ИСТИНА

VEGF and HGF have been used for therapeutic angiogenesis in clinic. We have previously shown that in rat MI model combination of these factors (GFs) has additive effect on angiogenesis, but not arteriogenesis. Moreover, HGF and VEGF differentially influenced monocyte accumulation in peri-infarct zone. In this study we investigated mechanisms of different effects of these GFs on monocyte infiltration. Methods: Endothelial cells (ECs) were treated with human recombinant VEGF, HGF or their combination. By RT-PCR and ELISA we estimated chemokine gene expression and production respectively. NFkB activation was assessed by blotting with a/b to pIKB and IkB. 6хHRE-promoter luciferase vector and siRNAs were used for estimation of HIF-1/2 activation. Results: VEGF increased expression/production of MCP-1 and IL-8 by ECs as well as expression of adhesion molecules ICAM-1 and VCAM-1. HGF in contrast to VEGF suppressed expression/production of MCP-1 and expression of ICAM-1 and VCAM-1, but increased them for IL-8. Treatment with VEGF165+HGF combination in case of MCP-1 led to suppression of VEGF-driven expression by HGF and in case of IL-8 led to an additive effect. GF-induced alterations in MCP-1 expression correlated with NFkB activity. As for mechanism of HGF-induced IL-8 expression it depended on HIF-2 stabilization. Conclusions: Our results demonstrated that HGF can suppress VEGF-induced expression of MCP-1 by inhibiting the NF-kB pathway in ECs thus possibly influences monocyte ischemic myocardium infiltration induced by VEGF and it’s effect on arteriogenesis. Both GFs stimulate expression of IL-8 and the main mechanism for HGF effect could be a stabilization of HIF-2 in ECs. Differential effects of these GFs on inflammatory molecules should be taken into consideration for development of combined approach for therapeutic angiogenesis.