Resveratrol prevents ISO-induced myocardial remodeling associated with regulating polarization of macrophages through VEGF-B/AMPK/NF-kB pathway.

Macrophage expansion and inflammatory responses are involved in induction of cardiac remodeling. Resveratrol has strong anti-inflammatory effects, however its effect on macrophage infiltration and polarization is unknown. This study aimed to investigate the anti-inflammatory effects of RSV on ISO-induced myocardial remodeling in mice and its regulatory role in macrophage polarization. BALB/c mice were orally administered with RSV (100 mg/kg) daily for one week, then were subcutaneously injected with ISO (50 mg/kg) daily for another week. ISO injections to mouse caused cardiac dysfunction evidenced by cardiac hypertrophy and cardiomyocyte fibrosis. Meanwhile, macrophage M1 polarization was found in ISO treated mice, which was evidenced by increased percentage of Ly6Clow macrophages in the heart, levels of M1 cytokines and expression of CD68, and decreased percentage of Ly6Chigh macrophage, levels of M2 cytokines and expression of CD206. All these changes in cardiac and macrophage M1 polarization were ameliorated when mice were pretreated with RSV. The effect of RSV on macrophage polarization was also tested in RAW264.7 cells. It was found that pre-treatment with RSV decreased the levels of M1 marker or proinflammatory cytokines, while increased the levels of M2 markers in ISO treated cells. In addition, it was found that RSV could upregulate the expression of VEGF-B and the activity of AMPK, while it downregulated the expression of phosphorylated NF-κB p65 both in RAW264.7 cells and in mice. Furthermore, pretreatment with VEGF-B siRNA greatly reversed changes in almost all above parameters evoked by RSV in RAW264.7 cells. Therefore, our findings suggest RSV has potential therapeutic effects in ISO-induced myocardial injury, which may be by inhibiting the M1 polarization of macrophages through VEGFB/AMPK/NF-кB pathway.

Redundant roles of VEGF-B and PlGF during selective VEGF-A blockade in mice.

Vascular endothelial growth factor-A (VEGF-A) and its 2 transmembrane tyrosine-kinase receptors, VEGFR-1 and VEGFR-2, constitute a ligand-receptor signaling system that is crucial for developmental angiogenesis. VEGF-B and placental growth factor (PlGF) activate VEGFR-1 selectively, however, mice lacking either ligand display only minor developmental defects. We hypothesized that the relative contributions of VEGF-B and PlGF to VEGFR-1 signaling may be masked in the presence of VEGF-A, which is abundantly expressed during postnatal development. To test this hypothesis, neonatal or adult mice were treated with a monoclonal antibody (G6-23-IgG) blocking murine VEGF-A or a soluble VEGFR-1 receptor IgG chimeric construct [mFlt(1-3)-IgG], which neutralizes VEGF-A, VEGF-B, and PlGF. Both compounds attenuated growth and survival of neonatal mice to similar extents and the pathophysiologic alterations, including a reduction in organ size and vascularization, changes in gene expression, and hematologic end points, were essentially indistinguishable. In adult mice, we observed only minor changes in response to treatment, which were similar between both anti-VEGF compounds. In conclusion, our findings suggest that PlGF and VEGF-B do not compensate during conditions of VEGF-A blockade, suggesting a minor role for compensatory VEGFR-1 signaling during postnatal development and vascular homeostasis in adults. The absence of compensatory VEGFR-1 signaling by VEGF-B and PlGF may have important implications for the development of anticancer strategies targeting the VEGF ligand/receptor system.