylated in bound but not unbound THP-1 cells in the mixed cocultures (Figure 2B), indicating that soluble factors were not involved. This agrees with our data in Figure 1A showing that unbound cells are not protected from apoptosis. When THP-1 cells were allowed to bind to paraformaldehyde-fixed HVSMCs (to avoid release of soluble factors), Akt phosphorylation was evident in the bound cells, and this effect was attenuated by blocking HVSMC VCAM-1 (Figure 2C). This further rules out soluble factors, although supporting a role for insoluble factors, such as VCAM-1 and associated ß1 integrin signaling in monocyte Akt phosphorylation.
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We also observed a time-dependent increase in protein (Figure 2A) and mRNA (not shown) levels of Bcl-2, a key antiapoptotic protein, in THP-1 cells on binding to HVSMCs. In contrast, the levels of Bax, a proapoptotic protein that antagonizes Bcl-2 function, was unchanged, thereby leading to increased Bcl-2/Bax ratios.
Binding-Mediated Apoptosis Protection Is Through PI3K Signaling
Specific kinase inhibitors were used to elucidate the signaling pathway(s) involved. As shown in Figure 2D, binding-mediated suppression of apoptosis in THP-1 cells was almost completely abolished (dose-dependently) by LY294002, a specific PI3K inhibitor. Binding-mediated apoptosis protection in PBMCs was also blocked by LY294002 (Figure 1B, bottom right). LY294002 also blocked the binding-induced prevention of DNA fragmentation (not shown). In contrast, although p38 (not shown) and extracellular signal-regulated kinase 1/2 (ERK 1/2) mitogen activated protein kinases (MAPKs, seen in Figure 3) were both activated during binding to HVSMCs, a specific p38MAPK inhibitor, SB202190, and an ERK1/2 pathway inhibitor, PD98059, had no effects on apoptosis regulation (not shown). Binding-induced Akt phosphorylation as well as Bcl-2 mRNA upregulation were both inhibited by pretreatment of THP-1 cells with LY294002 (Figure II, available online at http://atvb.ahajournals.org), indicating that PI3K is the upstream activator of Akt and Bcl-2 in our model.
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Induction of Monocyte CD36 Expression on Interaction With HVSMC
As illustrated in Figure 4A, in the basal state, 9.6±1.1% THP-1 cells were CD36 positive. However, after 24 hours in the mixed cocultures, 41.9±4.9% THP-1 cells bound to HVSMCs were positive for CD36 (P<0.01). Interestingly, unbound THP-1 cells also showed a significant increase in surface CD36 expression (31.7±3.5%, P<0.05). Furthermore, increased CD36 expression was associated with enhanced 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)–labeled ox-LDL uptake as evidenced by flow cytometry (Figure 4B). We next examined whether similar CD36 upregulation also occurs in PBMCs obtained from normal healthy adults. As shown in Figure 4C, after coculture with HVSMCs in the mixed cocultures, human PBMCs also showed significant increase in CD36 expression in bound (69.5±2.4%, P<0.001) and unbound (58.5±2.5%, P<0.001) PBMCs compared with basal levels (19.2±1.2%).
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Both direct cell–cell contact and soluble factors released from the cocultures appeared to be responsible for CD36 induction, because THP-1 cells in a transwell coculture (24 hours) with HVSMCs also showed increased CD36 expression (Figure 4D). Furthermore, THP-1 cells bound to paraformaldehyde-fixed HVSMCs also showed increased CD36 surface expression as assessed by flow cytometry (Figure 5). Meanwhile, CD36 mRNA levels were also increased both in unbound THP-1 cells in the mixed cocultures (P<0.05) or bound THP-1 cells in the fixed cocultures (P<0.05) (Figure III, available online at http://atvb.ahajournals.org).
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ERK1/2 MAPK Signaling Regulates Coculture-Mediated CD36 Upregulation
We further explored the signal transduction pathway(s) involved in THP-1 cell CD36 expression. We detected a time-dependent phosphorylation of ERK1/2 MAPK in both bound and unbound THP-1 cells in the mixed cocultures (Figure 3A, top) when compared with THP-1 cells cultured alone. Phosphorylation of ERK1/2 was also demonstrated in bound THP-1 cells in the cocultures with fixed HVSMCs as well as in THP-1 cells stimulated with HVSMC-conditioned medium (Figure 3A, middle), indicating that both direct binding as well as soluble factors released from the cocultures were responsible for monocyte ERK1/2 activation. Furthermore, THP-1 cell ERK1/2 was also phosphorylated in a transwell coculture with HVSMCs (Figure 3A, transwell), confirming the role of soluble factors.
