Emerging observations show that monocytes play important roles in the initiation, propagation, and progression of PAS [
16]. This study provides direct evidence that peripheral monocytes from PAS patients produced higher levels of inflammatory cytokines including IL-6 and VEGF-C, which were associated with severe PAS. Moreover, serum concentrations of fibrinogen were also significantly elevated in severe PAS patients. Numerous studies indicate soluble fibrinogen in the blood stream promotes clot formation [
17]; excess fibrinogen exaggerates inflammation and destroys the endothelium, which promotes atherosclerosis [
18]. Therefore, persistently elevated fibrinogen levels are a major risk factor for atherosclerosis, which predict heart attacks and strokes with exceptional accuracy. In addition, the inflammatory factors, such as IL-6, TNF-α, significantly contribute to the development, progression and destabilization of atherosclerotic plaques [
19]; production of fibrinogen might be enhanced by inflammatory process associated with atherosclerosis [
20]. However, few reports suggest the participation of fibrinogen and IL-6 in the development of PAS. Our study proposes that serum fibrinogen, IL-6 and VEGF-C concentrations might be used to diagnosis severe PAS. Compared with imaging techniques, such as Doppler Ultrasonography, Magnetic Resonance Angiography (MRA) or Computed Tomography Angiography (CTA), blood or serum biomarkers are easy to be detected by simple methods. Therefore, detecting serum fibrinogen, IL-6, VEGF-C enables less cost for high-throughput analysis of severe PAS in high-risk populations.
Apart from the role in inflammatory process, atherosclerosis plaques have been shown to contain fibrinogen degradation products [
21], which may act as chemoattractants for leukocytes. Furthermore, VEGF-C has also been reported to mediate cell migration [
10]. We observed elevated number of monocytes, but not lymphocytes, in peripheral blood stream, which was correlated to the severity of PAS. Notably, peripheral monocytes from PAS patients increased adhesion to fibrinogen-coated surface, whereas fibrinogen binds to integrin α5β1. The receptors for VEGF-C are VEGFR-3 and VEGFR-2, which express on monocytes, macrophages [
7,
11] as well as on lymphatic or vascular endothelial cells [
22,
23]. Previous studies have shown that exogenous VEGF-C treatment enhances transmigration ability of macrophages
in vitro [
11] and VEGF-C/VEGFR-3 signaling cooperates with PI3K to guide T lymphocyte migration
in vivo [
10]. It might be expected that increased VEGF-C production in severe PAS patients might trigger VEGFR-2/3 signaling in monocytes to enhance integrin-mediated adhesion to vascular wall for subsequent accumulation. We and others previously identified the intracellular signaling proteins ADAP (Adhesion- and Degranulation-promoting Adapter Protein, also known as FYB or SLAP-130), SKAP-HOM (SKAP55 homologue, also known as SKAP-2 or SKAP55R) for enhancing integrin-mediated immune cell adhesion [
24‐
32]. Since VEGF-C/VEGFR-3 signaling activates the PI3K/AKT pathway in macrophages [
7], and the ADAP/SKAP-HOM complex expresses in macrophages that is also linked to PI3K [
33], it is interesting to further investigate whether VEGF-C/VEGFR-3 signaling cooperates with the ADAP/SKAP-HOM complex to regulate integrin activation and monocytes/macrophage adhesion. Together, these data suggest that blood monocytes might stick and accumulate at narrowed local artery in response to high concentrations of serum fibrinogen and VEGF-C in PAS, then become one main source to produce inflammatory cytokines and exacerbate the severity of PAS.