Osteopontin, a Missing Link in PDGF-Induced Smooth Muscle Cell Migration

Cell migration might be considered one of the most basic requirements in vascular development and one of the most basic problems in vascular disease. Recruitment of vascular smooth muscle cells (SMC) is essential for the formation of vascular media in embryonic development (1), but it also fuels the growth of atherosclerotic plaques and neointimal hyperplasia after angioplasty (2, 3). Conversely, lack of recruitment of SMC precursor cells may contribute to arterio-venous malformations in hereditary hemorrhagic telangiectasia (4). Lack of pericytes, often considered to be the SMC correlate in the microvasculature, causes defective microvascular homeostasis (5).

The platelet-derived growth factor (PDGF), in particular PDGF-BB, is recognized as a key factor for SMC migration and proliferation (6). As such, it is essential for the formation of the vascular wall, and deletion of the PDGF-B gene results in embryonic lethality due to failure in the renal and cardiovascular systems (7). What might be considered a desirable role for PDGF in development may contribute in later life to vascular disease. PDGF has been recognized as one of the key factors in vascular remodeling and neointima formation during atherogenesis (6). Inhibition of PDGF or its receptors reduces myointimal hyperplasia in response to injury in vivo.

Even though the essential role of PDGF in SMC migration has been well documented, elucidation of the mechanism has proceeded more slowly. In an elegant study presented in this issue of Cardiovascular Research, Jalvy et al. (8) provide a missing mechanistic link in PDGF-induced SMC migration. They focused on the role of osteopontin (OPN), a secreted glycoprotein, in PDGF-induced SMC migration for several reasons. The integrin receptors αvβ3 and αvβ5, which have been implicated in PDGF-induced SMC migration, are also OPN receptors. Furthermore, the chemoattractive function of OPN is mediated by αvβ3, and autocrine OPN expression is essential in nucleotide-induced SMC migration. Finally, PDGF-BB and OPN together stimulate SMC production of matrix metalloproteinase-9 (MMP-9) (see (8) for references).

These investigators demonstrated that autocrine OPN expression is an essential step in PDGF-induced SMC migration (8). They provide evidence that PDGF activates two distinct signaling pathways, MAPK kinase (MAPKK) 1/2 and protein kinase A (PKA), previously shown to be important in SMC migration (9, 10) in order to activate CREB. In turn, CREB binds to two previously unidentified sites in the OPN promoter to stimulate the expression of OPN. It is the first time that CREB has been shown to be an activator of PDGF-induced OPN expression, and inhibition of CREB decreased SMC migration by 80%, mainly due to the decreased OPN expression. It is well documented that CREB is also activated by other SMC chemotactic factors such as tumor necrosis factor (TNF)-α, angiotensin II, thrombin and nucleotides (see (8) for references). Thus, CREB induction of OPN expression may be an important focal point for affecting SMC migration in both normal vascular development and disease involving inflammatory and atherogenic processes.

OPN is a multifunctional protein that appears to play several roles in the cardiovascular system. In addition to its effect on cell migration, it diminishes vascular calcification (11, 12). It is highly expressed at interfaces and surfaces of mineralized structures in calcified arteries, where it binds to calcium mineral and prevents crystal growth. It is also secreted by osteoclast-like cells and might act as a macrophage adhesion protein at the surface of mineral deposits, thereby facilitating mineral clearance (11, 12). Furthermore, one might speculate that expression of OPN in pericyte-like cells (13, 14), which are believed to contribute to vascular calcification, affects the migration that precedes the calcification in these cells. The pericyte-like cells are known to form cellular condensations or nodules where mineralization subsequently occurs. Thus, the ability of OPN to modulate mineralization may in part depend on inducing the “right” cells to move (or not) to the appropriate locations. It will be interesting to see whether the pathway identified by Jalvy et al. is active also in other cells.

Elucidation of this important PDGF-induced regulatory pathway connects PDGF directly with OPN. In addition, it provides new therapeutic targets for preventing unwanted cell migration such as the PDGF receptors, CREB, and the OPN receptors. Since blockade of either PDGF or osteopontin leads to attenuated atherogenesis in ApoE-deficient mice (6, 15), combining the targets may enhance the inhibitory effect. Therapies aimed at preventing vascular cell migration may not only be useful in cardiovascular disease but could also target vascularization of tumors and prevention of inflammatory injury.