We next examined whether ERK1/2 MAPK mediates coculture-mediated THP-1 cell CD36 expression. Figure 3B shows that induced CD36 expression (by flow cytometry) in bound and unbound THP-1 cells in the mixed cocultures were both dose-dependently blocked by the ERK1/2 inhibitor PD98059. However, although p38MAPK was activated during binding, the p38 inhibitor SB202190 had no effect (not shown). Induced surface CD36 expression on human PBMCs in the mixed cocultures and THP-1 cells in the transwell cocultures were also blocked by PD98059 (not shown). As shown in Figure 3C, increased CD36 mRNA levels in bound THP-1 cells in the fixed cocultures or in unbound THP-1 cells in the mixed cocultures were both blocked by preincubating THP-1 cells with PD98059. These results confirm that ERK1/2 MAPK can mediate coculture-induced monocyte CD36 expression.
Role of VCAM-1 and Monocyte Chemoattractant Protein-1 in THP-1 Cell CD36 Upregulation
Neutralizing antibodies were used to determine the roles of adhesion molecules and soluble factors involved in coculture-induced THP-1 cell CD36 expression. Upregulation of CD36 in bound THP-1 cells in the fixed cocultures was significantly blocked by preincubation of HVSMCs with an Ab to VCAM-1 (Figure 5A and 5B), but not to ICAM-1 (not shown). Furthermore, increases in both ERK1/2 phosphorylation and CD36 mRNA expression under these conditions were also inhibited by VCAM-1 Ab pretreatment of HVSMCs (Figure 5C and 5D).
Recent reports show that monocyte chemoattractant protein-1 (MCP-1) induces CD36 expression and foam cell differentiation in monocytes.23 Figure 6A shows a marked increase in MCP-1 mRNA levels in THP-1 cells (bound and unbound) as well as in HVSMCs on coculture. Furthermore, soluble factor–mediated upregulation of CD36 in unbound THP-1 cells in the mixed cocultures was significantly attenuated by a MCP-1 neutralizing Ab (Figure 6B and 6C). Thus CD36 expression in bound and unbound THP-1 cells may be mediated, at least in part, by MCP-1.
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Discussion |
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Compared with circulating blood, the intimal space is less conducive for monocyte survival. Furthermore, increased subendothelial levels of detrimental factors, such as reactive oxygen species and ox-LDL, are proapoptotic for monocytes/macrophages.24 However, pathological studies have found little if any monocyte apoptosis in early atherosclerosis,14 indicating that local subendothelial events may promote monocyte survival. Our results show for the first time that physical contact of monocytes with intimal VSMCs may represent a key mechanism to prevent migrated monocytes from apoptosis and thereby favor abnormal accumulation. This is of particular relevance for the development of early atherosclerotic lesions where abundant VSMCs are migrating from the media and proliferating in the intimal space.
We noted that serum starvation–induced monocyte apoptosis was markedly abrogated when they physically bind to VSMCs in cocultures. Furthermore, binding-mediated monocyte apoptosis protection was partially blocked by preincubating HVSMCs with a VCAM-1 Ab, suggesting that adhesive interactions between HVSMC VCAM-1 and monocyte ß1 integrins were involved. To our knowledge, this is the first report of integrin signaling–mediated regulation of monocyte apoptosis, although this phenomenon has been observed in epithelial cells.25 The signal transduction pathway(s) involved in ß1 integrin-mediated suppression of apoptosis are not fully resolved. PI3K/Akt, ERK1/2, and p38 MAPK have all been implicated and could therefore be cell-specific and contextual.25,26 In our study, although PI3K/Akt, ERK1/2, and p38 MAPK were all activated in THP-1 cells after binding to HVSMCs, only the PI3K/Akt pathway seemed to be responsible for HVSMC binding–mediated prevention of monocyte apoptosis. The PI3K/Akt pathway is of central importance in human monocyte survival.27–30 Once activated, PI3K generates inositol lipids and phosphorylates Akt, a critical regulator of PI3K-mediated cell survival.31,32 Akt stimulates the phosphorylation of the proapoptotic protein Bad,31,33 which subsequently releases and facilitates the functions of antiapoptotic mediators such as Bcl-XL or Bcl-2. Other downstream targets of Akt related to apoptosis include forkhead transcription factors of the FKHR family, IKK, and GSK-3ß.31,34,35 Phosphorylation of these kinases by Akt favors cell survival possibly by cell cycle regulation.31 In our study, we observed that binding to VSMCs increased the phosphorylation of Akt as well as Akt downstream apoptosis regulators Bad, FKHR, IKK, and GSK-3ß in monocytes. Akt phosphorylation was observed only in bound but not unbound THP-1 cells in the coculture. Meanwhile, Bcl-2 expression and Bcl-2 to Bax ratios were clearly enhanced. In addition, binding-induced suppression of monocyte apoptosis, Akt phosphorylation, and Bcl-2 expression were all blocked by a specific PI3K inhibitor. These new results demonstrate that the process of binding induces a cascade of antiapoptotic signals in monocytes. Interestingly, Akt phosphorylation was blocked by treating HVSMCs with a VCAM-1 Ab, further supporting the role of VCAM-1 and associated ß1 integrin signaling. The specific involvement of ß1 integrin counter-receptors of VCAM-1 in this process needs to be confirmed by additional studies.
It is interesting that Bcl-2, a major antiapoptotic protein, was upregulated on binding to HVSMCs. Although the nature of adhesion molecule interactions responsible for this is not clear, VCAM-1/ß1 interaction might be involved because Bcl-2 mRNA upregulation was attenuated by inhibition of PI3K/Akt, whereas Akt activation was blocked by a VCAM-1 Ab. Furthermore, Matter and Ruoslahti have found that ß1 integrin–mediated Bcl-2 transcription was inhibited by LY294002 in Chinese hamster ovary cells, indicating that PI3K is a component of the ß1–Bcl-2 pathway.36
Because monocyte survival was enhanced on coculture with HVSMCs, we next hypothesized that they may undergo differentiation to a more atherogenic phenotype expressing SRs such as CD36. A major novel finding in our current study is that monocyte ox-LDL uptake as well as CD36 expression at both mRNA and surface protein levels were upregulated on coculture with HVSMCs. CD36 induction was mediated by both direct physical contact and soluble factors as well as by ERK1/2 MAPK activation. We also found that contact-dependent CD36 upregulation was mediated at least in part by VCAM-1 and likely by ß1 integrin interactions. Interestingly, a very recent report showed that monocyte CD36 expression and differentiation were downregulated when they bind to endothelial cells.37 Therefore, binding-mediated monocyte CD36 regulation during cell–cell interactions seems to be cell-type specific, and the subendothelial space could be more favorable than blood vessel lumen for monocyte differentiation.
In our current study, we demonstrated that MCP-1 is a candidate soluble factor mediating CD36 expression. This is consistent with recent reports that exogenous MCP-1 dose-dependently upregulates CD36 expression and monocyte differentiation in an ERK-dependent manner.23 Our data suggest that MCP-1 in the cocultures could come from both HVSMCs and monocytes, because MCP-1 mRNA levels were elevated in both cell types. In support of our data, increased MCP-1 release has also been demonstrated during monocyte transendothelial migration in vitro.38 Upregulation of MCP-1 in THP-1 cells might be caused by both direct contact and soluble factors as demonstrated by our various culture conditions. On the other hand, although the mechanism for HVSMC MCP-1 upregulation is not clear in this study, soluble factors, such as tumor necrosis factor-, produced during coculture may be involved.38 Contact-dependent MCP-1 upregulation in HVSMCs may also be possible, because MCP-1 induction was observed in mesangial cells during interaction with extracellular matrix in ß1 integrin-dependent manner.39 Because MCP-1 is a potent monocyte chemoattractant, our results suggest that MCP-1 generated in the subendothelial space during monocyte/VSMC interactions may be a key factor mediating sustained monocyte infiltration in a vicious loop. However, MCP-1 may not be the only soluble factor involved, and additional studies are needed to identify the nature of other potential mediators.
In summary, we have used coculture systems mimicking the intercellular events in the subendothelial space to investigate the functional alterations of monocytes after exposure to VSMCs. We found for the first time that tethered binding of monocytes to VSMCs initiates an orchestrated program of monocyte survival and differentiation into an atherogenic phenotype. Our data suggest that monocytes trapped in the subendothelial space may bind to VSMCs and undergo survival and differentiation through key signaling pathways and soluble and insoluble factors from VSMCs and monocytes. Overall, we have demonstrated novel new local VSMC-dependent mechanisms for monocyte dysfunction in the pathogenesis of atherosclerosis.
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Acknowledgments |
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These studies were supported by grants from the National Institutes of Health (RO1 DK065073 and PO1 HL55798), Juvenile Diabetes Foundation International, and in part by a General Clinic Research Center (GCRC) grant from National Center for Research Resources (MO1RR00043 to City of Hope). We thank City of Hope flow cytometry facility, Dr N. Shanmugam, Dr S.-L. Li, and the GCRC staff for all their help.
Received June 24, 2004; accepted September 20, 2004.
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